Eestlased laias maailmas katastroofiohvreid abistamas

Eesti Arst 2015; 94(6):379–38

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

Covered versus uncovered self-expandable nitinol stents in the palliative treatment of malignant distal biliary obstruction: results from a randomized, multicenter study

Background: Covered biliary metal stents have been developed to prevent tumor ingrowth. Previous comparative studies are limited and often include few patients. Objective: To compare differences in stent patency, patient survival, and complication rates between covered and uncovered nitinol stents in patients with malignant biliary obstruction. Design: Randomized, multicenter trial conducted between January 2006 and October 2008. Setting: Ten sites serving a total catchment area of approximately 2.8 million inhabitants. Patients: A total of 400 patients with unresectable distal malignant biliary obstruction. Interventions: ERCP with insertion of covered or uncovered metal stent. Follow-up conducted monthly for symptoms indicating stent obstruction. Main Outcome Measurements: Time to stent failure, survival time, and complication rate. Results: The patient survival times were 116 days (interquartile range 242 days) and 174 days (interquartile range 284 days) in the covered and uncovered stent groups, respectively (P = .320). The first quartile stent patency time was 154 days in the covered stent group and 199 days in the uncovered stent group (P = .326). There was no difference in the incidence of pancreatitis or cholecystitis between the 2 groups. Stent migration occurred in 6 patients (3%) in the covered group and in no patients in the uncovered group (P = .030). Limitations: Randomization was not blinded. Conclusions: There were no significant differences in stent patency time, patient survival time, or complication rates between covered and uncovered nitinol metal stents in the palliative treatment of malignant distal biliary obstruction. However, covered stents migrated significantly more often compared with uncovered stents, and tumor ingrowth was more frequent in uncovered stents. (Clinical trial registration number: NCT00280709.) (Gastrointest Endosc 2010;72:915-23.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9-10-9 to P = 1.8-10-40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9-10-3 to P = 1.2-10-13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation