The genetics of differential fat distribution: The Insulin Resistance Atherosclerosis Family Study.

摘要

Obesity is a growing epidemic worldwide and within the U.S. Although obesity increases the risk of developing type 2 diabetes and cardiovascular disease, not all obese people actually have these adverse health outcomes. Multiple studies have shown that an excess of visceral adipose tissue (VAT), when compared to subcutaneous adipose tissue (SAT), causes an increased risk for developing these diseases. Although a multitude of factors contribute to fat distribution, such as age, gender, ethnicity, sex hormones, diet, and the environment, individuals of similar weights and body mass index (BMI) have large variation in the amount of VAT and SAT in their abdomen. These observations and heritability estimates suggest that genetic factors influence where fat is placed in the body. In addition, minority cohorts are disproportionally affected by obesity, have different fat distributions, and are understudied compared to European-derived cohorts. The Insulin Resistance Atherosclerosis Family Study (IRASFS) is a well phenotyped cohort with measures of glucose homeostasis and adiposity for 1,424 Hispanic Americans (HA) and 604 African Americans (AA). In particular, the study includes computed-tomography derived measures of SAT, VAT, and visceral to subcutaneous ratio (VSR), making it an ideal population to elucidate the genetic determinants of differential fat distribution in other ethnicities. The main goal of this research project was to identify genes that control where fat is stored in the body and to aid in the explanation of why individuals have different body fat distributions.Association studies of 26 FTO intron 1 SNPs in the IRASFS and IRAS cohorts replicated association seen in the literature with BMI and WAIST within the HA, but also illustrated that FTO variants do not affect VAT. Due to the lack of consistent association within the IRASFS AA, we investigated whether ethnic differences could explain why we did not observe any evidence of association in IRAS. A SNP by ethnicity interaction analysis gave statistical evidence that there is genetic heterogeneity in the FTO intron I region between AA, HA, and Non-Hispanic Whites.Two separate multi-stage genome wide association studies (GWAS) have been performed in the IRASFS evaluating evidence of association with biometric (BMI waist circumference, WAIST and waist to hip ratio, WHR) and direct (VAT, SAT, VSR) adiposity measures. In the HA GWAS, several novel VSR genes were identified, such as TMTC2, VAV2, ASB18, ASB4, and SCD5. Denser coverage of these genes identified several other SNPs within ASB18 and ASB4 associated with VSR and other obesity measures. In the AA GWAS, novel VSR (MYO18B, PDSS2, and IQGAP1) and VAT (FETUB, PTPRD , STAT3, and FAAH) genes were identified. In the analysis of 99 SNPs within these candidate genes in the AA of the Diabetes Heart Study (DHS), MYO18B was the only gene that illustrated evidence of association for obesity measures with the original exonic SNP (rs6004901), as well as additional variants in the region. Meta-analysis of the IRASFS and DHS increased the magnitude of association for this SNP. In summary, this project has successfully identified several functionally relevant genes associated with VAT and VSR, which may contribute to differential fat distribution in HA and AA.