Physicians' Academy for Cardiovascular Education

Genetic variants of BMI associated with increased risk of AF

Chatterjee NA, Circulation, 2016

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

 
Chatterjee NA, Giulianini F, Geelhoed B, et al.
Circulation 2016; published online ahead of print
 

Background

Changes in BMI have been associated with changes in AF risk, suggesting that AF risk can be modified with weight interventions [1,2]. If the observed associations between BMI and AF are causal, targeting obesity with preventive and weight reduction strategies may lead to lower AF incidence [3].
 
However, causality cannot be established based on observational analyses, and there are no randomised controlled trials of obesity interventions for the primary prevention of AF [4].
 
In this study, it was evaluated whether the relationship between BMI and incident AF is causal, with the use of a Mendelian randomisation analysis with two genetic instrumental variables:
  • FTO genotype
  • BMI gene score comprised of 39 single nucleotide polymorphisms (SNPs) associated with BMI
These instruments were assessed in seven European prospective cohorts including 51,646 participants without AF at baseline. The cohort-specific mean follow-up ranged from 7.4 to 19.2 years, in which 4,178 cases of AF occurred.
 

Main results

Observational risk estimates
  • In observational analysis, increasing BMI was associated with significantly increased risk of incident AF, and ranged from 3-6% per 1 kg/m2 increase in BMI.  
  • In age- and gender-adjusted analysis, the pooled HR for incident AF was 1.05 per kg/m2 (95% CI: 1.04-1.06; P<0.001) without significant heterogeneity (I2=24.1%, Qp=0.37). Adjustment for additional potential confounders slightly changed the association between BMI and AF.
 
Association FTO genotype and BMI gene score with BMI
  • In age- and gender-adjusted analysis, FTO genotype and BMI gene score were associated with a significant increase in BMI, with effect sizes that ranged between all 7 cohorts from 0.21-0.55 kg/m2 per A-allele of the FTO SNP and 0.78-1.25 kg/m2 per 1-unit increase in BMI gene score (P<0.001).
    The meta-analysis observational estimates were 0.43 (95% CI: 0.32-0.54) kg/m2 for FTO and 1.05 (95% CI: 0.90-1.20) kg/m2 per 1 unit increase for BMI gene score (both P<0.001).
  • There was a moderate heterogeneity across studies (FTO: I2=67.9%, Qp<0.01; BMI gene score: I2=72.3%, Qp<0.01 in age- and gender-adjusted models), with greater instrument-BMI effect size in cohorts with younger populations.  
  • Heterogeneity was significantly mitigated following meta-regression accounting for differences in mean age between cohorts (residual heterogeneity: FTO: I2=37.5%, Qp=0.17; BMI gene score: I2=37.5%, Qp=0.16 in age- and gender-adjusted models).
 
Association FTO genotype and BMI gene score with AF
  • In the meta-analysis of age- and gender-adjusted FTO and BMI gene score models, increase in both instruments was associated with a significantly increased risk of incident AF (FTO: HR 1.07; 95% CI: 1.02-1.12 per A-allele of the FTO SNP, P=0.004; BMI gene score: HR: 1.11; 95% CI: 1.05-1.18 per 1-unit increase in BMI gene score; P<0.001) with minimal heterogeneity across studies.  
 
Estimates for causal association between BMI and incident AF
  • In the meta-analysis of instrumental variable estimates from age- and gender-adjusted models, each 1 kg/m2 increase in BMI was associated with a significantly increased risk of incident AF for both FTO (HR: 1.15; 95% CI: 1.05-1.27; P=0.004) and the BMI gene score (HR: 1.11; 95% CI: 1.05-1.17; P<0.001) with minimal heterogeneity across studies.

Conclusion

In a Mendelian randomisation study of more than 50,000 individuals of European ancestry, genetic variants associated with BMI were significantly associated with an increased risk of incident AF and the instrumental variable analysis supported a causal relationship between BMI and AF. These data support the primordial prevention of obesity as a public health target, in order to lower the AF burden.
 
Find this article online at Circulation
 

References

1. Tedrow UB, Conen D, Ridker PM, et al. The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the WHS. J Am Coll Cardiol.2010;55(21):2319-2327.
2. Huxley RR, Misialek JR, Agarwal SK, et al. Physical activity, obesity, weight change, and risk of atrial fibrillation: the atherosclerosis risk in communities study. Circulation Arrhythm Electrophysiol. 2014;7(4):620-625.
3. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310(19):2050-2060.
4. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89-98.