Pleiotropic genes for metabolic syndrome and inflammation

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation. (C) 2014 Elsevier Inc. All rights reserved

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

Adult height is a classic polygenic trait of high heritability (h2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

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

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

A Prospective Study of Spectrum, Risk Factors and Immediate Outcome of Congenital Anomalies in Bida, North Central Nigeria

Background: Congenital disorders are structural, metabolic, behavioral and functional disorders that are present at birth. Their manifestations are protean ranging from mild anomalies to life‑threatening conditions. Aim: The objectives of this study were to describe the congenital anomalies in children seen at Federal Medical Center, Bida over a 12 month period, determine possible factors associated with these anomalies; and their short term outcome. Subjects and Methods: Children with clinically recognized congenital malformations were recruited consecutively over a 12 month period and socio‑demographic, etiologic and other relevant clinical data were obtained. A detailed examination was also performed and abnormalities documented. The data was analyzed using Epi‑info version 6 (Atlanta, USA). The Chi‑square was used to identify significant differences for categorical variables. Mid‑P and Fisher’s exact tests were utilized as appropriate. A P &lt; 0.05 was considered to be significant.Results: A total of 46 children with congenital anomalies were seen during the study period, all which were recruited into the study. The hospital based prevalence amongst neonates was 111/1000 neonates. The most common system affected was the digestive system (50.0%) followed by the central nervous system and head and neck anomalies. There was no significant difference in distribution of anomalies amongst the various ethnic groups. About 22% of families were consanguineous, all being first cousins and 8.7% of mothers were greater than 35 years of age. The case fatality rate for congenital malformations was 2.2%, while 60.9% were referred to other hospitals for further care. Conclusion: The study has demonstrated a wide variety of congenital anomalies in Bida, North‑Central Nigeria with the digestive system anomalies being the most frequent. The findings of this study strengthen the need for empowerment of the institution in appropriate management of these disorders.Keywords: Anomalies, Bida, Congenital malformation

Measles in a Tertiary Institution in Bida, Niger State, Nigeria: Prevalence, Immunization Status and Mortality Pattern

Objectives: Measles is a highly infectious immunizable disease with potential for eradication but is still responsible for high mortality among children, particularly in developing nations like Nigeria. This study aims to determine the hospital based prevalence of measles, describe the vaccination status of children managed for measles at the Federal Medical Centre, Bida, Niger state and to identify the parental disposition to measles vaccination.Methods: This is a cross-sectional study carried out over a period of 18 months beginning from July 2007. All children with a diagnosis of measles made clinically and reinforced with serological test in the WHO Measles, Rubella and Yellow Fever laboratory in Maitama District Hospital, Abuja were recruited. Informed consent was obtained from the parents/care givers. Structured questionnaire was used to obtain information and data analysis was by SPSS version 15.Results: One hundred and nine children were managed for measles, constituting 8�0of total admission over the study period. The male to female ratio was 1.2:1. Of the 109 children with measles, 90 (82�20did not receive measles vaccination. Eighty-eight (80�20of the parents or guardian felt vaccination was bad for various reasons. Of the 23 (21.1�20children whose parents or guardians were positively disposed to vaccination, one death was recorded while the remaining seven deaths were recorded among children whose parents were negatively disposed to vaccination. All the deaths were in the non-vaccinated group below 2 years of age.Conclusion: Measles is still a major health burden in our community. The majority of affected children were not vaccinated due to negative parental disposition. Continuous health education is required for change the disposition of the parents/guardian and improve vaccination coverage to minimize measles associated morbidity and mortality

Knowledge And Experience Of Work-Related Hazards And Utilization Of Safety Practices Among Solid Waste Scavengers In Ilorin Metropolis, Kwara State, Nigeria

Waste collection is considered one of the most dangerous job in the world since it exposes the workers to hazards as well as to certain occupation related morbidities. Health status of scavengers is therefore a public health concern, as they could be potential pathways for the transmission of various communicable diseases to the general public. This study assessed the awareness of work-related hazards and utilization of safety practices among Solid waste scavengers in Ilorin Metropolis. The study was a descriptive cross-sectional by design involving solid wastes Scavengers in Ilorin metropolis, North-central Nigeria. A total of 410 solid waste scavengers were recruited following a multi stage sampling method from all the 20 clusters of Scrap dealers. Data was obtained through the use of interviewer administered semi-structured questionnaire. Data was analyzed using SPSS Version 20. P-value of &lt;0.05 at 95% confidence limits were considered statistically significant. More than half (57.3%) of the respondents had awareness of work-related hazards. Similarly, more than half of the respondents have good knowledge of safety boots and hand gloves as ways of preventing work hazards with 58.3% and 56.8% respectively while poor knowledge was recorded for nose guard, face mask and overall/apron with 43.2%, 39.3% and 9.3% respectively. About two-thirds of the respondents, 65.1% have hand gloves however, only 33.2% were making use of it, 52.7% were willing to use it, 57.3% used it always, 74.2% used it for protection while 42.3% were not using it because they felt it was not important. Despite having fair knowledge on the importance of practicing safety measures, only few of the respondents practice these measures. The waste scavengers should be educated on the utilization of PPE and safety measure.Key words: waste scavengers, hazards, PPE, solid waste, Ilorin