New genetic loci link adipose and insulin biology to body fat distribution

Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

A short leucocyte telomere length is associated with development of insulin resistance

“…We therefore investigated whether LTL predicts changes in insulin resistance independent of BMI, by adding BMI to the models in ESM Table 1. The BMI effect may differ between the sexes [27,28]; therefore, we also tested the interaction between sex and BMI in these models. A higher BMI was associated with a larger increase in insulin resistance, but adding BMI to the model in ESM Table 1 had little effect on the association between LTL at baseline and change in insulin resistance (ESM Table 2).…”

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…Thus, we considered the MR analyses viable and obtained summary statistics for circulating PAI‐1 levels, CHD and CHD risk factors from previous GWASs as listed in Table 1. These are based on the largest GWAS meta‐analysis for each phenotype at the time of analysis and primarily conducted on European ancestry samples 28, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42…”

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

“…Like the FGF21 allele, for some of these alleles the apparent paradox is explained by the higher fat mass being concentrated in the lower body, at least in women, (e.g. those in or near FAM, LYPLAL1, GRB14) [35].There are two further limitations to our study that also mean caution is needed when translating the human genetic findings to implications for FGF21 therapies. First, despite being in the exon of FGF21, we cannot rule out the possibility that the variant associated with macronutrient intake operates through a nearby gene, and we note that the rs838133 allele is associated with the expression of a nearby gene FUT2, involved in vitamin B12 metabolism [38].…”

“…The FGF21 rs838133 minor allele is not the first common allele to be associated with apparently paradoxical effects on fat mass and metabolic markers. Previous human genetic studies of alleles associated with insulin sensitivity have shown that most are also associated with an apparently paradoxical higher fat mass (and the insulin resistance allele is associated with lower fat mass) [32][33][34][35][36][37]. Like the FGF21 allele, for some of these alleles the apparent paradox is explained by the higher fat mass being concentrated in the lower body, at least in women, (e.g.…”

“…Like the FGF21 allele, for some of these alleles the apparent paradox is explained by the higher fat mass being concentrated in the lower body, at least in women, (e.g. those in or near FAM, LYPLAL1, GRB14) [35].…”