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Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.

TitleGenetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.
Publication TypeJournal Article
Year of Publication2017
AuthorsChatterjee NA, Giulianini F, Geelhoed B, Lunetta KL, Misialek JR, Niemeijer MN, Rienstra M, Rose LM, Smith AV, Arking DE, Ellinor PT, Heeringa J, Lin H, Lubitz SA, Soliman EZ, Verweij N, Alonso A, Benjamin EJ, Gudnason V, Stricker BHC, van der Harst P, Chasman DI
Secondary AuthorsAlbert CM
JournalCirculation
Volume135
Issue8
Pagination741-754
Date Published2017 Feb 21
ISSN1524-4539
KeywordsAged, Alleles, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Atrial Fibrillation, Body Mass Index, Cohort Studies, Female, Genotype, Humans, Incidence, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Random Allocation, Risk Factors
Abstract

BACKGROUND: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI.

METHODS: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis.

RESULTS: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (: 0.43 [95% confidence interval, 0.32-0.54] kg/m per A-allele,

CONCLUSIONS: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.

DOI10.1161/CIRCULATIONAHA.116.024921
Alternate JournalCirculation
PubMed ID27974350
PubMed Central IDPMC5322057
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
R01 CA047988 / CA / NCI NIH HHS / United States
R01 HL080467 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01 HL043851 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
16EIA26410001 / AHA / American Heart Association-American Stroke Association / United States
T32 HL007575 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
RC1 HL101056 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R01 HL116690 / HL / NHLBI NIH HHS / United States
R01 HL102214 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R21 HL093613 / HL / NHLBI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
HHSN271201200022C / AG / NIA NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
2014105 / DDCF / Doris Duke Charitable Foundation / United States
RC1 HL099355 / HL / NHLBI NIH HHS / United States