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

Neal A. Chatterjee, Franco Giulianini, Bastiaan Geelhoed, Kathryn L. Lunetta, Jeffrey R. Misialek, Maartje N. Niemeijer, Michiel Rienstra, Lynda M. Rose, Albert V. Smith, Dan Arking, Patrick T. Ellinor, Jan Heeringa, Honghuang Lin, Steven A. Lubitz, Elsayed Z. Soliman, Niek Verweij, Alvaro Alonso, Emelia J. Benjamin, Vilmundur Gudnason, Bruno H C StrickerPim van der Harst, Daniel I. Chasman, Christine M. Albert

Research output: Contribution to journalArticle

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 using genetic predictors of BMI. METHODS—: We identified 51 646 individuals of European ancestry without AF at baseline from seven 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 7.4 to 19.2 years, over which period there were 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 utilized: FTO genotype (rs1558902) and a BMI gene score comprised of 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 (FTO: 0.43 [95% CI: 0.32 – 0.54] kg/m per A-allele, p<0.001); BMI gene score: 1.05 [95% CI: 0.90-1.20] kg/m per 1 unit increase, p<0.001) and incident AF (FTO – HR: 1.07 [1.02-1.11] per A-allele, p=0.004; BMI gene score – HR: 1.11 [1.05-1.18] per 1-unit increase, p<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were HR 1.15 [1.04-1.26] per kg/m, p=0.005 (FTO) and 1.11 [1.05-1.17] per kg/m, p<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted HR 1.05 [1.04-1.06] per kg/m, p<0.001). Multivariable adjustment did not significantly change findings. 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.

Original languageEnglish (US)
JournalCirculation
DOIs
StateAccepted/In press - Jan 3 2017

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Random Allocation
Body Mass Index
Obesity
Atrial Fibrillation
Causality
Genes
Observational Studies
Meta-Analysis
Alleles
Iceland
Genome-Wide Association Study
Primary Prevention
Netherlands
Single Nucleotide Polymorphism
Public Health
Genotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Chatterjee, N. A., Giulianini, F., Geelhoed, B., Lunetta, K. L., Misialek, J. R., Niemeijer, M. N., ... Albert, C. M. (Accepted/In press). Genetic Obesity and the Risk of Atrial Fibrillation–Causal Estimates from Mendelian Randomization. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.116.024921

Genetic Obesity and the Risk of Atrial Fibrillation–Causal Estimates from Mendelian Randomization. / Chatterjee, Neal A.; Giulianini, Franco; Geelhoed, Bastiaan; Lunetta, Kathryn L.; Misialek, Jeffrey R.; Niemeijer, Maartje N.; Rienstra, Michiel; Rose, Lynda M.; Smith, Albert V.; Arking, Dan; Ellinor, Patrick T.; Heeringa, Jan; Lin, Honghuang; Lubitz, Steven A.; Soliman, Elsayed Z.; Verweij, Niek; Alonso, Alvaro; Benjamin, Emelia J.; Gudnason, Vilmundur; Stricker, Bruno H C; van der Harst, Pim; Chasman, Daniel I.; Albert, Christine M.

In: Circulation, 03.01.2017.

Research output: Contribution to journalArticle

Chatterjee, NA, Giulianini, F, Geelhoed, B, Lunetta, KL, Misialek, JR, Niemeijer, MN, Rienstra, M, Rose, LM, Smith, AV, Arking, D, 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 & Albert, CM 2017, 'Genetic Obesity and the Risk of Atrial Fibrillation–Causal Estimates from Mendelian Randomization', Circulation. https://doi.org/10.1161/CIRCULATIONAHA.116.024921
Chatterjee, Neal A. ; Giulianini, Franco ; Geelhoed, Bastiaan ; Lunetta, Kathryn L. ; Misialek, Jeffrey R. ; Niemeijer, Maartje N. ; Rienstra, Michiel ; Rose, Lynda M. ; Smith, Albert V. ; Arking, Dan ; Ellinor, Patrick T. ; Heeringa, Jan ; Lin, Honghuang ; Lubitz, Steven A. ; Soliman, Elsayed Z. ; Verweij, Niek ; Alonso, Alvaro ; Benjamin, Emelia J. ; Gudnason, Vilmundur ; Stricker, Bruno H C ; van der Harst, Pim ; Chasman, Daniel I. ; Albert, Christine M. / Genetic Obesity and the Risk of Atrial Fibrillation–Causal Estimates from Mendelian Randomization. In: Circulation. 2017.
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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 using genetic predictors of BMI. METHODS—: We identified 51 646 individuals of European ancestry without AF at baseline from seven 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 7.4 to 19.2 years, over which period there were 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 utilized: FTO genotype (rs1558902) and a BMI gene score comprised of 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 (FTO: 0.43 [95{\%} CI: 0.32 – 0.54] kg/m per A-allele, p<0.001); BMI gene score: 1.05 [95{\%} CI: 0.90-1.20] kg/m per 1 unit increase, p<0.001) and incident AF (FTO – HR: 1.07 [1.02-1.11] per A-allele, p=0.004; BMI gene score – HR: 1.11 [1.05-1.18] per 1-unit increase, p<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were HR 1.15 [1.04-1.26] per kg/m, p=0.005 (FTO) and 1.11 [1.05-1.17] per kg/m, p<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted HR 1.05 [1.04-1.06] per kg/m, p<0.001). Multivariable adjustment did not significantly change findings. 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.",
author = "Chatterjee, {Neal A.} and Franco Giulianini and Bastiaan Geelhoed and Lunetta, {Kathryn L.} and Misialek, {Jeffrey R.} and Niemeijer, {Maartje N.} and Michiel Rienstra and Rose, {Lynda M.} and Smith, {Albert V.} and Dan Arking and Ellinor, {Patrick T.} and Jan Heeringa and Honghuang Lin and Lubitz, {Steven A.} and Soliman, {Elsayed Z.} and Niek Verweij and Alvaro Alonso and Benjamin, {Emelia J.} and Vilmundur Gudnason and Stricker, {Bruno H C} and {van der Harst}, Pim and Chasman, {Daniel I.} and Albert, {Christine M.}",
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month = "1",
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doi = "10.1161/CIRCULATIONAHA.116.024921",
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TY - JOUR

T1 - Genetic Obesity and the Risk of Atrial Fibrillation–Causal Estimates from Mendelian Randomization

AU - Chatterjee, Neal A.

AU - Giulianini, Franco

AU - Geelhoed, Bastiaan

AU - Lunetta, Kathryn L.

AU - Misialek, Jeffrey R.

AU - Niemeijer, Maartje N.

AU - Rienstra, Michiel

AU - Rose, Lynda M.

AU - Smith, Albert V.

AU - Arking, Dan

AU - Ellinor, Patrick T.

AU - Heeringa, Jan

AU - Lin, Honghuang

AU - Lubitz, Steven A.

AU - Soliman, Elsayed Z.

AU - Verweij, Niek

AU - Alonso, Alvaro

AU - Benjamin, Emelia J.

AU - Gudnason, Vilmundur

AU - Stricker, Bruno H C

AU - van der Harst, Pim

AU - Chasman, Daniel I.

AU - Albert, Christine M.

PY - 2017/1/3

Y1 - 2017/1/3

N2 - 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 using genetic predictors of BMI. METHODS—: We identified 51 646 individuals of European ancestry without AF at baseline from seven 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 7.4 to 19.2 years, over which period there were 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 utilized: FTO genotype (rs1558902) and a BMI gene score comprised of 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 (FTO: 0.43 [95% CI: 0.32 – 0.54] kg/m per A-allele, p<0.001); BMI gene score: 1.05 [95% CI: 0.90-1.20] kg/m per 1 unit increase, p<0.001) and incident AF (FTO – HR: 1.07 [1.02-1.11] per A-allele, p=0.004; BMI gene score – HR: 1.11 [1.05-1.18] per 1-unit increase, p<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were HR 1.15 [1.04-1.26] per kg/m, p=0.005 (FTO) and 1.11 [1.05-1.17] per kg/m, p<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted HR 1.05 [1.04-1.06] per kg/m, p<0.001). Multivariable adjustment did not significantly change findings. 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.

AB - 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 using genetic predictors of BMI. METHODS—: We identified 51 646 individuals of European ancestry without AF at baseline from seven 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 7.4 to 19.2 years, over which period there were 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 utilized: FTO genotype (rs1558902) and a BMI gene score comprised of 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 (FTO: 0.43 [95% CI: 0.32 – 0.54] kg/m per A-allele, p<0.001); BMI gene score: 1.05 [95% CI: 0.90-1.20] kg/m per 1 unit increase, p<0.001) and incident AF (FTO – HR: 1.07 [1.02-1.11] per A-allele, p=0.004; BMI gene score – HR: 1.11 [1.05-1.18] per 1-unit increase, p<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were HR 1.15 [1.04-1.26] per kg/m, p=0.005 (FTO) and 1.11 [1.05-1.17] per kg/m, p<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted HR 1.05 [1.04-1.06] per kg/m, p<0.001). Multivariable adjustment did not significantly change findings. 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.

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