Gene- Environment Interac0ons, Metabolomics, and Racial Dispari0es in CardioMetabolic Diseases
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1 Gene- Environment Interac0ons, Metabolomics, and Racial Dispari0es in CardioMetabolic Diseases Frank Hu, MD, PhD Professor of Nutri5on and Epidemiology Harvard School of Public Health Professor of Medicine Harvard Medical School
2 Racial Disparity in Diseases Gene- Environment Interac5ons Metabolomics Personalized Preven5on 2
3 The Change of US Popula5on Percent, % Non- Hispanic white Black Hispanic Asian Year Modified from US Census Bureau
4 Percentage Surviving by Race and Sex, U.S. 2008
5 Prevalence of Diseases across Races 0.5 Prevalence Mexican Americans Whites Blacks 0 Total CVD HBP CHD MI Stroke HF Data source: Heart Disease and Stroke Sta5s5cs 2011 AHA Update
6 Why racial disparity on complex disease?
7 ene5c vs. Non Gene5c on Complex Disease Type 2 Diabetes Coronary artery disease Hypertension Body Mass Index
8 T2D and related complica5ons Murea et al. Rev Diabet Stud, 2012
9 Gene5c effects
10 Published Genome- wide Associa5ons (~June 2013) hap://
11 19 loci were tested 5 ethnic groups were compared Waters et al. PLoS Genet. 2010
12 Direction in association (null=50%) Heterogeneity in ORs All ethnic groups >63%; 100% in Japanese 5 of the 19 risk variants showed nominal evidence for heterogeneity; Only one remained significant after correction of multiple comparison; CDKAL1 Combined genetic effect, per allele of genetic risk score European Americans, 1.11, African Americans: 1.09, Native Hawaiians, 1.10, Latinos, 1.12, Japanese, 1.20, Waters et al. PLoS Genet. 2010
13 Difference among African origin popula5ons Age- adjusted prevalence of disease Hypertension rural Cameroon Urban Cameroon Jamaica Caribbean migrants to Britain Type 2 Diabetes Cruickshank et al. 2001
14 Environmental factors on racial disparity Life style Socioeconomic status Educa5on, income, Residen5al segrega5on Health prac5ces Racial discrimina5on
15 Prevalence of regular leisure- 5me physical ac5vity among adults by race/ethnicity and sex (NHIS: 2009) Percent of Population Men NH White NH Black Hispanic Source: CDC/NCHS, Health Data Interac5ve. All percentages are age- adjusted. NH indicates non- Hispanic. * Includes both Hispanics and non- Hispanics. Women Roger VL et al. Circulation. 2010
16 Prevalence of current smoking for adults by race/ethnicity and sex (NHIS: ) Percent of Popula0on Men Women NH White NH Black Hispanic Asian* American Indian/Alaska Na5ve* Source: CDC/NCHS, Health Data Interac5ve. All percentages are age- adjusted. NH indicates non- Hispanic. * Includes both Hispanics and non- Hispanics. Roger VL et al. Circulation. 2010
17 Educa5on Effects on Hypertension by Races Anderson et al. 2004
18 Racial difference in drug response " (the same environmental effect) JAMA. 2005;294(8): "
19 Causes of Human Disease Who took my piece of pizza?
20 Disparity in Diabetes Gene- Environment Interac5ons Metabolomics Personalized medicine 20
21 Missing Heritability of Complex Disease Manolio et al Sabah et al. 2009
22 Sources of missing heritability 1. Other gene5c determinants, such as common copy number varia5ons, and rare variants; 2. Interplay of different factors, such as epistasis, and gene- environment interac0on
23 An illustra5on of gene- diet interac5on Manolio et al. Nat Rev Gen.2006
24 A Classic GXE Example Phenylketonuria
25
26 Sugar- Sweetened Beverages & Gene0c Effect Difference in BMI per 10 risk alleles, kg/m Sugar- sweetened Beverage consump0on <1 serving/mo 1-4 servings/mo 2-6 servings/wk 1 servings/day P for interac5on =0.008 P for interac5on =0.02 P for interac5on =0.001 P for interac5on < NHS HPFS WGHS Pooled (n=6,934) (n=4,423) (n=21,740) Qi Q et al. N Engl J Med 2012
27 The Effects of SSB Intake (1 serving/day) on BMI According to quar5les of gene5c risk score Beta=0.44 P=0.003 Beta=-0.07 P=0.36 Quartiles of Obesity Genetic Risk Score
28 Physical Ac0vity, Television Watching and Gene0c Predisposi0on in rela0on to Body Mass Index in Women and Men
29 Gene0c Predisposi0on Score and BMI by Physical Ac0vity
30 Gene0c Predisposi0on Score and BMI by TV Watching
31 GENETICS & METABOTYPES the Human Metabolome IP: Intermediate Phenotype Suhre K, et al. Nat Rev Genet, 2012
32 Disparity in Diabetes Gene- environment interac5ons Metabolomics Personalized medicine 32
33 3000+ metabolites Metabolome: the complete set of small- molecule metabolites to be found within a biological sample (cell, 5ssue, or organism). Metabolomics: the systema5c study of small- molecule metabolites in a biological sample under a given set of condi5ons.
34 Metabolome
35 GXE Metabolome
36 In Caucasians BCAAs *Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Wang et al., Nature Medicine 17, (2011).
37 Dietary BCAA intake and plasma BCAA levels Age- adjusted Age- and BMI- adjusted Qi et al. unpublished data
38 Metabolomics in African Americans The Atherosclerosis Risk in Communi5es (ARIC) Study is a popula5on- based prospec5ve biracial cohort study to inves5gate the causes of atherosclerosis and its clinical outcomes. Metabolomic profiles were measured in ~2000 African- Americans at baseline examina5on Characteris5cs of study popula5on at baseline examina5on in characteris0cs Total popula0on (N=1977) Females (N=1275) Males (N=702) Age, y 52.9 ± ± ± 5.8 Current smoker, n (%) 498 (28.8) 308 (24.2) 261 (37.2) Physical ac5vity 6.6 ± ± ± 1.4 BMI, kg/m ± ± ± 4.5 Prevalent hypertension, n (%) 1050 (53.1) 694 (54.4) 356 (50.7) Prevalent diabetes, n (%) 319 (16.2) 218 (17.1) 101 (14.4) Prevalent heart failure, n (%) 97 (4.9) 76 (6.0) 21 (3.0)
39 GWAS Metabolomics Cofactors and vitamins bilirubin (E,E) UGT1A bilirubin (Z,Z) UGT1A biliverdin UGT1A 3- hydroxy decanoate THEM4 Lipid [H]HWESAS LLR[OH] ACE acetyl carni5ne SIAE deoxy carni5ne SLC6A13 aspartyl phenyl alanine ACE threonylp henyl alanine ACE hexade canedioate ADH4 palmitoleate (16:1n7) PKD2L1 Pep5de HXGXA KLKB1 LEU- PHE KLKB1 crea5ne GATM trehalose TREH N- acetyl phenyl alanine ACY3 phenyl acetate ACSM2B N- acetyl ornithine NAT8 Metabolite gene Carbohydrate glycine CPS1 Amino acid Common variants with p- value < 1.6Í Yu, et al. PLoS GeneIcs. 2014
![GWAS Metabolomics Cofactors and vitamins bilirubin (E,E) UGT1A bilirubin (Z,Z) UGT1A biliverdin UGT1A 3- hydroxy decanoate THEM4 Lipid [H]HWESAS LLR[OH] ACE acetyl carni5ne SIAE deoxy carni5ne](/docs-images/82/86975947/images/40-0.jpg "SLC6A13 aspartyl phenyl alanine ACE threonylp henyl alanine ACE hexade canedioate ADH4 palmitoleate (16:1n7) PKD2L1 Pep5de HXGXA KLKB1 LEU- PHE KLKB1 crea5ne GATM trehalose TREH N- acetyl phenyl")
40 GWAS Metabolomics Cofactors and vitamins bilirubin (E,E) UGT1A bilirubin (Z,Z) UGT1A biliverdin UGT1A 3- hydroxy decanoate THEM4 Lipid [H]HWESAS LLR[OH] ACE acetyl carni5ne SIAE deoxy carni5ne SLC6A13 aspartyl phenyl alanine ACE threonylp henyl alanine ACE hexade canedioate ADH4 palmitoleate (16:1n7) PKD2L1 Pep5de HXGXA KLKB1 LEU- PHE KLKB1 crea5ne GATM trehalose TREH N- acetyl phenyl alanine ACY3 phenyl acetate ACSM2B Carbohydrate N- acetyl ornithine NAT8 glycine CPS1 Amino acid Common variants with p- value < 1.6Í Yu, et al. PLoS GeneIcs
41 Gene- Metabolite- Disease Pathway Yu, et al. PLoS GeneIcs. 2014
42 Nutri5onal Metabolomics # related metabolites Super pathway of metabolites cofactors and vitamins carbohydrate xenobio5cs energy pep5de lipid amino acid Zheng, et al. Am J Epidemiol. In press. 42 Zheng, et al. In submission.
43 Metabolomics in Diseases Research 204 metabolites Reliability of human metabolome Metabolomics in incident heart failure Metabolomics in incident hypertension 4- hydroxyhippurate Oxida5ve break- down of benzenoid substances in guts Zheng, et al. Am J Epidemiol Zheng, et al. Hypertension
44
45 Meta- analysis of red meat intake and T2 diabetes Pan et al., AJCN 2011
46 Three major pathways via which intestinal microbiota can alter human cardio-metabolism. Vinjé S et al. Eur Heart J 2013;eurheartj.eht467 Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oup.com
47
48 Gut Microbiota as a Cardiometabolic Target Gut bacteria play a critical role in metabolism of nutritional factors in the pathogenesis of diabetes: Components in red meat Plant-based foods: soluble fiber, polyphenols from fruits, vegetables, coffee, etc. Emerging evidence indicates that gut flora metabolites in development of complex metabolic phenotypes including obesity, diabetes, and CVD. This research can provide novel prevention and therapeutic strategies for metabolic diseases (including diet/lifestyle, probiotic, and prebiotic approaches).
49 Franks PW et al. Diabetes Care 2013;36: Franks et al. Diabetes Care 2013
50 Racial Disparity in diseases Gene- environment interac5ons Metabolomics Personalized medicine 50
51 Personalized preven0on and racial disparity NOT racialized BUT personalized medicine Race and Pharmacogene5cs Advance in GXE research and systems epidemiology approach Applica5on of Metabolomics in clinical sehng
52 Yan Zheng Qibin Qi Lu Qi Marilyn Cornelis Peter Kra Brian Wolpert Mike Pan Rob van Dam Qi Sun Acknowledgement
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