New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

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

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Genomic and functional analysis of multidrug resistant bacteria

La résistance aux antibiotiques est une problématique mondiale majeure. Le caractère alarmant de cette situation a conduit à une surveillance active des bactéries résistantes aux carbapénèmes et/ou à la colistine. Ce projet de thèse intitulé « Analyse génomique et fonctionnelle de bactéries multi-résistantes » a ainsi été divisé en trois objectifs : i) faire le point sur les différentes approches à utiliser ainsi que sur les nouveaux axes à considérer pour pouvoir découvrir de nouveaux gènes de résistance aux antibiotiques, ii) exposer l’apport de la biologie moléculaire et la génomique dans la détection et l’étude de la résistance aux carbapénèmes, iii) décrire l’apport de ces approches dans l’étude de la résistance chromosomique et plasmidique à la colistine dans divers pays et divers écosystèmes. Des associations synergiques d’antibiotiques capables de reverser cette résistance ont été également proposées comme alternative thérapeutique.Antibiotic resistance is a major global issue. The alarming nature of this situation has led to active surveillance of bacteria resistant to carbapenems and/or colistin. This thesis project entitled "Genomic and functional analysis of multidrug resistant bacteria" was thus divided into three objectives: (i) to provide an overview of the different approaches to be used and the new approaches to be considered in order to discover new antibiotic resistance genes, (ii) to present the contribution of molecular biology and genomics in the detection and study of carbapenem resistance, (iii) to describe the contribution of these approaches in studying chromosome and plasmid resistance to colistin in various countries and ecosystems. Synergistic combinations of antibiotics capable of reversing this resistance have also been proposed as a therapeutic alternative

Co-occurrence of carbapenemase encoding genes in Acinetobacter baumannii, a dream or reality?

International audienceBackground: Acinetobacter baumannii is an important opportunistic pathogen that is rapidly evolving towards multidrug resistance and is responsible for life-threatening infections. Carbapenems are commonly used to treat A. baumannii infections but the emergence of carbapenemase encoding genes, such as bla(OXA-23-like), bla(OXA-24-like), bla(OXA-58-like), and bla(NDM) has been reported. Moreover, several studies have reported the co-occurrence of two distinct carbapenemases in some isolates. The aim of the present study is to demonstrate whether the phenomenon of co-occurrence of two distinct carbapenemase encoding genes in a single isolate still exists. Results: We studied six strains of A. baumannii including one harboring bla(OXA-23-like) and bla(OXA-24-like) genes and five with bla(OXA-23-like) and bla(NDM) genes. One colony of each strain was inoculated in sterile water and diluted ten-fold. Each dilution was cultivated on trypticase soy agar plates for 24 h at 37 degrees C and the isolated bacteria were analyzed. For two of the six tested strains, we identified two different populations of A. baumannii, each with a different carbapenemase, genes encoding aminoglycoside modifying enzymes, resistance phenotype, and clonal type. In addition, the two different populations had the same aspect on the agar plate. Conclusions: Here, we demonstrate that A. baumannii infections could be linked to multiple clones harboring different carbapenemase encoding genes in the same sample. In addition, we describe an easy method of verifying the presence of co-occurrence of carbapenemase in one isolate

Comparative genomics of two Shewanella xiamenensis strains isolated from a pilgrim before and during travels to the Hajj

International audienceAbstract Background Shewanella xiamenensis has been reported in water environment and in patients and can act as the originator of oxacillinase in gram-negative bacteria. In order to assess genome plasticity and its functional properties related diarrhea symptoms in pilgrim, comparisons of draft genome sequences of the two isolates were conducted with other closely related genomes. Results We isolated S. xiamenensis 111B and 111D strains from a pilgrim before travels to the Hajj and during travels with diarrhea symptom, respectively. Whole-genome sequencing showed that draft genome size of 111B strain was 5,008,191 bp, containing 49 kb of a putative plasmid. The genome size of 111D was 4,964,295 bp containing 225 kb of a putative plasmid that shared the backbone sequences with the hospital wastewater strain T17. Comparatively, two Hajj strains are identical at 97.3% identity and 98.7% coverage. They are closely related to river water strain, AS58 by SNPs analysis. Notably, a novel bla OXA-48 allele bla OXA-547 was identified in 111D, sharing 99.5% identity with bla OXA-546 and bla OXA-894 . Multiple copies of virulence specific genes, such as capsular polysaccharide biosynthesis, O-antigen and lasB (vibriolysin related gene) have been identified specifically in 111D, but absent in 111B strain. Conclusions The whole genome sequences of S. xiamenensis strain 111B and 111D, including comparative genomic analysis, highlight here the potential for virulence factors that might be related to the cause of diarrhea in humans and also indicate the possible acquisition of pathogenic bacteria, including antibiotic resistance genes or plasmids during the Hajj

Dual infections of two carbapenemase-producing Acinetobacter baumannii clinical strains isolated from the same blood culture sample of a patient in Iran

Abstract In this study, the draft genome sequences of two different carbapenem-resistant Acinetobacter baumannii clinical strains isolated from the same blood culture sample of an Iranian patient were determined. The strain A. baumannii 554S harbouring bla oxa72 gene belonged to ST 307 whereas A. baumannii 554L carrying bla oxa23 gene belonged to ST 2. We found that this sample contains two different isolates of A. baumannii, each phenotypically and genetically different