A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

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

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, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display 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

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Obesity alters composition and diversity of the oral microbiota in patients with type 2 diabetes mellitus independently of glycemic control

BACKGROUND AND OBJECTIVE The involvement of the oral microbiota as a possible link between periodontitis, type 2 diabetes mellitus and obesity is still not well understood. The objective of the study was to investigate if glycemic control and obesity play a role in modulating the composition and diversity of the oral microbial ecology. MATERIAL AND METHODS A cohort of patients with type 2 diabetes mellitus (n = 18) was recruited. Participants demonstrating improved glycemic control after 3 months (n = 6) were included in a second examination. A full mouth examination was performed to estimate periodontitis severity followed by sample collection (subgingival plaque and saliva). Generation of large sequence libraries was performed using the high-throughput Illumina MiSeq sequencing platform. RESULTS The majority of participants (94.4%, n = 17) presented with moderate or severe forms of periodontitis. Differences in microbial composition and diversity between obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) groups were statistically significant. Cross-sectional and longitudinal approaches failed to reveal statistically significant associations between HbA1c level and species composition or diversity. CONCLUSIONS Obesity was significantly associated with the oral microbial composition. The impact of glycemic control on oral microbiota, however, could not be assured statistically

Obesity alters composition and diversity of the oral microbiota in patients with type 2 diabetes mellitus independently of glycemic control.

BACKGROUND AND OBJECTIVE:The involvement of the oral microbiota as a possible link between periodontitis, type 2 diabetes mellitus and obesity is still not well understood. The objective of the study was to investigate if glycemic control and obesity play a role in modulating the composition and diversity of the oral microbial ecology. MATERIAL AND METHODS:A cohort of patients with type 2 diabetes mellitus (n = 18) was recruited. Participants demonstrating improved glycemic control after 3 months (n = 6) were included in a second examination. A full mouth examination was performed to estimate periodontitis severity followed by sample collection (subgingival plaque and saliva). Generation of large sequence libraries was performed using the high-throughput Illumina MiSeq sequencing platform. RESULTS:The majority of participants (94.4%, n = 17) presented with moderate or severe forms of periodontitis. Differences in microbial composition and diversity between obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) groups were statistically significant. Cross-sectional and longitudinal approaches failed to reveal statistically significant associations between HbA1c level and species composition or diversity. CONCLUSIONS:Obesity was significantly associated with the oral microbial composition. The impact of glycemic control on oral microbiota, however, could not be assured statistically

Type 2 Diabetes in Octogenarians Is Associated with Decreased Low Molecular Weight Adiponectin

Background: Adiponectin circulates in the blood in three different multimer isoforms, of which the high molecular weight form (HMW) is presumed to mediate insulin sensitivity. We examined whether adiponectin oligomer distribution is associated with aging and type 2 diabetes (T2D) in octogenarians without characteristic features of metabolic syndrome. Methods: The study included 154 octogenarians (58 men, 96 women), 24 normoglycemic middle-aged controls (11 men, 13 women; mean age 44 years), and 33 middle-aged individuals (14 men, 19 women; mean age 55 years) with T2D. Based on oral glucose tolerance test 62 octogenarians had normal, 63 impaired glucose tolerance, and 29 octogenarians had newly detected T2D. Serum adiponectin multimer isoforms were measured after overnight fast by enzyme-linked immunosorbent assays. Results:Compared to the normoglycemic middle-aged control group, male normoglycemic octogenarians revealed significantly higher total adiponectin and all adiponectin isoforms. The same was true for females with the exception of low molecular weight (LMW) adiponectin, which was not statistically higher in octogenarians. Male and female octogenarians with T2D had significantly higher levels of total, HMW, and middle molecular weight (MMW) adiponectin, but not LMW adiponectin, than middle-aged individuals with T2D. Female, but not male, octogenarians revealed significantly lower total adiponectin than normoglycemic octogenarians. Compared with normoglycemic octogenarians, male and female octogenarians with T2D were characterized by significantly lower LMW adiponectin. In male and female octogenarians, total adiponectin and all multimer isoforms were directly correlated with HDL cholesterol. LMW adiponectin in octogenarians of both sexes was inversely correlated with glucose level at 2-hour oral glucose tolerance test. Conclusions: Serum levels of total adiponectin as well as its HMW and MMW isoforms were significantly higher in octogenarians with normoglycemia or T2D than in corresponding middle-aged control groups. In male and female octogenarians without metabolic syndrome, T2D was associated with lower LMW adiponectin, while the HMW and MMW isoforms were not statistically different.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape

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

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, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P &lt; 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display 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