Is There A Genetic Basis to Atrial Fibrillation?

Transcription

1 Prior reports of familial AF Is There A Genetic Basis to Atrial Fibrillation? Patrick T. Ellinor, MD, PhD Cardiac Arrhythmia Service & Cardiovascular Research Center Massachusetts General Hospital, Harvard Medical School Original description of a family of three brothers with AF dates to Wolff, L. NEJM 229: Three families with AF have been mapped to a locus on chromosome 10. Brugada, R. et al., NEJM 336: Hypothesis MGH Lone AF Study Patients with lone atrial fibrillation may have a genetic contribution to their condition We determined the prevalence of atrial fibrillation in the family members of patients with lone atrial fibrillation Ongoing enrollment of a cohort of subjects with lone atrial fibrillation since 6/01 At enrollment subjects undergo a physical examination, detailed medical and family history. Results of ECHO, Holter, ECG, and basic laboratory studies are obtained. Blood samples for DNA and protein analyses ~700 probands and ~250 family members enrolled to date 1

2 Kindreds with multiple affected individuals Offspring AF risk by Parental h/o AF 100 AF 1 parent OR 1.9; (P=0.02) <75yo, w/o h/o heart disease OR 3.2; (P< 0.001) Fox Benjamin JAMA 2004;291:2851 4yr AF Risk/1,000 person yr Men Women Ellinor et al. Human Genetics HTN Diabetes Heart Disease Parent hx AF Atrial fibrillation in the general population is heritable Three broad genetic approaches to AF (or any other common disease) Iceland AF in a first degree relative confers a 1.77 RR of AF First degree relatives of those with AF under age 60 have risk of AF five times that of the general population (Arnar et al. Eur Heart J. 2006; 27(6): ) Danish Twins Study Concordance rate of AF in monozygotic vs. dizygotic twins was 22 vs 12%. Estimated heritability of 62% (Christopherson et al. Circ EP 2009) Traditional mapping and cloning Hypertrophic cardiomyopathy Candidate gene studies Ion channels in LQTS Association studies Case-control Whole genome association studies 2

3 FAF-1 Known genes within the Chr 6 locus 7 living individuals with documented AF, 2 with peripartum cardiomyopathy Age of onset ranging from years of age. KCNQ1 (I Ks ) Mutation Leading to AF Experimental approaches Notable features: -24 yrs of age mean onset -Prolonged QT -Three patients developed cardiomyopathy after AF Three broad strategies: Traditional mapping and cloning Candidate gene studies Association studies Gain of function mutation in KCNQ1 can lead to AF. Chen et al., Science Jan :

4 Connexin 40 (GJA5) mutations in lone AF Family AF pts that had surgical PV isolation 3 somatic & 1 germline mutation found 5 of 19 family members with AF Mutation in heart but not lymphocytes Gollob et al., NEJM 2006, 354: Age of onset 32 years (range 16-59) Longer QRS duration of 100 vs. 86 ms (p=0.009) Prolonged P wave duration on SAECG of 132 vs. 104 ms (p=0.01) None of the family members had a prolonged QT interval (422 ms for unaffected vs. 424 ms for affected individuals) Mutation in S3 of KCNQ1 leads to AF Mutation in S3 of KCNQ1 leads to AF Das et al. Heart Rhythm,

5 Failure to deactivate in S209P mutation Ion channel mutations are rare in lone AF Screened lone AF cohort for mutations in: NPPA KCNQ1 Das et al. Heart Rhythm, KCNQ1 1 SCN5A 1 KCNE KCNA5 0 KCNJ2 0 GJA5 0 Ellinor et al. Heart 2004;90: Ellinor et al. BMC Med. Genetics Unpublished data GJA5/ Connexin 40 Lone AF SCN5A KCNE KCNA5 KCNJ2 Problems in the genetic dissection of AF Evaluate other families AF can be asymptomatic and/or paroxysmal AF is common in general population Phenotypic and genetic heterogeneity Genetic models are limited Mutations identified to date are not typical of patients seen in the office 5

6 Possible endophenotypes of AF BNP levels are elevated in both paroxysmal and chronic AF A Echocardiography Holter SA ECG - P wave alternans MRI - pulmonary venous or atrial abnormalities Plasma - ANP, BNP, Endothelin, CRP nt-probnp (fmol/ml) p= p= p=0.75 p= Controls PAF: SB or NSR PAF: AF or AFl Permanent AF Ellinor et al. JACC Experimental approaches Simple versus complex traits Three broad strategies: Traditional mapping and cloning Candidate gene studies Association studies Simple Complex Examples HCM, FH, LQTS HTN, CAD, AF Disease prevalence Rare Common Genes involved Single Many Frequency of genetic variant Rare / mutation Effect on protein function Severe Mild Common / polymorphism Effect on phenotype Large / causative Small / susceptibility 6

7 Genome Wide Association Studies (GWAS) Genome wide association study Use large population with AF vs controls. AF No AF Compare 300,000 to 1 million single nucleotide polymorphisms (SNPs) throughout the genome. Look for regions shared by those with AF but not in those without AF. Recently used to study repolarization, macular degeneration, diabetes, premature coronary disease, prostate cancer. Genetic variant more common in those with AF Genome wide association study 2/3 Genome wide association study 3/3 Identify top hits Replicate in additional populations Fingerprint each individual Pfeufer et al, Nature Genetics,

8 GWAS identifies common variants for AF on 4q25 Risk of AF with rs Iceland Study populations rs T Allelic Frequency Case Cont. OR [95% c.i.] P value 3 Total of 7,088 subjects with AF & 31,429 controls Discovery (550/4,476) [1.54, 2.21] 2.0x10-11 Replication (2,251/13,238) [1.49, 1.81] 2.7x10-23 Combined (2,801/17,714) [1.53, 1.83] 1.9x10-30 Other European ancestry Sweden (143/738) [1.38, 2.93] Odds Ratio 2 1 US - MGH (636/804) [1.51, 2.23] 9.8x10-10 Combined [1.58, 2.23] 1.1x10-12 All combined 0 Iceland Massachusetts General Hospital Sweden Hong Kong Fram ingham Heart Study Rotterdam Study German AF Network Vanderbilt AF Registry Combined [1.58, 1.84] 6.1x10-41 Gudbjartsson et al. Nature, Kääb Ellinor, Eur Heart J, 2009 Fine mapping of Chr 4q25 locus for AF Regional plot of Chr 4q25 locus for AF MGH AFNet Stage Discovery Replication Affection status AF No AF AF No AF Number 790 1,177 2,145 4,073 Age (yrs) 63 ± ± ± ± 12 Men 547 (69) 627 (53) 1,564 (73) 2,005 (49) Hypertension 383 (49) 670 (57) 1,148 (56) 730 (18) 8

9 After adjustment for rs Protective region for AF Combination of SNPs predicts large risk of AF How do variants at 4q25 lead to AF? Non-coding variants in a genomic desert. Closest gene is PITX2. One isoform, Pitx2c: Critical for left/right asymmetry Including specification of the left atrium and pulmonary myocardium Suppresses a default program for sinoatrial node formation in the left atrium Mommersteeg et al,

10 No relationship between rs genotype and PITX2 RNA levels Where are we headed? Integrate clinical, pharmacologic, and outcome data with genetic variation. Association between variants at 4q25 ischemic and cryptogenic stroke (Gretarsdottir S et al., Ann Neurol Oct;64(4):402-9.) Larger genetic studies with greater power Left atrial tissue from 51 transplant donors AF Gen Consortium Performed Three Analyses for Early Onset AF, Community AF, and PR interval AGES: Age, Gene, Environment Susceptibility ARIC: Atherosclerosis Risk in Communities Study CHS: Cardiovascular Health Study Cleveland Clinic decode genetics FHS: Framingham Heart Study RS: Rotterdam Study GHS: Gutenberg Heart Study MONICA/KORA/German AF Network MGH: Massachusetts General Hospital SHIP: Study of Health in Pomerania WGHS: Women s Genome Health Study Goal is to perform GWAS data for AF and the PR interval: AF: ~8,500 with AF & ~85,000 without AF PR: ~28,000 subjects Cases/ Controls AF Early-Onset AF Community AF PR interval 1,335 /12,844 Prevalent; No structural heart disease 896 prevalent / 15,629 controls 2,712 incident / 23,220 controls Incident/Prevalent - 28,517 subjects 10

11 GWAS of AF in the community: Chr 4q25 strongly associated with AF SNPs on Chr 16 within ZFHX3 are associated with AF in the community. Replicated in German AFNET Study Benjamin et al. Nature Genetics, 2009 Overall RR 1.25; P= 1.8x10-15 What do we know about ZFHX3? Future Directions for AF Regulates myogenic and neuronal differentiation Tumor suppressor gene in multiple cancers Susceptibility to Kawasaki disease Function in cardiac tissue unknown decode found no associations between rs t with 2 ZFHX3 expression probes blood & adipose tissue Identify other genetic loci for AF Examine gene-environment interactions such as age, sex, HTN Determine if identified variants are associated with outcomes such as stroke, heart failure and death. Develop animal models of identified genes for AF Berry J Biol. Chem 2001;276:25057 Sun,X., et al., Nat. Genet. 2005;37:407 Gudbjartsson Nat Genet 2009; epub Jung Development2005;132:5137 Burgner PLoS. Genet. 2009;5:e Slide courtesy of Emelia Benjamin 11

12 Conclusions Acknowledgements AF and particularly lone AF are heritable Mutations have been identified in a number of ion channels, but are rare causes of AF Genome wide association study has identified common variants on Chr 4q25 and 16 strongly associated with AF. Framingham Heart Study Emelia J. Benjamin Renate Schnabel Kathryn L. Lunetta Rotterdam Study Jacqueline Witteman Charlotte van Noord Cardiovascular Health Study Susan Heckbert Ken Rice Vanderbilt University Dawood Darbar Dan M. Roden German AF Network Arne Pfeufer Moritz F. Sinner Martina Muller Stefan Kääb AGES Albert Smith Vilmundur Gudnason ARIC Alvaro Alonso Dan Arking Cleveland Clinic Mina Chung John Barnard MGH Steve Lubitz Seiko Makino Saumya Das David J. Milan Jeremy N. Ruskin Cardiac Arrhythmia Service at MGH 12