The Risk of Atrial Fibrillation Increases with Earlier Onset of Obesity: A Mendelian Randomization Study

Abstract

Background: Obesity is a well-established risk factor for atrial fibrillation (AF). Previous epidemiological research on obesity and AF often focused on adult populations and now broadened to earlier in life. Therefore, this study aimed to determine the relationships between obesity at different periods of life and the risk of AF. Methods: A two-sample Mendelian randomization (MR) study design using summarised data from 6 genome-wide association studies (GWASs) was employed in this study. Single nucleotide polymorphisms (SNPs) associated with adult obesity, childhood obesity, childhood body mass index (BMI), waist-to-hip ratio adjusted for BMI (WHRadjBMI), birth weight and AF were independently retrieved from large-scale GWASs. For SNP identification, the genome-wide significance threshold was set at p <5.00×10 -8 . To obtain causal estimates, MR analysis was conducted using the inverse variance-weighted (IVW) method. The weighted median, MR-Egger methods and MR-robust adjusted profile score (MR-RAPS) were used to evaluate the robustness of MR analysis. Results: A total of 204 SNPs were identified as the genetic instrumental variables (5 SNPs for childhood obesity, 13 SNPs for childhood BMI, 137 SNPs for birth weight, 35 SNPs for adult WHRadjBMI, and 14 SNPs for adult obesity). The results of MR analysis demonstrated that the genetically predicted adult obesity, childhood BMI, and birth weight were associated with AF risk. Notably, a 1 unit standard deviation (1-SD) increase in adult obesity was related to a 13% increased risk of AF [p=6.51×10 -7 , OR, 1.13 (95% CI, 1.08-1.19)], a 1-SD increase in childhood BMI was related to a 18% increased risk of AF [p=1.77×10 -4 , OR, 1.18 (95% CI, 1.08-1.29)], and a 1-SD increase in birth weight was related to a 26% increased risk of OR, 1.26 (95% CI,]. There was no evidence of pleiotropy or heterogeneity between the MR estimates obtained from multiple SNPs. Conclusion: Our study reveals the association of genetic susceptibility to obesity with a higher risk of AF. Moreover, an earlier age at obesity was associated with an increased risk of AF. Therefore, public awareness of the dangers of obesity and active early weight control may prevent the development of AF.

Causal relationship between nutritional assessment phenotypes and heart failure: A Mendelian randomization study

“…BMI has long been a well-recognized metric for nutritional assessment because of its simplicity and established relationships with associated comorbidities. Previous studies have shown that a high BMI is a risk factor for the development of HF and atrial fibrillation, a finding that is consistent with the results of our MR analysis [ [23] , [24] , [25] , [26] , [27] ]. However, there is still the so-called "obesity-survival paradox [ [28] , [29] , [30] , [31] ]."…”

GWAS advancements to investigate disease associations and biological mechanisms

“…Recent studies leveraging MR showcase its statistical power in revealing certain underlying factors that increase disease risks. Within the context of AF, MR surveys have accentuated the spectrum of risk factors, ranging from obesity 68 and obstructive sleep apnoea (OSA) 69 to even a 1‐unit standard deviation increase in childhood body mass index, 68 birth weight 68 and height 70 all of which indicate an elevated risk of AF 71 . Similarly, when leveraged to understand the aetiology of HF, it reveals a spectrum of risk factors, including higher diastolic and systolic blood pressures, elevated triglyceride levels, genetic predisposition to AF and coronary artery disease as significant contributors to heightened HF risk.…”

Obesity-Related Atrial Fibrillation: Cardiac Manifestation of a Systemic Disease

“…Interestingly, an analysis by Zhou et al, which pooled data from 6 genome-wide association studies, demonstrated that the risk of AF in adulthood increases with earlier onset of obesity. They found that a 1 standard deviation increase in adult obesity, childhood BMI, and birth weight was associated with a 13%, 18%, and 26% increased risk of AF in adulthood, respectively [ 35 ]. These interesting findings may thus point to a causal relationship between obesity and AF.…”