Abstract P360: Meta-Analysis of up to 14,262 Individuals Identifies Loci Associated with Measures of Subcutaneous Fat Volume and Attenuation
Background: Defects in subcutaneous adipose tissue (SAT) may limit adipose tissue expansion and lead to ectopic fat deposition. Adipose tissue with adverse cellular characteristics contain higher lipid content, larger adipocytes, more stromal fibrosis and less angiogenesis - characteristics that can limit SAT expansion and are believed to be associated with increased pathogenicity and may influence cardiometabolic risk. In addition to SAT volume, characteristics of SAT can be estimated indirectly using Hounsfield units (HU), a radiographic index derived from computed tomography (CT) imaging to reflect attenuation and differentiate tissue types.
Methods: To identify genetic factors associated with SAT volume and attenuation, we performed a genome-wide meta-analysis of SAT and SATHU including 2.6 million SNPs in up to 14,262 participants from 10 cohorts of European ancestry (AGES, DHS, Family Heart Study, Fels Longitudinal Study, Framingham Heart Study, HealthABC, MESA, PIVUS, SHIP-2 and SHIP-TREND) as part of the VATGen Consortium. Within each cohort, regression models were stratified by sex and adjusted for age, study specific covariates and kinship and/or measures of ancestry; for SATHU we also included a model with adjustment for SAT volume (SATHUadjSAT). We performed a sample-size weighted Z-score based meta-analysis in the overall sample and in men and women separately.
Results: Within 3,312 participants of the Framingham Heart Study, the estimated heritability of SAT volume was 59% (p=1e-55) and SAT attenuation (SATHU) was 30%, even after adjusting for SAT volume (p<1e-15). We identified two genome-wide significant loci (p<5e-8) with SAT volume: one at the BMI-associated FTO locus (SAT overall; p=1.3e-9) and the other in an intergenic region on chromosome 17q12 (SAT in women; p=2.8e-9). Although the 17q12 region has not been previously associated with adiposity, variants near this locus have been identified in genome-wide analyses of autoimmune disease (asthma, type 1 diabetes and ulcerative colitis). No genome-wide significant associations were identified for either SATHU or SATHUadjSAT in the overall analysis or stratified by sex; however many suggestive (p<1e-5) and sub-genome-wide significant (p<1e-7) loci were identified (Nloci~80). The most significant association identified was at the CASP2 locus (p=7.1e-8) with SATHUadjSAT among women only; no association was observed among men (p=0.85). CASP2 encodes the caspase 2 enzyme, an apoptosis-related cysteine peptidase, and may play a role in stress-induced cell death and suppress tumorigenesis.
Conclusions: We have performed a large-scale genome-wide analysis for SAT volume and attenuation. Unbiased genetic scans may provide insight into pathophysiologic mechanisms linking SAT volume with cellular characteristics of fat that ultimately may determine global cardiometabolic risk.
Author Disclosures: A.Y. Chu: None. M. Allison: None. I. Borecki: None. A.C. Choh: None. L. Cupples: None. E. Demerath: None. X. Deng: None. M. Feitosa: None. V. Fisher: None. C.S. Fox: None. T. Harris: None. T. Harris: None. N. Heard-Costa: None. T. Kacprowski: None. C. Langefeld: None. C.M. Lindgren: None. L. Lu: None. Y. Liu: None. A. Mahajan: None. J. Stafford: None. A. Smith: None. H. Völzke: None. H. Wallaschofski: None. J. Yao: None.
- © 2015 by American Heart Association, Inc.