Variant in PNPLA3 is associated with alcoholic liver disease

Size: px
Start display at page:

Download "Variant in PNPLA3 is associated with alcoholic liver disease"

Transcription

1 Variant in PNPLA3 is associated with alcoholic liver disease Chao Tian 1, Renee P. Stokowski 1, David Kershenobich 2, Dennis G. Ballinger 1,3, David A. Hinds 1 1 Perlegen Sciences, 2021 Stierlin Court, Mountain View, CA 94043, USA. 2 Departamento de Medicina Experimental, Facultad de Medicina de la Universidad Nacional Autónoma de México, Mexico D.F. 3 Current address: Complete Genomics, 2071 Stierlin Court, Mountain View, CA 94043, USA. Supplementary Methods Samples Subjects were recruited from clinics in Mexico City based on a history of alcohol dependence. Subjects with liver disease were recruited from new patients in the liver, gastroenterology, and internal medicine clinics at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ). Alcoholic controls were enrolled from INCMNSZ, as well as the Instituto Mexicano de Psiquiatria (IMP) and the Centro de Ayuda al Alcoholico y sus Familiares (CAAF). We excluded individuals with other than self-reported Mestizo ancestry. All subjects provided written informed consent for research studies of the genetic basis of alcoholic liver disease, and recruitment was approved by the Institutional Review Board at INCMNSZ. All participants satisfied DSM-IV criteria for alcohol dependence 1. Typical current alcohol consumption was determined by interview using the AUDIT questionnaire 2. We used a standard drink unit of 25 grams of alcohol, to cover the full range of consumption in this cohort of heavy drinkers. We estimated weekly intake from the first two AUDIT questions, using the 1

2 midpoints of the response ranges 3. In addition, we assessed total years of alcohol consumption by personal interview. We excluded individuals reporting fewer than 5 years or less than 200 gm/week of alcohol consumption. All study participants received biochemical and clinical assessments at INCMNSZ regardless of the site at which they were recruited, and diagnoses of liver disease were made in accordance with usual clinical practice at INCMNSZ. Subjects were screened for viral hepatitis (B and C), and individuals with positive test results were excluded. Patients with known systemic chronic disease (cardiac insufficiency, HIV or autoimmune disease, chronic renal insufficiency, or neoplastic disease) were also excluded from the study. Subjects were assessed for overt liver disease using a combination of clinical and biochemical criteria: Clinical criteria: jaundice, hepatomegaly, spider angiomas, palmar erythema, abnormal collateral circulation, ascites, hepatic encephalopathy, esophageal varices, portal hypertension Biochemical criteria (with normal ranges in brackets): abnormal aminotransferases [ALT: IU/L males, 9-52 IU/L females; AST: IU/L males, IU/L females], gamma-glutamyl transpeptidase [0-51 IU/L], alkaline phosphatase [ IU/L], decreased serum albumin [ g/dl], increased serum globulin [ g/dl], increased prothrombin time [ s], serum bilirubin [total: mg/dl, direct: mg/dl]. Subjects were classified as controls if they had no biochemical or clinical indications of overt liver disease. For patients with abnormal biochemistry indicative of liver disease, clinical findings were used to make an initial diagnosis of either alcoholic liver disease (ALD) or cirrhosis. Thus, a diagnosis of cirrhosis was established by findings of complications such as portal hypertension, esophageal varices with or without a previous episode of bleeding, 2

3 splenomegaly, ascites in the absence of other non-hepatic causes, hepatic encephalopathy in the absence of other metabolic causes, and hypoalbuminemia or hyperbilirubinemia in the absence of a known cause of bile duct obstruction. Patients were considered to have clinically evident alcoholic cirrhosis when other causes of liver cirrhosis were excluded, particularly viral hepatitis, hemochromatosis, autoimmunity, or biliary obstruction. Ultrasound (digital color Doppler ultrasound, Siemens) or CT screening (64 multicut tomography scanner, Siemens) was used to corroborate diagnoses of ALD and cirrhosis, and individuals with imaging results inconsistent with their initial diagnosis were excluded. Imaging was used to assess nodularity and irregularity of the liver surface, small liver size, echo coarseness, spleen length, monophasic suprahepatic vein flow, and reduced portal flow velocity. Subjects were also assessed for liver fat accumulation and acute alcoholic hepatitis. Individuals with imaging evidence of liver fat accumulation without other signs of chronic disease or significant inflammation were excluded. Evidence for acute hepatitis (hepatalgia, fever, increased white cell counts) was also an exclusion, as this could obscure an individual s chronic disease status. In summary, individuals diagnosed with cirrhosis had biochemical, clinical, and imaging results all supporting that diagnosis. Individuals with ALD had abnormal biochemistry and could have some clinical indications of chronic liver disease (i.e. jaundice, hepatomegaly), but had no biochemical, clinical, or imaging findings specifically indicative of cirrhosis. Control individuals had no clinical or biochemical features of chronic liver disease. Participants were originally recruited in the context of a pooled genome-wide association study of alcoholic cirrhosis, that was ultimately unsuccessful due to a combination of technical limitations and high experimental variance in the pooled allele frequency estimates. All patient identifying information was destroyed following completion of that project, and the anonymized 3

4 phenotype data that was retained did not include the underlying test results contributing to the categorical liver disease diagnoses. This substantially limits the range of possible analyses in our current study, and limits our ability to characterize the disease status of individual study participants. Genotyping We genotyped samples on microarrays across 312 autosomal SNPs uniformly distributed across the genome for assessment of global population structure. We eliminated microarray scans with call rate < 90% and SNPs with call rate < 95%. The microarray data was collected in several batches processed at different times. We clustered the combined data together and tested all SNPs for batch effects by ANOVA. We identified 2 SNPs with strong batch effects (P < and r 2 > 0.2), and an additional 7 SNPs with smaller effects (P < and r 2 > 0.01). We manually inspected cluster plots for these SNPs to confirm that these SNPs did show clustering artifacts, and that SNPs with P > appeared to be unaffected. We also removed SNPs with Hardy Weinberg P < 10 7, based again on manual inspection of cluster diagrams. Across 291 SNPs passing these filters, the mean call rate was 99.9%. Separately, the samples were genotyped across 61 SNPs on the MassArray platform by Sequenom. These included the two non-synonymous variants rs and rs reported in Romeo et al.; 17 common tagging SNPs from the region surrounding the PNPLA3 gene; 16 ancestry informative markers (AIMs) flanking PNPLA3 for assessing local admixture; 7 SNPs previously reported to be associated with cirrhosis in patients with chronic hepatitis C; and 18 quality control (QC) SNPs selected from the microarray panel for verification of sample identities. We also included rs738408, a synonymous SNP 3 base pairs away from and in perfect LD with rs in the HapMap CEU panel. Where possible, we designed redundant assays in opposite orientations, and selected the assay with highest call rate for each SNP. We excluded 4

5 samples with call rate < 80%, SNPs with call rate < 90%, and SNPs with Hardy Weinberg P < We used more generous call rate thresholds for the Sequenom data because missing data rates were more broadly distributed than in the microarray data, and these SNPs were considered to be of higher value. There were 4 SNPs (2 tag SNPs, 2 QC SNPs) for which no assays passed the quality filters. The remaining 57 SNPs had an average call rate of 98.7%. We identified 36 pairs of samples that had nearly identical microarray genotype patterns. These cryptic duplicates tended to have correlated ages (r 2 = 0.3, P = ) and diagnoses (Fisher s exact test: P = ), suggesting that in at least some cases the same individual had been recruited twice. Multiple recruitment is less problematic than laboratory handling error because it is always detectable and does not compromise the correspondence between samples and phenotypes. An additional 21 samples had low concordance across the 16 SNPs successfully genotyped on both platforms. These two groups of samples were excluded from analyses. Across the remaining samples, the 16 shared SNPs had an average concordance of 99.9% across platforms. Statistical Analysis The significance of the differences in mean sample characteristics such as gender, age, alcoholic intake and duration among diagnostic groups were tested using ANOVA. Tests for Hardy- Weinberg equilibrium were performed for each SNP in each diagnosis group using a likelihood ratio test (LRT). All of the tested SNPs were in Hardy-Weinberg equilibrium (P > 0.001) in each group. Association Tests Allelic odds ratios (OR) were estimated from 2 2 contingency tables, and approximate 95% confidence intervals (CI) for odds ratios were estimated using Woolf s method 4. The allelic association test is the 1 degree of freedom Pearson Chi-square test of the allele frequency 5

6 differences between case and control subjects. A stepwise logistic regression using Akaike information criterion (AIC) was also used to select covariates associated with disease risk. Age, alcohol intake and duration, and an interaction between age and duration were identified as significant based on AIC. ORs for cirrhosis risk under an additive genetic model were estimated using logistic regression with adjustment for these covariates. The model for our primary single SNP association tests can be written as: Logit(π) = β 0 + β 1 *age+ β 2 *duration + β 3 *intake+ β 4 *(age x duration) + β 5 *genotype where π is the likelihood of membership in the case group. The LRT compared models with and without the genotype covariate. Detailed results are shown in Supplementary Table 2. Estimating Genetic Ancestry The genetic diversity due to admixture within the Mestizo population is a known confounder for our association tests. To control for spurious association due to differences in ancestry between diagnosis groups, we inferred individual global and local ancestry using Principal Components Analysis (PCA). Global ancestry was determined for each individual using 291 SNPs distributed across the genome. Local ancestry was determined for each individual using 16 AIMs for Amerindian and European genetic ancestry flanking the PNPLA3 locus (Supplementary Table 1). We incorporated data from additional individuals with self-reported Otomi Indian and European ancestry to facilitate interpretation of the PCA results. Individuals with more Native American ancestry have larger loadings along the first principal component (Supplementary Fig. 2). We also applied PCA to just the Mestizo individuals, and found that PC1 had a correlation of with corresponding results from PCA with the additional samples. PC1 explained substantially more genetic variance than the higher order components (Supplementary Fig. 3). ANOVA tests of the loadings across diagnosis groups show that only PC1 is substantially associated with outcomes, for both local and global PCA results. Both local and global ancestry estimation were 6

7 also confirmed by the Bayesian Markov Chain-Monte Carlo (MCMC) method implemented in the program STRUCTURE 5. STRUCTURE 2.1 was run under the admixture model with k=3 for global ancestry estimation, and the linkage model with k=2 for local ancestry estimation. We ran the MCMC method with burn-in length of 20,000 for 20,000 repetitions. The admixture proportions estimated for the most representative ancestry group had a correlation of with PC1 of the corresponding PCA. It is broadly known that the Mestizo population has an admixture of Native American, European and African ancestry. We used STRUCTURE to obtain ancestry proportions for our combined Otomi, European, and Mestizo data, together with data from the HapMap YRI panel for the same 291 SNPs (Supplementary Fig. 4). The results shows that our Mestizo samples have about 36.5% (sd 0.214) European, 61.6% (0.22) Native American and 1.9% (0.033) African ancestry on average, consistent with a previous report 6. The mean individual African ancestry estimated using STRUCTURE software is not significantly different among the diagnosis groups and is small (< 2%). Thus, we expect to see little confounding in our association studies due to African admixture. Association tests controlling for the STRUCTURE results gave nearly identical results as controlling for the first PC from global PCA. The first PC has a correlation of 0.99 with the estimated Native American or European proportion from STRUCTURE. Structured Association Tests We adjusted for differences in individual global ancestry in association tests by including the first PC from global PCA as a covariate in the logistic regression. These tests indicate the strength of association attributable to a SNP that is independent of information that SNP might indirectly provide about overall ancestry across the genome. To verify that associations could not be explained by confounding with local admixture, we also tested SNPs in the PNPLA3 region 7

8 with adjustment for local ancestry by additionally including the first PC from local PCA as a covariate. Our models for structured association tests can be written as: Logit(π) = β 0 +β 1 *age+β 2 *duration+β 3 *intake+β 4 *(age*duration)+β 5 *GPC1+β 6 *genotype Logit(π) = β 0 +β 1 *age+β 2 *duration+β 3 *intake+β 4 *(age*duration)+β 5 *GPC1+β 6 *LPC1+β 7 *genotype where GPC1 is the first PC from global PCA and LPC1 is the first PC from local PCA. The LRT compared models with and without the genotype covariate. Detailed results for each SNP are shown in Supplementary Table 2. To study the genetic risk models for rs738409, we used the AIC to compare four possible genetic models: a 2-degree-of-freedom general model, and 1-degree-of-freedom additive, dominant, and recessive models. The three possible genotypes [AA,AB,BB] of tested SNPs were coded as a three-level factor for the general model, [0,1,2] for the additive model, [0,0,1] for the dominant model, and [0,1,1] for the recessive model. The most parsimonious model was defined as the one with the smallest AIC. We also assessed the ability of rs to explain ancestry differences in cirrhosis susceptibility. Since the rs sequence variation is substantially correlated with global ancestry (r = 0.34), we calculated ancestry-adjusted genotypes in which redundancies between rs and ancestry were removed, and fit four logistic regression models: (1) Logit(π) = β 0 +β 1 *age+β 2 *duration+β 3 *intake+β 4 *(age*duration)+β 5 *GPC1+β 6 *rs738409, (2) Logit(π) = β 0 +β 1 *age+β 2 *duration+β 3 *intake+β 4 *(age*duration)+β 5 *rs (3) Logit(π) = β 0 +β 1 *age+β 2 *duration+β 3 *intake+β 4 *(age*duration)+β 5 *GPC1+β 6 *rs738409_adj, (4) Logit(π) = β 0 +β 1 *age+β 2 *duration+β 3 *intake+β 4 *(age*duration)+β 5 *rs738409_adj Here, rs738409_adj represents residuals from linear regression of rs genotypes against global PC1. The proportion of residual deviance explained by global PC1 estimated from models (3) and (4) is 6.43%, while the proportion explained by global PC1 estimated from models (1) 8

9 and (2) is 3.28%. Thus, rs accounted for 49% of the observed ancestry-related difference in cirrhosis susceptibility. Confounding and Interaction Our study design does not match for potential confounders, and as a result, there are large differences in age and alcohol consumption across diagnostic categories. Our regression models adjust for the significant main effects and interactions of these phenotypes, which is a standard analytical approach to addressing potential confounders in unmatched designs 7. A traditional matched design in this case would have necessitated leaving out a substantial proportion of the subjects to achieve balance across these covariates. To determine the extent of confounding, we tested each phenotypic covariate for association with rs genotype, and also evaluated whether the apparent effect of rs was sensitive to inclusion of these covariates in the model. Tests of association of the covariates with rs by linear regression with adjustment for diagnostic group and global PC1 were all negative (age: P = 0.70; duration: P = 0.33; intake: P = 0.93). Odds ratios for cirrhosis versus control status were essentially unchanged when these covariates were left out of the model one at a time (leave out none: OR = 1.79; age: OR = 1.68; duration: OR = 1.78; intake: OR = 1.77). Thus, these covariates are independently associated with liver disease and are not distorting the observed effect of rs We tested for interactions between the covariates and rs genotype, using likelihood ratio tests to evaluate addition of individual interaction terms to the logistic regression model for cirrhosis versus control status. No interaction term significantly improved the model fit (age: P = 0.97; duration: P = 0.30; intake: P = 0.92; global PC1: P = 0.90). These results indicate that the observed effect of rs is stable and is not substantially modulated by the 9

10 values of these covariates. We estimate that we had 80% power to detect an interaction that accounted for roughly 20% of the deviance attributable to rs genotype. As an alternative method of accounting for potential confounding, we estimated the effect of rs in a matched analysis using the coarsened exact matching (CEM) method 8. We used CEM to construct strata that were matched for age, alcohol intake, and duration across genotypes; 95 samples fell in strata that carried a single genotype and were excluded. We then estimated the effect of genotype on cirrhosis versus control status in the matched data, adjusting for global PC1. The point estimate of the genotype effect (OR = 1.76, 95% CI: 1.33 to 2.35) was very close to the estimate from the unmatched analysis. We also used CEM to construct a matched dataset in which the covariates were balanced across cases and controls. Here, 28 control and 126 cirrhosis subjects were excluded, and the genotype effect estimate was OR = 1.74 (95% CI: 1.34 to 2.28). Haplotype Analyses We used MACH 9 version 1.1 to phase genotype data for 18 SNPs in the PNPLA3 region. We performed association tests for each 18-SNP haplotype with observed MAF > 0.01, versus all other haplotypes, both using Pearson χ 2 tests on 2 2 tables, and logistic regression as in the single SNP analyses (Supplementary Table 4). 10

11 Supplementary Note Two studies 10,11 have reported associations between variation in PNPLA3 and obesity, which is a known contributor to alcoholic as well as non-alcoholic liver disease. This raises the possibility that associations with liver disease could be mediated by systemic metabolic effects. However, these studies indicated that the allele of rs associated with liver disease is protective for obesity. Other studies have not corroborated these associations. The largest study to consider this issue examined BMI, fasting glucose, insulin, HOMA-IR, and plasma lipids and observed no significant associations with rs in any ancestry group 12. Their primary association result for rs with hepatic fat content became slightly stronger after correction for covariates including BMI and diabetes status, which suggests that while these may be independent risk factors for hepatic fat content, they do not mediate the effects of rs on liver function 12. A Finnish study confirmed the association of rs with hepatic fat content, and found that this association was independent of BMI and insulin resistance 13. Another recent study found that the association of rs with liver enzyme levels is stable across cohorts with large differences in metabolic syndrome components 14. These results suggest that the effects of variation in PNPLA3 on liver function are not mediated by systemic metabolic phenotypes. Our measures of current alcohol intake and duration are likely to only capture a fraction of the relevant variation in alcohol consumption. The AUDIT test was developed and validated as a screen for harmful drinking, and not to quantify alcohol intake. Liver toxicity may also depend on beverage type and patterns of consumption, in addition to total quantity consumed. Unexplained variance in consumption should not by itself bias the analysis of rs genotype effects. As with other sources of unexplained variance, it would bias our analysis only if it is confounded with genotype, after adjustment for ancestry. We cannot rule out the possibility that 11

12 a more detailed accounting of alcohol intake might explain substantially more variance in diagnoses, and might reveal interactions between intake and genotype. However, we feel that our data constrains the likely magnitudes of such interactions. The key phenotypes in our study (diagnosis, Child-Pugh class) are categorical and the unavailability of underlying quantitative biochemical measurements is a fundamental limitation of the work. The clinical and biochemical presentation of alcoholic liver disease is variable, and more detailed phenotypic characterization may reveal disease features that are more directly associated with PNPLA3 genotype than the categorical phenotypes available to us. Clinical examination and imaging have high specificity for advanced cirrhosis, but limited sensitivity, particularly for early-stage disease 15,16. As a result, we cannot rule out compensated cirrhosis in some fraction of our ALD group. Cirrhosis is fundamentally a pathologically defined entity 17, and biopsy is the gold standard for diagnosis. However, liver biopsy is an invasive procedure with significant morbidity and mortality as well as substantial false positive and negative rates, and its routine use in diagnosis of alcoholic cirrhosis is controversial 18. Clinical and biochemical characterization in conjunction with imaging is routinely used for presumptive diagnosis of alcoholic liver disease and alcoholic cirrhosis 19,20. As a result, we feel that the phenotypes and findings in our study are clinically relevant, though quantitative measures of effect sizes should be interpreted with caution. 12

13 Supplementary References 1. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (American Psychological Association, 1994). 2. Babor, T.F., Higgins-Biddle, J.C., Saunders, J.B., & Monteiro, M.G. AUDIT: the alcohol use disorders identification test. Guidelines for use in primary care. (WHO, Geneva, 2001). 3. Lima, C.T. et al. Alcohol Alcohol. 40: (2005). 4. Woolf, B. Ann. Hum. Genet. 19, (1955). 5. Falush, D., Stephens, M., & Pritchard, J.K. Genetics 164, (2003). 6. Wang, S. et al. PLOS Genet. 4(3), e doi: /journal.pgen (2008). 7. Woodward, M. Epidemiology: Study Design and Data Analysis. 2nd Ed. (Boca Raton, USA, 2004). 8. Iacus, S., King, G., & Porro, G. Matching for Causal Inference Without Balance Checking Li, Y. & Abecasis, G.R. Am. J. Hum. Genet. S79, 2290 (2006). 10. Johansson, J.E. et al. Diabetes 55, Johansson, L.E., Lindblad, U., Larsson, C.A., Råstam, L., & Ridderstråle, M. Eur. J. Endocrinol. 159, (2008). Also erratum, Endocrinol. 159, 584 (2008). 12. Romeo, S. et al. Nat. Genet. 40, (2008). 13. Kotronen, A. et al. Diabetologia 52: (2009). 14. Kollerits, B. et al. J. Med. Genet. doi: /jmg (18 June 2009). 15. de Bruyn, G. & Graviss, E.A. BMC Med. Inform. Decis. Mak. 1, 6 (2001). 16. Dodd, G.D. Imaging in cirrhosis. In Freeny, P.C. (ed.) Radiology of the liver, biliary tree and pancreas (American Roentgen Ray Society, Reston, VA, USA, 1996),

14 17. Bacon, B.R. Cirrhosis and its Complications. In Fauci, A.S. et al. Harrison s Principles of Internal Medicine, 17 th Ed. (McGraw-Hill, New York, NY, USA, 2008), Poynard, T., Ratziu, V., & Bedossa, P. Can. J. Gastroenterol. 14, (2000). 19. McCullough, A.J. & O Conner, J.F. Am. J. Gastroenterol. 93, (1998). 20. Heidelbaugh, J.J. & Bruderly, M. Am. Fam. Physician 74, (2006). 21. Barrett, J.C., Fry, B., Maller, J., & Daly, M.J. Bioinformatics 21, (2005). 14

15 Supplementary Table 1. Markers used for local ancestry assessment. rsid Chromosome Position rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs

16 Supplementary Table 2a. Cirrhosis versus Control Association Tests. Alleles Alt Frequency Allelic Test rsid Chromosome Position Category LD Ref Alt Control Case P OR (95% CI) rs Huang C G E ( ) rs Huang G A E ( ) rs Huang G A E ( ) rs Huang C T E ( ) rs Huang T C E ( ) rs Huang G C E ( ) rs Huang G A E ( ) rs LDtag G A E ( ) rs LDtag C T E ( ) rs LDtag C T E ( ) rs LDtag A G E ( ) rs LDtag A G E ( ) rs LDtag T G E ( ) rs LDtag G T E ( ) rs LDtag T C E ( ) rs LDtag A G E ( ) rs Romeo C G E ( ) rs Romeo C T E ( ) rs LDtag T C E ( ) rs LDtag G A E ( ) rs LDtag G C E ( ) rs LDtag T G E ( ) rs LDtag A G E ( ) rs Romeo G T E ( ) rs LDtag C T E ( ) Logistic Regression Likelihood Ratio Tests No Ancestry Correction Global Correction Global & Local Correction Condition on rs rsid P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) rs E ( ) 7.0E ( ) rs E ( ) 6.3E ( ) rs E ( ) 3.3E ( ) rs E ( ) 9.0E ( ) rs E ( ) 3.5E ( ) rs E ( ) 3.5E ( ) rs E ( ) 7.1E ( ) rs E ( ) 5.9E ( ) 1.7E ( ) 7.0E ( ) rs E ( ) 8.8E ( ) 9.4E ( ) 5.6E ( ) rs E ( ) 9.0E ( ) 9.0E ( ) 9.6E ( ) rs E ( ) 8.3E ( ) 7.6E ( ) 6.1E ( ) rs E ( ) 9.3E ( ) 8.8E ( ) 9.6E ( ) rs E ( ) 6.9E ( ) 8.6E ( ) 5.9E ( ) rs E ( ) 4.6E ( ) 3.6E ( ) 2.3E ( ) rs E ( ) 1.1E ( ) 3.2E ( ) 5.3E ( ) rs E ( ) 8.6E ( ) 4.1E ( ) 9.3E ( ) rs E ( ) 1.9E ( ) 4.7E ( ) rs E ( ) 2.8E ( ) 5.5E ( ) 9.9E ( ) rs E ( ) 4.2E ( ) 1.2E ( ) 2.0E ( ) rs E ( ) 1.8E ( ) 4.9E ( ) 1.0E ( ) rs E ( ) 4.0E ( ) 2.8E ( ) 1.4E ( ) rs E ( ) 2.0E ( ) 6.9E ( ) 3.5E ( ) rs E ( ) 2.9E ( ) 1.1E ( ) 7.9E ( ) rs E ( ) 6.8E ( ) 9.4E ( ) 9.1E ( ) rs E ( ) 1.3E ( ) 6.9E ( ) 4.0E ( ) Chromosomal positions and alleles are given for the forward strand of NCBI Build 36. LD indicates r 2 with rs Odds ratios are specified per alternate allele. Category: Huang, loci associated with cirrhosis in Hepatitis C patients by Huang et al., 2007; 16

17 LDtag, tagging SNPs from the PNPLA3 region; Romeo, SNPs directly implicated by Romeo et al.,

18 Supplementary Table 2b. Cirrhosis versus ALD Association Tests. Alleles Alt Frequency Allelic Test rsid Chromosome Position Category LD Ref Alt Control Case P OR (95% CI) rs Huang C G E ( ) rs Huang G A E ( ) rs Huang G A E ( ) rs Huang C T E ( ) rs Huang T C E ( ) rs Huang G C E ( ) rs Huang G A E ( ) rs LDtag G A E ( ) rs LDtag C T E ( ) rs LDtag C T E ( ) rs LDtag A G E ( ) rs LDtag A G E ( ) rs LDtag T G E ( ) rs LDtag G T E ( ) rs LDtag T C E ( ) rs LDtag A G E ( ) rs Romeo C G E ( ) rs Romeo C T E ( ) rs LDtag T C E ( ) rs LDtag G A E ( ) rs LDtag G C E ( ) rs LDtag T G E ( ) rs LDtag A G E ( ) rs Romeo G T E ( ) rs LDtag C T E ( ) Logistic Regression Likelihood Ratio Tests No Ancestry Correction Global Correction Global & Local Correction Condition on rs rsid P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) rs E ( ) 6.9E ( ) rs E ( ) 1.5E ( ) rs E ( ) 9.3E ( ) rs E ( ) 6.8E ( ) rs E ( ) 2.0E ( ) rs E ( ) 1.2E ( ) rs E ( ) 9.6E ( ) rs E ( ) 9.5E ( ) 9.1E ( ) 8.2E ( ) rs E ( ) 3.8E ( ) 3.0E ( ) 6.1E ( ) rs E ( ) 4.1E ( ) 4.5E ( ) 4.2E ( ) rs E ( ) 5.2E ( ) 4.6E ( ) 5.8E ( ) rs E ( ) 9.4E ( ) 7.7E ( ) 9.0E ( ) rs E ( ) 2.4E ( ) 1.3E ( ) 5.0E ( ) rs E ( ) 5.6E ( ) 6.3E ( ) 3.0E ( ) rs E ( ) 2.1E ( ) 8.1E ( ) 5.2E ( ) rs E ( ) 2.2E ( ) 8.5E ( ) 6.8E ( ) rs E ( ) 1.4E ( ) 2.8E ( ) rs E ( ) 2.1E ( ) 4.8E ( ) 3.1E ( ) rs E ( ) 1.3E ( ) 5.0E ( ) 3.4E ( ) rs E ( ) 5.9E ( ) 1.0E ( ) 6.0E ( ) rs E ( ) 6.3E ( ) 4.4E ( ) 4.3E ( ) rs E ( ) 1.1E ( ) 2.6E ( ) 3.6E ( ) rs E ( ) 5.7E ( ) 4.1E ( ) 3.2E ( ) rs E ( ) 1.4E ( ) 1.1E ( ) 2.3E ( ) rs E ( ) 4.3E ( ) 2.9E ( ) 4.5E ( ) 18

19 Supplementary Table 2c. ALD versus Control Association Tests. Alleles Alt Frequency Allelic Test rsid Chromosome Position Category LD Ref Alt Control Case P OR (95% CI) rs Huang C G E ( ) rs Huang G A E ( ) rs Huang G A E ( ) rs Huang C T E ( ) rs Huang T C E ( ) rs Huang G C E ( ) rs Huang G A E ( ) rs LDtag G A E ( ) rs LDtag C T E ( ) rs LDtag C T E ( ) rs LDtag A G E ( ) rs LDtag A G E ( ) rs LDtag T G E ( ) rs LDtag G T E ( ) rs LDtag T C E ( ) rs LDtag A G E ( ) rs Romeo C G E ( ) rs Romeo C T E ( ) rs LDtag T C E ( ) rs LDtag G A E ( ) rs LDtag G C E ( ) rs LDtag T G E ( ) rs LDtag A G E ( ) rs Romeo G T E ( ) rs LDtag C T E ( ) Logistic Regression Likelihood Ratio Tests No Ancestry Correction Global Correction Global & Local Correction Condition on rs rsid P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) rs E ( ) 3.9E ( ) rs E ( ) 2.9E ( ) rs E ( ) 5.1E ( ) rs E ( ) 4.7E ( ) rs E ( ) 1.3E ( ) rs E ( ) 9.7E ( ) rs E ( ) 4.1E ( ) rs E ( ) 4.0E ( ) 6.8E ( ) 1.0E ( ) rs E ( ) 9.9E ( ) 9.3E ( ) 8.9E ( ) rs E ( ) 3.5E ( ) 5.8E ( ) 3.4E ( ) rs E ( ) 5.1E ( ) 5.5E ( ) 4.7E ( ) rs E ( ) 9.9E ( ) 7.7E ( ) 8.8E ( ) rs E ( ) 4.7E ( ) 4.6E ( ) 2.7E ( ) rs E ( ) 2.1E ( ) 2.1E ( ) 3.3E ( ) rs E ( ) 1.5E ( ) 3.4E ( ) 9.8E ( ) rs E ( ) 7.4E ( ) 3.2E ( ) 4.3E ( ) rs E ( ) 5.1E ( ) 1.9E ( ) rs E ( ) 7.7E ( ) 2.7E ( ) 7.1E ( ) rs E ( ) 1.3E ( ) 3.1E ( ) 7.0E ( ) rs E ( ) 5.0E ( ) 2.0E ( ) 6.1E ( ) rs E ( ) 5.7E ( ) 6.3E ( ) 5.4E ( ) rs E ( ) 9.2E ( ) 3.3E ( ) 9.8E ( ) rs E ( ) 4.3E ( ) 1.4E ( ) 1.8E ( ) rs E ( ) 9.2E ( ) 7.9E ( ) 6.3E ( ) rs E ( ) 5.9E ( ) 6.1E ( ) 5.5E ( ) 19

20 Supplementary Table 3. Akaike information criterion (AIC) for rs738409[g] model selection. Model Cirrhosis vs. Control Cirrhosis vs. ALD General 2-df Additive Dominant Recessive Supplementary Table 4. Haplotype association tests, for cirrhosis vs control status. Pearson Logistic Regression Frequency 2 test Corrected for Global PC1 Haplotype case control P OR 95% CI P GCCAATGCAGTCACGGGC (1.01,1.80) GTCGAGGCAGTCACGGGC (1.09,2.27) GCTGATGCAGTCACGGGC (1.19,2.63) GCCAATGTGCCTGCTAGC (0.36,0.83) GTCGATGCAGTCACGGGC (0.50,1.67) GCCAAGGCAGTCACGGGC (0.61,2.17) GCCAATGTACCTGGTGGT (0.61,2.38) GCCGATGCAGTCACGGGC (0.54,2.30) GCTGGTGTGCCTGCTAGC (0.41,3.03) GCCGATTTACCTGGTGGT (0.24,1.22) GCTGATGTGCCTGCTAGC (0.19,1.08)

21 Supplementary Figure 1. Flow chart of inclusion and exclusion criteria for the study. 21

22 a b Supplementary Figure 2. Distribution of (a) global and (b) local genetic ancestry along PC1 and PC2 estimated from PCA, colored by self-reported ancestry. In both analyses, PC1 measures Native American versus European ancestry; PC2 and higher components were not strongly correlated with self-reported ancestry. 22

23 a b Supplementary Figure 3. Variance components from (a) global and (b) local PCA. The first principal components account for substantially more variance than the higher order components. 23

24 100% 90% 80% 70% 60% 50% 40% 30% African Native American European 20% 10% 0% Mestizo i European Otom Supplementary Figure 4. Global admixture proportions estimated from STRUCTURE. The individuals are sorted according to their global PC1 loadings, where larger loadings indicate higher Native American admixture proportions. 24

25 Supplementary Figure 5. Linkage disequilibrium of genotyped SNPs in the PNPLA3 region, generated by Haploview 21. Scores represent r 2 observed in our sample set. 25

Variation in PNPLA3 is associated with outcomes. in alcoholic liver disease

Variation in PNPLA3 is associated with outcomes. in alcoholic liver disease Variation in PNPLA3 is associated with outcomes in alcoholic liver disease Chao Tian 1, Renee P. Stokowski 1, David Kershenobich 2, Dennis G. Ballinger 1,3, David A. Hinds 1 1. Perlegen, 2021 Stierlin

More information

Supplementary Table 1. The distribution of IFNL rs and rs and Hardy-Weinberg equilibrium Genotype Observed Expected X 2 P-value* CHC

Supplementary Table 1. The distribution of IFNL rs and rs and Hardy-Weinberg equilibrium Genotype Observed Expected X 2 P-value* CHC Supplementary Table 1. The distribution of IFNL rs12979860 and rs8099917 and Hardy-Weinberg equilibrium Genotype Observed Expected X 2 P-value* CHC rs12979860 (n=3129) CC 1127 1145.8 CT 1533 1495.3 TT

More information

Supplementary Figure 1. Principal components analysis of European ancestry in the African American, Native Hawaiian and Latino populations.

Supplementary Figure 1. Principal components analysis of European ancestry in the African American, Native Hawaiian and Latino populations. Supplementary Figure. Principal components analysis of European ancestry in the African American, Native Hawaiian and Latino populations. a Eigenvector 2.5..5.5. African Americans European Americans e

More information

Supplementary Figures

Supplementary Figures Supplementary Figures Supplementary Fig 1. Comparison of sub-samples on the first two principal components of genetic variation. TheBritishsampleisplottedwithredpoints.The sub-samples of the diverse sample

More information

Cirrhosis and Portal Hypertension Gastroenterology Teaching Project American Gastroenterological Association

Cirrhosis and Portal Hypertension Gastroenterology Teaching Project American Gastroenterological Association CIRRHOSIS AND PORTAL HYPERTENSION Cirrhosis and Portal Hypertension Gastroenterology Teaching Project American Gastroenterological Association WHAT IS CIRRHOSIS? What is Cirrhosis? DEFINITION OF CIRRHOSIS

More information

CHAPTER 1. Alcoholic Liver Disease

CHAPTER 1. Alcoholic Liver Disease CHAPTER 1 Alcoholic Liver Disease Major Lesions of Alcoholic Liver Disease Alcoholic fatty liver - >90% of binge and chronic drinkers Alcoholic hepatitis precursor of cirrhosis Alcoholic cirrhosis end

More information

New Enhancements: GWAS Workflows with SVS

New Enhancements: GWAS Workflows with SVS New Enhancements: GWAS Workflows with SVS August 9 th, 2017 Gabe Rudy VP Product & Engineering 20 most promising Biotech Technology Providers Top 10 Analytics Solution Providers Hype Cycle for Life sciences

More information

Approach to the Patient with Liver Disease

Approach to the Patient with Liver Disease Approach to the Patient with Liver Disease Diagnosis of liver disease Careful history taking Physical examination Laboratory tests Radiologic examination and imaging studies Liver biopsy Liver diseases

More information

Ct=28.4 WAT 92.6% Hepatic CE (mg/g) P=3.6x10-08 Plasma Cholesterol (mg/dl)

Ct=28.4 WAT 92.6% Hepatic CE (mg/g) P=3.6x10-08 Plasma Cholesterol (mg/dl) a Control AAV mtm6sf-shrna8 Ct=4.3 Ct=8.4 Ct=8.8 Ct=8.9 Ct=.8 Ct=.5 Relative TM6SF mrna Level P=.5 X -5 b.5 Liver WAT Small intestine Relative TM6SF mrna Level..5 9.6% Control AAV mtm6sf-shrna mtm6sf-shrna6

More information

CS2220 Introduction to Computational Biology

CS2220 Introduction to Computational Biology CS2220 Introduction to Computational Biology WEEK 8: GENOME-WIDE ASSOCIATION STUDIES (GWAS) 1 Dr. Mengling FENG Institute for Infocomm Research Massachusetts Institute of Technology mfeng@mit.edu PLANS

More information

During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin,

During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin, ESM Methods Hyperinsulinemic-euglycemic clamp procedure During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin, Clayton, NC) was followed by a constant rate (60 mu m

More information

CIRROSI E IPERTENSIONE PORTALE NELLA DONNA

CIRROSI E IPERTENSIONE PORTALE NELLA DONNA Cagliari, 16 settembre 2017 CIRROSI E IPERTENSIONE PORTALE NELLA DONNA Vincenza Calvaruso, MD, PhD Ricercatore di Gastroenterologia Gastroenterologia & Epatologia, Di.Bi.M.I.S. Università degli Studi di

More information

Supplementary Methods

Supplementary Methods Supplementary Methods Populations ascertainment and characterization Our genotyping strategy included 3 stages of SNP selection, with individuals from 3 populations (Europeans, Indian Asians and Mexicans).

More information

Human population sub-structure and genetic association studies

Human population sub-structure and genetic association studies Human population sub-structure and genetic association studies Stephanie A. Santorico, Ph.D. Department of Mathematical & Statistical Sciences Stephanie.Santorico@ucdenver.edu Global Similarity Map from

More information

DISCLOSURES. This activity is jointly provided by Northwest Portland Area Indian Health Board and Cardea

DISCLOSURES. This activity is jointly provided by Northwest Portland Area Indian Health Board and Cardea DISCLOSURES This activity is jointly provided by Northwest Portland Area Indian Health Board and Cardea Cardea Services is approved as a provider of continuing nursing education by Montana Nurses Association,

More information

Statistical Tests for X Chromosome Association Study. with Simulations. Jian Wang July 10, 2012

Statistical Tests for X Chromosome Association Study. with Simulations. Jian Wang July 10, 2012 Statistical Tests for X Chromosome Association Study with Simulations Jian Wang July 10, 2012 Statistical Tests Zheng G, et al. 2007. Testing association for markers on the X chromosome. Genetic Epidemiology

More information

Assessing Accuracy of Genotype Imputation in American Indians

Assessing Accuracy of Genotype Imputation in American Indians Assessing Accuracy of Genotype Imputation in American Indians Alka Malhotra*, Sayuko Kobes, Clifton Bogardus, William C. Knowler, Leslie J. Baier, Robert L. Hanson Phoenix Epidemiology and Clinical Research

More information

WEEK. MPharm Programme. Liver Biochemistry. Slide 1 of 49 MPHM14 Liver Biochemistry

WEEK. MPharm Programme. Liver Biochemistry. Slide 1 of 49 MPHM14 Liver Biochemistry MPharm Programme Liver Biochemistry Slide 1 of 49 MPHM Liver Biochemistry Learning Outcomes Assess and evaluate the signs and symptoms of illness Assess and critically appraise a patients medication regimen,

More information

Big Data Training for Translational Omics Research. Session 1, Day 3, Liu. Case Study #2. PLOS Genetics DOI: /journal.pgen.

Big Data Training for Translational Omics Research. Session 1, Day 3, Liu. Case Study #2. PLOS Genetics DOI: /journal.pgen. Session 1, Day 3, Liu Case Study #2 PLOS Genetics DOI:10.1371/journal.pgen.1005910 Enantiomer Mirror image Methadone Methadone Kreek, 1973, 1976 Methadone Maintenance Therapy Long-term use of Methadone

More information

Hepatocytes produce. Proteins Clotting factors Hormones. Bile Flow

Hepatocytes produce. Proteins Clotting factors Hormones. Bile Flow R.J.Bailey MD Hepatocytes produce Proteins Clotting factors Hormones Bile Flow Trouble.. for the liver! Trouble for the Liver Liver Gall Bladder Common Alcohol Hep C Fatty Liver Cancer Drugs Viruses Uncommon

More information

Tutorial on Genome-Wide Association Studies

Tutorial on Genome-Wide Association Studies Tutorial on Genome-Wide Association Studies Assistant Professor Institute for Computational Biology Department of Epidemiology and Biostatistics Case Western Reserve University Acknowledgements Dana Crawford

More information

Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels.

Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Supplementary Online Material Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. John C Chambers, Weihua Zhang, Yun Li, Joban Sehmi, Mark N Wass, Delilah Zabaneh,

More information

The association between TCM syndromes and SCAP polymorphisms in subjects with non-alcoholic fatty liver disease

The association between TCM syndromes and SCAP polymorphisms in subjects with non-alcoholic fatty liver disease The association between TCM syndromes and SCAP polymorphisms in subjects with non-alcoholic fatty liver disease Shanshan Sun, Tao Wu, Miao Wang, Wei Li, Lin Wang, Songhua He, Huafeng Wei, Haiyan Song,

More information

World Health Organization. Western Pacific Region

World Health Organization. Western Pacific Region Basic modules for hepatitis 1 Basic Module 1 Liver anatomy and physiology 2 Position of liver Midline Located in right upper abdomen Protected by the right rib cage Right upper Measures: 12 15 cm in vertical

More information

2) Cases and controls were genotyped on different platforms. The comparability of the platforms should be discussed.

2) Cases and controls were genotyped on different platforms. The comparability of the platforms should be discussed. Reviewers' Comments: Reviewer #1 (Remarks to the Author) The manuscript titled 'Association of variations in HLA-class II and other loci with susceptibility to lung adenocarcinoma with EGFR mutation' evaluated

More information

A total of 2,822 Mexican dyslipidemic cases and controls were recruited at INCMNSZ in

A total of 2,822 Mexican dyslipidemic cases and controls were recruited at INCMNSZ in Supplemental Material The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL-receptor degradation in humans by Daphna Weissglas-Volkov et al. Supplementary Methods Mexican

More information

Cirrhosis of the Liver

Cirrhosis of the Liver 235 60th Street, West New York, NJ 07093 T: (201) 854-4646 F: (201) 854-4647 810 Main Street, Hackensack, NJ 07601 T: (201) 488-0095 Cirrhosis of the Liver The liver, the largest organ in the body, is

More information

LTA Analysis of HapMap Genotype Data

LTA Analysis of HapMap Genotype Data LTA Analysis of HapMap Genotype Data Introduction. This supplement to Global variation in copy number in the human genome, by Redon et al., describes the details of the LTA analysis used to screen HapMap

More information

Nature Genetics: doi: /ng Supplementary Figure 1

Nature Genetics: doi: /ng Supplementary Figure 1 Supplementary Figure 1 Illustrative example of ptdt using height The expected value of a child s polygenic risk score (PRS) for a trait is the average of maternal and paternal PRS values. For example,

More information

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22. Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.32 PCOS locus after conditioning for the lead SNP rs10993397;

More information

ABNORMAL LIVER FUNCTION TESTS. Dr Uthayanan Chelvaratnam Hepatology Consultant North Bristol NHS Trust

ABNORMAL LIVER FUNCTION TESTS. Dr Uthayanan Chelvaratnam Hepatology Consultant North Bristol NHS Trust ABNORMAL LIVER FUNCTION TESTS Dr Uthayanan Chelvaratnam Hepatology Consultant North Bristol NHS Trust INTRODUCTION Liver function tests Cases Non invasive fibrosis measurement Questions UK MORTALITY RATE

More information

Laboratory Tests and Diagnostic Procedures in Liver Disease: Adventures in Liverland

Laboratory Tests and Diagnostic Procedures in Liver Disease: Adventures in Liverland Laboratory Tests and Diagnostic Procedures in Liver Disease: Adventures in Liverland Sanjiv Chopra, MD, MACP Professor of Medicine Harvard Medical School Editor In Chief Hepatology Section Up To Date Serum

More information

Prognosis of untreated Primary Sclerosing Cholangitis (PSC) Erik Christensen Copenhagen, Denmark

Prognosis of untreated Primary Sclerosing Cholangitis (PSC) Erik Christensen Copenhagen, Denmark Prognosis of untreated Primary Sclerosing Cholangitis (PSC) Erik Christensen Copenhagen, Denmark Study of Prognosis of PSC Difficulties: Disease is rare The duration of the course of disease may be very

More information

SUPPLEMENTARY DATA. 1. Characteristics of individual studies

SUPPLEMENTARY DATA. 1. Characteristics of individual studies 1. Characteristics of individual studies 1.1. RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) The RISC study is based on unrelated individuals of European descent, aged 30 60

More information

Large-scale identity-by-descent mapping discovers rare haplotypes of large effect. Suyash Shringarpure 23andMe, Inc. ASHG 2017

Large-scale identity-by-descent mapping discovers rare haplotypes of large effect. Suyash Shringarpure 23andMe, Inc. ASHG 2017 Large-scale identity-by-descent mapping discovers rare haplotypes of large effect Suyash Shringarpure 23andMe, Inc. ASHG 2017 1 Why care about rare variants of large effect? Months from randomization 2

More information

Hepatitis C: Management of Previous Non-responders with First Line Protease Inhibitors

Hepatitis C: Management of Previous Non-responders with First Line Protease Inhibitors Hepatitis C: Management of Previous Non-responders with First Line Protease Inhibitors Fred Poordad, MD The Texas Liver Institute Clinical Professor of Medicine University of Texas Health Science Center

More information

Supplementary Figure 1 Dosage correlation between imputed and genotyped alleles Imputed dosages (0 to 2) of 2-digit alleles (red) and 4-digit alleles

Supplementary Figure 1 Dosage correlation between imputed and genotyped alleles Imputed dosages (0 to 2) of 2-digit alleles (red) and 4-digit alleles Supplementary Figure 1 Dosage correlation between imputed and genotyped alleles Imputed dosages (0 to 2) of 2-digit alleles (red) and 4-digit alleles (green) of (A) HLA-A, HLA-B, (C) HLA-C, (D) HLA-DQA1,

More information

IL10 rs polymorphism is associated with liver cirrhosis and chronic hepatitis B

IL10 rs polymorphism is associated with liver cirrhosis and chronic hepatitis B IL10 rs1800896 polymorphism is associated with liver cirrhosis and chronic hepatitis B L.N. Cao 1, S.L. Cheng 2 and W. Liu 3 1 Kidney Disease Department of Internal Medicine, Xianyang Central Hospital,

More information

FTO Polymorphisms Are Associated with Obesity But Not with Diabetes in East Asian Populations: A Meta analysis

FTO Polymorphisms Are Associated with Obesity But Not with Diabetes in East Asian Populations: A Meta analysis BIOMEDICAL AND ENVIRONMENTAL SCIENCES 22, 449 457 (2009) www.besjournal.com FTO Polymorphisms Are Associated with Obesity But Not with Diabetes in East Asian Populations: A Meta analysis BO XI #, + AND

More information

Ammonia level at admission predicts in-hospital mortality for patients with alcoholic hepatitis

Ammonia level at admission predicts in-hospital mortality for patients with alcoholic hepatitis Gastroenterology Report, 5(3), 2017, 232 236 doi: 10.1093/gastro/gow010 Advance Access Publication Date: 1 May 2016 Original article ORIGINAL ARTICLE Ammonia level at admission predicts in-hospital mortality

More information

For more information about how to cite these materials visit

For more information about how to cite these materials visit Author(s): Kerby Shedden, Ph.D., 2010 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/

More information

Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians

Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians Diabetologia (2007) 50:985 989 DOI 10.1007/s00125-007-0611-6 SHORT COMMUNICATION Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians

More information

LIVER, PANCREAS, AND BILIARY TRACT

LIVER, PANCREAS, AND BILIARY TRACT CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:1028 1033 LIVER, PANCREAS, AND BILIARY TRACT Prevalence and Indicators of Portal Hypertension in Patients With Nonalcoholic Fatty Liver Disease FLAVIA D.

More information

The genetic architecture of type 2 diabetes appears

The genetic architecture of type 2 diabetes appears ORIGINAL ARTICLE A 100K Genome-Wide Association Scan for Diabetes and Related Traits in the Framingham Heart Study Replication and Integration With Other Genome-Wide Datasets Jose C. Florez, 1,2,3 Alisa

More information

University of Groningen. Metabolic risk in people with psychotic disorders Bruins, Jojanneke

University of Groningen. Metabolic risk in people with psychotic disorders Bruins, Jojanneke University of Groningen Metabolic risk in people with psychotic disorders Bruins, Jojanneke IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

More information

Diseases of liver. Dr. Mohamed. A. Mahdi 4/2/2019. Mob:

Diseases of liver. Dr. Mohamed. A. Mahdi 4/2/2019. Mob: Diseases of liver Dr. Mohamed. A. Mahdi Mob: 0123002800 4/2/2019 Cirrhosis Cirrhosis is a complication of many liver disease. Permanent scarring of the liver. A late-stage liver disease. The inflammation

More information

Complex Trait Genetics in Animal Models. Will Valdar Oxford University

Complex Trait Genetics in Animal Models. Will Valdar Oxford University Complex Trait Genetics in Animal Models Will Valdar Oxford University Mapping Genes for Quantitative Traits in Outbred Mice Will Valdar Oxford University What s so great about mice? Share ~99% of genes

More information

Alpha-1 Antitrypsin Deficiency: Liver Disease

Alpha-1 Antitrypsin Deficiency: Liver Disease Alpha-1 Antitrypsin Deficiency: Liver Disease Who is at risk to develop Alpha-1 liver disease? Alpha-1 liver disease may affect children and adults who have abnormal Alpha-1 antitrypsin genes. Keys to

More information

Title:Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population

Title:Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population Author's response to reviews Title:Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population Authors: Jin-Kyu Park (cardiohy@gmail.com)

More information

BST227 Introduction to Statistical Genetics. Lecture 4: Introduction to linkage and association analysis

BST227 Introduction to Statistical Genetics. Lecture 4: Introduction to linkage and association analysis BST227 Introduction to Statistical Genetics Lecture 4: Introduction to linkage and association analysis 1 Housekeeping Homework #1 due today Homework #2 posted (due Monday) Lab at 5:30PM today (FXB G13)

More information

Evidence Analysis Library Research Project

Evidence Analysis Library Research Project Evidence Analysis Library Research Project EAL question: What is the evidence to support the use of supplementing BCAA in patients with cirrhosis to 1) prevent further liver damage or improve liver function;

More information

Su Yon Jung 1*, Eric M. Sobel 2, Jeanette C. Papp 2 and Zuo-Feng Zhang 3

Su Yon Jung 1*, Eric M. Sobel 2, Jeanette C. Papp 2 and Zuo-Feng Zhang 3 Jung et al. BMC Cancer (2017) 17:290 DOI 10.1186/s12885-017-3284-7 RESEARCH ARTICLE Open Access Effect of genetic variants and traits related to glucose metabolism and their interaction with obesity on

More information

Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene. McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S.

Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene. McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S. Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S. December 17, 2014 1 Introduction Asthma is a chronic respiratory disease affecting

More information

Advanced IPD meta-analysis methods for observational studies

Advanced IPD meta-analysis methods for observational studies Advanced IPD meta-analysis methods for observational studies Simon Thompson University of Cambridge, UK Part 4 IBC Victoria, July 2016 1 Outline of talk Usual measures of association (e.g. hazard ratios)

More information

2. Liver blood tests and what they mean p2 Acute and chronic liver screen

2. Liver blood tests and what they mean p2 Acute and chronic liver screen 1 Scope For use within hepatology Contents 2. Liver blood tests and what they mean p2 Acute and chronic liver screen p2 Common reasons for referral 3. Raised ALT +/- GGT p3 4. Non alcoholic fatty liver

More information

Jaundice. Agnieszka Dobrowolska- Zachwieja, MD, PhD

Jaundice. Agnieszka Dobrowolska- Zachwieja, MD, PhD Jaundice Agnieszka Dobrowolska- Zachwieja, MD, PhD Jaundice definition Jaundice, as in the French jaune, refers to the yellow discoloration of the skin. It arises from the abnormal accumulation of bilirubin

More information

UNIVERSITY OF CALIFORNIA, LOS ANGELES

UNIVERSITY OF CALIFORNIA, LOS ANGELES UNIVERSITY OF CALIFORNIA, LOS ANGELES BERKELEY DAVIS IRVINE LOS ANGELES MERCED RIVERSIDE SAN DIEGO SAN FRANCISCO UCLA SANTA BARBARA SANTA CRUZ DEPARTMENT OF EPIDEMIOLOGY SCHOOL OF PUBLIC HEALTH CAMPUS

More information

DISEASE LEVEL MEDICAL EVIDENCE PROTOCOL

DISEASE LEVEL MEDICAL EVIDENCE PROTOCOL DISEASE LEVEL MEDICAL EVIDENCE PROTOCOL 1. This Protocol sets out the medical evidence that must be delivered to the Administrator for proof of Disease Level. It is subject to such further and other Protocols

More information

Our Stage 1 genotype scan was performed using Illumina Human1 Beadarrays, which have a

Our Stage 1 genotype scan was performed using Illumina Human1 Beadarrays, which have a Supplementary Note Analysis of Stage 1 GWAS and design of the Stage 2 iselect array Our Stage 1 genotype scan was performed using Illumina Human1 Beadarrays, which have a gene-centric design, and Illumina

More information

Liver Disease. By: Michael Martins

Liver Disease. By: Michael Martins Liver Disease By: Michael Martins Recently I have been getting a flurry of patients that have some serious liver complications. This week s literature review will be the dental management of the patients

More information

Statistical power and significance testing in large-scale genetic studies

Statistical power and significance testing in large-scale genetic studies STUDY DESIGNS Statistical power and significance testing in large-scale genetic studies Pak C. Sham 1 and Shaun M. Purcell 2,3 Abstract Significance testing was developed as an objective method for summarizing

More information

Int. J. Pharm. Sci. Rev. Res., 46(1), September - October 2017; Article No. 07, Pages: 37-41

Int. J. Pharm. Sci. Rev. Res., 46(1), September - October 2017; Article No. 07, Pages: 37-41 Research Article Assessment of Clinical Profile and Prescription Pattern of Drugs in Alcoholic Liver Disease and Hepatitis in a Tertiary Care Hospital Christeena James*, Dr.ShirishInamdar, Dr.Bharathi

More information

Module 1 Introduction of hepatitis

Module 1 Introduction of hepatitis Module 1 Introduction of hepatitis 1 Training Objectives At the end of the module, trainees will be able to ; Demonstrate improved knowledge of the global epidemiology of the viral hepatitis Understand

More information

ASSOCIATION OF KCNJ1 VARIATION WITH CHANGE IN FASTING GLUCOSE AND NEW ONSET DIABETES DURING HCTZ TREATMENT

ASSOCIATION OF KCNJ1 VARIATION WITH CHANGE IN FASTING GLUCOSE AND NEW ONSET DIABETES DURING HCTZ TREATMENT ONLINE SUPPLEMENT ASSOCIATION OF KCNJ1 VARIATION WITH CHANGE IN FASTING GLUCOSE AND NEW ONSET DIABETES DURING HCTZ TREATMENT Jason H Karnes, PharmD 1, Caitrin W McDonough, PhD 1, Yan Gong, PhD 1, Teresa

More information

What Is Cirrhosis? CIRRHOSIS. Cirrhosis occurs when the liver is. by chronic conditions and diseases. permanently scarred or injured

What Is Cirrhosis? CIRRHOSIS. Cirrhosis occurs when the liver is. by chronic conditions and diseases. permanently scarred or injured What Is Cirrhosis? Cirrhosis occurs when the liver is permanently scarred or injured by chronic conditions and diseases. Common causes of cirrhosis include: Long-term alcohol abuse. Chronic viral hepatitis

More information

A Review of Liver Function Tests. James Gray Gastroenterology Vancouver

A Review of Liver Function Tests. James Gray Gastroenterology Vancouver A Review of Liver Function Tests James Gray Gastroenterology Vancouver Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted

More information

Quality Control Analysis of Add Health GWAS Data

Quality Control Analysis of Add Health GWAS Data 2018 Add Health Documentation Report prepared by Heather M. Highland Quality Control Analysis of Add Health GWAS Data Christy L. Avery Qing Duan Yun Li Kathleen Mullan Harris CAROLINA POPULATION CENTER

More information

Supplementary Online Content

Supplementary Online Content Supplementary Online Content Hartwig FP, Borges MC, Lessa Horta B, Bowden J, Davey Smith G. Inflammatory biomarkers and risk of schizophrenia: a 2-sample mendelian randomization study. JAMA Psychiatry.

More information

Introduction to Genetics and Genomics

Introduction to Genetics and Genomics 2016 Introduction to enetics and enomics 3. ssociation Studies ggibson.gt@gmail.com http://www.cig.gatech.edu Outline eneral overview of association studies Sample results hree steps to WS: primary scan,

More information

Supplementary note: Comparison of deletion variants identified in this study and four earlier studies

Supplementary note: Comparison of deletion variants identified in this study and four earlier studies Supplementary note: Comparison of deletion variants identified in this study and four earlier studies Here we compare the results of this study to potentially overlapping results from four earlier studies

More information

8/10/2012. Education level and diabetes risk: The EPIC-InterAct study AIM. Background. Case-cohort design. Int J Epidemiol 2012 (in press)

8/10/2012. Education level and diabetes risk: The EPIC-InterAct study AIM. Background. Case-cohort design. Int J Epidemiol 2012 (in press) Education level and diabetes risk: The EPIC-InterAct study 50 authors from European countries Int J Epidemiol 2012 (in press) Background Type 2 diabetes mellitus (T2DM) is one of the most common chronic

More information

LIVER CIRRHOSIS. The liver extracts nutrients from the blood and processes them for later use.

LIVER CIRRHOSIS. The liver extracts nutrients from the blood and processes them for later use. LIVER CIRRHOSIS William Sanchez, M.D. & Jayant A. Talwalkar, M.D., M.P.H. Advanced Liver Disease Study Group Miles and Shirley Fiterman Center for Digestive Diseases Mayo College of Medicine Rochester,

More information

Alcohol-Related Liver Disease

Alcohol-Related Liver Disease Alcohol-Related Liver Disease Nonalcoholic Fatty Liver Disease (NAFLD) 1 Why is the liver important? Your liver is a vital organ that performs many essential functions. It filters out harmful substances

More information

What to do with abnormal LFTs? Andrew M Smith Hepatobiliary Surgeon

What to do with abnormal LFTs? Andrew M Smith Hepatobiliary Surgeon What to do with abnormal LFTs? Andrew M Smith Hepatobiliary Surgeon "it looks like there's something wrong.with your television set. Matt Groenig, creator of The Simpsons Probability of an abnormal screening

More information

Noncalculous Biliary Disease Dean Abramson, M.D. Gastroenterologists, P.C. Cedar Rapids. Cholestasis

Noncalculous Biliary Disease Dean Abramson, M.D. Gastroenterologists, P.C. Cedar Rapids. Cholestasis Noncalculous Biliary Disease Dean Abramson, M.D. Gastroenterologists, P.C. Cedar Rapids Cholestasis Biochemical hallmark Impaired bile flow from liver to small intestine Alkaline phosphatase is primary

More information

Introduction to the Genetics of Complex Disease

Introduction to the Genetics of Complex Disease Introduction to the Genetics of Complex Disease Jeremiah M. Scharf, MD, PhD Departments of Neurology, Psychiatry and Center for Human Genetic Research Massachusetts General Hospital Breakthroughs in Genome

More information

Supplementary Figures

Supplementary Figures Supplementary Figures Supplementary Figure 1. Heatmap of GO terms for differentially expressed genes. The terms were hierarchically clustered using the GO term enrichment beta. Darker red, higher positive

More information

Supplementary Online Content

Supplementary Online Content 1 Supplementary Online Content Friedman DJ, Piccini JP, Wang T, et al. Association between left atrial appendage occlusion and readmission for thromboembolism among patients with atrial fibrillation undergoing

More information

Psychology Research Institute, University of Ulster, Northland Road, Londonderry, BT48 7JL, UK

Psychology Research Institute, University of Ulster, Northland Road, Londonderry, BT48 7JL, UK Patterns of Alcohol Consumption and Related Behaviour in Great Britain: A Latent Class Analysis of the Alcohol Use Disorder Identification Test (AUDIT) Gillian W. Smith * and Mark Shevlin Psychology Research

More information

Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis

Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis Supplementary Material Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis Kwangwoo Kim 1,, So-Young Bang 1,, Katsunori Ikari 2,3, Dae

More information

Gastrointes*nal and Liver Pathology. Kris*ne Kra5s, M.D.

Gastrointes*nal and Liver Pathology. Kris*ne Kra5s, M.D. Gastrointes*nal and Liver Pathology Kris*ne Kra5s, M.D. GI Pathology Outline Esophagus Stomach Intes*ne Liver Gallbladder Pancreas GI Pathology Outline Esophagus Stomach Intes*ne Liver Hepa**s Alcoholic

More information

EVALUATION OF ABNORMAL LIVER TESTS

EVALUATION OF ABNORMAL LIVER TESTS EVALUATION OF ABNORMAL LIVER TESTS MIA MANABAT DO PGY6 MOA 119 TH ANNUAL SPRING SCIENTIFIC CONVENTION MAY 19, 2018 EVALUATION OF ABNORMAL LIVER TESTS Review of liver enzymes vs liver function tests Clinical

More information

Association between the -77T>C polymorphism in the DNA repair gene XRCC1 and lung cancer risk

Association between the -77T>C polymorphism in the DNA repair gene XRCC1 and lung cancer risk Association between the -77T>C polymorphism in the DNA repair gene XRCC1 and lung cancer risk B.B. Sun, J.Z. Wu, Y.G. Li and L.J. Ma Department of Respiratory Medicine, People s Hospital Affiliated to

More information

Whole-genome detection of disease-associated deletions or excess homozygosity in a case control study of rheumatoid arthritis

Whole-genome detection of disease-associated deletions or excess homozygosity in a case control study of rheumatoid arthritis HMG Advance Access published December 21, 2012 Human Molecular Genetics, 2012 1 13 doi:10.1093/hmg/dds512 Whole-genome detection of disease-associated deletions or excess homozygosity in a case control

More information

Patterns of abnormal LFTs and their differential diagnosis

Patterns of abnormal LFTs and their differential diagnosis Patterns of abnormal LFTs and their differential diagnosis Professor Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Plymouth Outline liver function tests / tests of

More information

Genetic variants on 17q21 are associated with asthma in a Han Chinese population

Genetic variants on 17q21 are associated with asthma in a Han Chinese population Genetic variants on 17q21 are associated with asthma in a Han Chinese population F.-X. Li 1 *, J.-Y. Tan 2 *, X.-X. Yang 1, Y.-S. Wu 1, D. Wu 3 and M. Li 1 1 School of Biotechnology, Southern Medical University,

More information

Monitoring Hepatitis C

Monitoring Hepatitis C Monitoring Hepatitis C Section Six Monitoring Hepatitis C Screening for hepatitis C is not routinely done, so you may have to request a test from your medical provider. This usually involves an antibody

More information

Pirna Sequence Variants Associated With Prostate Cancer In African Americans And Caucasians

Pirna Sequence Variants Associated With Prostate Cancer In African Americans And Caucasians Yale University EliScholar A Digital Platform for Scholarly Publishing at Yale Public Health Theses School of Public Health January 2015 Pirna Sequence Variants Associated With Prostate Cancer In African

More information

Clinical Trials & Endpoints in NASH Cirrhosis

Clinical Trials & Endpoints in NASH Cirrhosis Clinical Trials & Endpoints in NASH Cirrhosis April 25, 2018 Peter G. Traber, MD CEO & CMO, Galectin Therapeutics 2018 Galectin Therapeutics NASDAQ: GALT For more information, see galectintherapeutics.com

More information

Mendelian Randomization

Mendelian Randomization Mendelian Randomization Drawback with observational studies Risk factor X Y Outcome Risk factor X? Y Outcome C (Unobserved) Confounders The power of genetics Intermediate phenotype (risk factor) Genetic

More information

Association mapping (qualitative) Association scan, quantitative. Office hours Wednesday 3-4pm 304A Stanley Hall. Association scan, qualitative

Association mapping (qualitative) Association scan, quantitative. Office hours Wednesday 3-4pm 304A Stanley Hall. Association scan, qualitative Association mapping (qualitative) Office hours Wednesday 3-4pm 304A Stanley Hall Fig. 11.26 Association scan, qualitative Association scan, quantitative osteoarthritis controls χ 2 test C s G s 141 47

More information

Gene-Environment Interactions

Gene-Environment Interactions Gene-Environment Interactions What is gene-environment interaction? A different effect of an environmental exposure on disease risk in persons with different genotypes," or, alternatively, "a different

More information

Value and challenges of combining large cohorts

Value and challenges of combining large cohorts Value and challenges of combining large cohorts Rory Collins UK Biobank Principal Investigator BHF Professor of Medicine & Epidemiology Nuffield Department of Population Health Richard Doll Building University

More information

MANAGEMENT OF LIVER CIRRHOSIS: PRACTICE ESSENTIALS AND PATIENT SELF-MANAGEMENT

MANAGEMENT OF LIVER CIRRHOSIS: PRACTICE ESSENTIALS AND PATIENT SELF-MANAGEMENT MANAGEMENT OF LIVER CIRRHOSIS: PRACTICE ESSENTIALS AND PATIENT SELF-MANAGEMENT Sherona Bau, ACNP The Pfleger Liver Institute 200 UCLA Medical Plaza, Suite 214 Los Angeles, CA 90095 September 30, 2017 I

More information

A Rational Evidence-based Approach to Abnormal Liver Tests

A Rational Evidence-based Approach to Abnormal Liver Tests A Rational Evidence-based Approach to Abnormal Liver Tests Jane D. Ricaforte-Campos, MD FPCP, FPSG, FPSDE 2013 HSP Post-graduate Course Radisson Blu Hotel, Cebu City misnomer Liver Function Tests Does

More information

Non-Invasive Assessment of Liver Fibrosis. Patricia Slev, PhD University of Utah Department of Pathology

Non-Invasive Assessment of Liver Fibrosis. Patricia Slev, PhD University of Utah Department of Pathology Non-Invasive Assessment of Liver Fibrosis Patricia Slev, PhD University of Utah Department of Pathology Disclosure Patricia Slev has no relevant financial relationships to disclose. 2 Chronic Liver Disease

More information

Ecological Statistics

Ecological Statistics A Primer of Ecological Statistics Second Edition Nicholas J. Gotelli University of Vermont Aaron M. Ellison Harvard Forest Sinauer Associates, Inc. Publishers Sunderland, Massachusetts U.S.A. Brief Contents

More information

GENOME-WIDE ASSOCIATION STUDIES

GENOME-WIDE ASSOCIATION STUDIES GENOME-WIDE ASSOCIATION STUDIES SUCCESSES AND PITFALLS IBT 2012 Human Genetics & Molecular Medicine Zané Lombard IDENTIFYING DISEASE GENES??? Nature, 15 Feb 2001 Science, 16 Feb 2001 IDENTIFYING DISEASE

More information

SHORT COMMUNICATION. K. Lukacs & N. Hosszufalusi & E. Dinya & M. Bakacs & L. Madacsy & P. Panczel

SHORT COMMUNICATION. K. Lukacs & N. Hosszufalusi & E. Dinya & M. Bakacs & L. Madacsy & P. Panczel Diabetologia (2012) 55:689 693 DOI 10.1007/s00125-011-2378-z SHORT COMMUNICATION The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the

More information

SUPPLEMENTARY FIGURES

SUPPLEMENTARY FIGURES SUPPLEMENTARY FIGURES Supplementary Figure 1 Regional association plots for genome-wide significant PCOS signals. Dots represents individual SNP association P-values (on the log10 scale) in the 23andMe

More information