Genetics of height and risk of atrial fibrillation: A Mendelian randomization study


Autoři: Michael G. Levin aff001;  Renae Judy aff004;  Dipender Gill aff005;  Marijana Vujkovic aff002;  Shefali S. Verma aff010;  Yuki Bradford aff010aff012;  Marylyn D. Ritchie aff010;  Matthew C. Hyman aff001;  Saman Nazarian aff001;  Daniel J. Rader aff002;  Benjamin F. Voight aff010;  Scott M. Damrauer aff003
Působiště autorů: Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff001;  Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff002;  Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America aff003;  Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff004;  Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom aff005;  Centre for Pharmacology & Therapeutics, Department of Medicine, Imperial College London, London, United Kingdom aff006;  Novo Nordisk Research Centre Oxford, Oxford, United Kingdom aff007;  Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom aff008;  Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom aff009;  Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff010;  Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff011;  Tarrytown, New York, United States of America aff012;  Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff013;  Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff014
Vyšlo v časopise: Genetics of height and risk of atrial fibrillation: A Mendelian randomization study. PLoS Med 17(10): e32767. doi:10.1371/journal.pmed.1003288
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003288

Souhrn

Background

Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.

Methods and findings

In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10−42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55–72; 38% female; recruitment 2008–2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.

Conclusions

In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.

Klíčová slova:

Atrial fibrillation – Cardiovascular disease risk – Coronary heart disease – Diabetes mellitus – Genetics – Genetics of disease – Genome-wide association studies – Instrumental variable analysis


Zdroje

1. Chugh SS, Roth GA, Gillum RF, Mensah GA. Global burden of atrial fibrillation in developed and developing nations. Global Heart. 2014;9:113–9. doi: 10.1016/j.gheart.2014.01.004 25432121

2. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2014;64:e1–76. doi: 10.1016/j.jacc.2014.03.022 24685669

3. Tikkanen E, Gustafsson S, Ingelsson E. Associations of fitness, physical activity, strength, and genetic risk with cardiovascular disease: longitudinal analyses in the UK Biobank study. Circulation. 2018;137:2583–91. doi: 10.1161/CIRCULATIONAHA.117.032432 29632216

4. Crump C, Sundquist J, Winkleby MA, Sundquist K. Height, weight, and aerobic fitness level in relation to the risk of atrial fibrillation. Am J Epidemiol. 2018;187:417–26. doi: 10.1093/aje/kwx255 28641376

5. Fenger-Grøn M, Overvad K, Tjønneland A, Frost L. Lean body mass is the predominant anthropometric risk factor for atrial fibrillation. J Am Coll Cardiol. 2017;69:2488–97. doi: 10.1016/j.jacc.2017.03.558 28521886

6. Choi SH, Weng L-C, Roselli C, Lin H, Haggerty CM, Shoemaker MB, et al. Association between titin loss-of-function variants and early-onset atrial fibrillation. JAMA. 2018;320:2354–64. doi: 10.1001/jama.2018.18179 30535219

7. Roselli C, Chaffin MD, Weng L-C, Aeschbacher S, Ahlberg G, Albert CM, et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet. 2018;50:1225–33. doi: 10.1038/s41588-018-0133-9 29892015

8. Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham SE, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet. 2018;50:1234–9. doi: 10.1038/s41588-018-0171-3 30061737

9. Lai FY, Nath M, Hamby SE, Thompson JR, Nelson CP, Samani NJ. Adult height and risk of 50 diseases: a combined epidemiological and genetic analysis. BMC Med. 2018;16:187. doi: 10.1186/s12916-018-1175-7 30355295

10. Nelson CP, Hamby SE, Saleheen D, Hopewell JC, Zeng L, Assimes TL, et al. Genetically determined height and coronary artery disease. N Engl J Med. 2015;372:1608–18. doi: 10.1056/NEJMoa1404881 25853659

11. Marott JL, Skielboe AK, Dixen U, Friberg JB, Schnohr P, Jensen GB. Increasing population height and risk of incident atrial fibrillation: the Copenhagen City Heart Study. Eur Heart J. 2018;39:4012–9. doi: 10.1093/eurheartj/ehy367 29961878

12. Siscovick DS, Ix JH, Gottdiener JS, Kizer JR, Mukamal KJ, Yee LM, et al. Measures of body size and composition and risk of incident atrial fibrillation in older people: the Cardiovascular Health Study. Am J Epidemiol. 2016;183:998–1007. doi: 10.1093/aje/kwv278 27188936

13. Schmidt M, Bøtker HE, Pedersen L, Sørensen HT. Adult height and risk of ischemic heart disease, atrial fibrillation, stroke, venous thromboembolism, and premature death: a population based 36-year follow-up study. Eur J Epidemiol. 2014;29:111–8. doi: 10.1007/s10654-013-9867-y 24337942

14. Chang JD, Zimetbaum PJ, Rosenberg MA, Patton KK, Sotoodehnia N, Karas MG, et al. The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study. Eur Heart J. 2012;33:2709–17. doi: 10.1093/eurheartj/ehs301 22977225

15. Suzuki S, Yamashita T, Ohtsuka T, Sagara K, Uejima T, Oikawa Y, et al. Body size and atrial fibrillation in Japanese outpatients. Circ J. 2010;74:66–70. doi: 10.1253/circj.cj-09-0431 19797821

16. Rosengren A, Hauptman PJ, Lappas G, Olsson L, Wilhelmsen L, Swedberg K. Big men and atrial fibrillation: effects of body size and weight gain on risk of atrial fibrillation in men. Eur Heart J. 2009;30:1113–20. doi: 10.1093/eurheartj/ehp076 19304990

17. Mont L, Tamborero D, Elosua R, Molina I, Coll-Vinent B, Sitges M, et al. Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals. Europace. 2008;10:15–20. doi: 10.1093/europace/eum263 18178694

18. Hanna IR, Heeke B, Bush H, Brosius L, King-Hageman D, Beshai JF, et al. The relationship between stature and the prevalence of atrial fibrillation in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006;47:1683–8. doi: 10.1016/j.jacc.2005.11.068 16631009

19. Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry. Hum Mol Genet. 2018;27:3641–9. doi: 10.1093/hmg/ddy271 30124842

20. Yang J, Bakshi A, Zhu Z, Hemani G, Vinkhuyzen AAE, Lee SH, et al. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat Genet. 2015;47:1114–20. doi: 10.1038/ng.3390 26323059

21. Yang J, Zeng J, Goddard ME, Wray NR, Visscher PM. Concepts, estimation and interpretation of SNP-based heritability. Nat Genet. 2017;49:1304–10. doi: 10.1038/ng.3941 28854176

22. Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014;46:1173–86. doi: 10.1038/ng.3097 25282103

23. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7:e34408. doi: 10.7554/eLife.34408 29846171

24. Verbanck M, Chen C-Y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8. doi: 10.1038/s41588-018-0099-7 29686387

25. Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–85. doi: 10.1038/ng.2797 24097068

26. Shungin D, Winkler T, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–96. doi: 10.1038/nature14132 25673412

27. DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Mahajan A, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014;46:234–44. doi: 10.1038/ng.2897 24509480

28. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42:105–16. doi: 10.1038/ng.520 20081858

29. Palmer TM, Lawlor DA, Harbord RM, Sheehan NA, Tobias JH, Timpson NJ, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res. 2012;21:223–42. doi: 10.1177/0962280210394459 21216802

30. Burgess S, Davies NM, Thompson SG. Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol. 2016;40:597–608. doi: 10.1002/gepi.21998 27625185

31. Carroll RJ, Bastarache L, Denny JC. R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment. Bioinformatics. 2014;30:2375–6. doi: 10.1093/bioinformatics/btu197 24733291

32. Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26:2333–55. doi: 10.1177/0962280215597579 26282889

33. Davies NM, Holmes M V, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601 30002074

34. R Development Core Team. R: a language and environment for statistical computing. Version 3.5.1. Vienna: R Foundation for Statistical Computing; 2017.

35. Johnson LSB, Salonen M, Kajantie E, Conen D, Healey JS, Osmond C, et al. Early life risk factors for incident atrial fibrillation in the Helsinki Birth Cohort Study. J Am Heart Assoc. 2017;6:e006036. doi: 10.1161/JAHA.117.006036 28649086

36. Pritchett AM, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol. 2003;41:1036–43. doi: 10.1016/s0735-1097(02)02981-9 12651054

37. Leung DY, Chi C, Allman C, Boyd A, Ng AC, Kadappu KK, et al. Prognostic implications of left atrial volume index in patients in sinus rhythm. Am J Cardiol. 2010;105:1635–9. doi: 10.1016/j.amjcard.2010.01.027 20494675

38. Gupta DK, Shah AM, Giugliano RP, Ruff CT, Antman EM, Grip LT, et al. Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48. Eur Heart J. 2014;35:1457–65. doi: 10.1093/eurheartj/eht500 24302269

39. Rodevand O, Bjornerheim R, Ljosland M, Maehle J, Smith HJ, Ihlen H. Left atrial volumes assessed by three- and two-dimensional echocardiography compared to MRI estimates. Int J Card Imaging. 1999;15:397–410. doi: 10.1023/a:1006276513186 10595406

40. Tikkanen E, Gustafsson S, Knowles JW, Perez M, Burgess S, Ingelsson E. Body composition and atrial fibrillation: a Mendelian randomization study. Eur Heart J. 2019;40:1277–82. doi: 10.1093/eurheartj/ehz003 30721963

41. Nielsen JB, Fritsche LG, Zhou W, Teslovich TM, Holmen OL, Gustafsson S, et al. Genome-wide study of atrial fibrillation identifies seven risk loci and highlights biological pathways and regulatory elements involved in cardiac development. Am J Hum Genet. 2018;102:103–15. doi: 10.1016/j.ajhg.2017.12.003 29290336

42. Alonso A, Krijthe BP, Aspelund T, Stepas KA, Pencina MJ, Moser CB, et al. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013;2:e000102. doi: 10.1161/JAHA.112.000102 23537808

43. Alonso A, Roetker NS, Soliman EZ, Chen LY, Greenland P, Heckbert SR. Prediction of atrial fibrillation in a racially diverse cohort: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc. 2016;5:e003077. doi: 10.1161/JAHA.115.003077 26908413

44. Schnabel RB, Sullivan LM, Levy D, Pencina MJ, Massaro JM, D’Agostino RB, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet. 2009;373:739–45. doi: 10.1016/S0140-6736(09)60443-8 19249635


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