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Genome-wide association of pericardial fat identifies a unique locus for ectopic fat.

ABSTRACT: Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.

SUBMITTER: Fox CS

PROVIDER: S-EPMC3349742 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND Pericardial adipose tissue (PAT) is the visceral adipose tissue compartment surrounding the heart. Experimental and observational research has suggested that greater PAT deposition might mediate cardiovascular disease, independent of general or subcutaneous adiposity. We characterize the genetic architecture of adiposity-adjusted PAT and identify causal associations between PAT and adverse cardiac magnetic resonance imaging measures of cardiac structure and function in 28 161 UK Biobank participants. METHODS AND RESULTS The PAT phenotype was extracted from cardiac magnetic resonance images using an automated image analysis tool previously developed and validated in this cohort. A genome-wide association study was performed with PAT area set as the phenotype, adjusting for age, sex, and other measures of obesity. Functional mapping and Bayesian colocalization were used to understand the biologic role of identified variants. Mendelian randomization analysis was used to examine potential causal links between genetically determined PAT and cardiac magnetic resonance-derived measures of left ventricular structure and function. We discovered 12 genome-wide significant variants, with 2 independent sentinel variants (rs6428792, P=4.20×10-9 and rs11992444, P=1.30×10-12) at 2 distinct genomic loci, that were mapped to 3 potentially causal genes: T-box transcription factor 15 (TBX15), tryptophanyl tRNA synthetase 2, mitochondrial (WARS2) and early B-cell factor-2 (EBF2) through functional annotation. Bayesian colocalization additionally suggested a role of RP4-712E4.1. Genetically predicted differences in adiposity-adjusted PAT were causally associated with adverse left ventricular remodeling. CONCLUSIONS This study provides insights into the genetic architecture determining differential PAT deposition, identifies causal links with left structural and functional parameters, and provides novel data about the pathophysiological importance of adiposity distribution.

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Genome-wide association of pericardial fat identifies a unique locus for ectopic fat.

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