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Impaired glucose tolerance is a major risk factor for type 2 diabetes (T2D) and several cardiometabolic disorders. To identify genetic loci underlying fasting glucose levels, we conducted an analysis of 9,232 individuals of European ancestry who at enrollment were either nondiabetic or had untreated type 2 diabetes. Multivariable linear mixed models were used to test for associations between fasting glucose and 7.9 million SNPs, with adjustment for age, body mass index (BMI), sex, significant principal components of the genotypes, and cryptic relatedness. Three previously discovered loci were genome-wide significant, with the lead SNPs being rs1260326, a missense variant in GCKR ( p = 1.06×10 −8 ); rs560887, an intronic variant in G6PC2 ( p = 3.39×10 −11 ); and rs13266634, a missense variant in SLC30A8 ( p = 4.28×10 −10 ). Fine mapping, genome-wide conditional analysis, and functional annotation indicated that the three loci were independently associated with fasting glucose. Each copy of an alternate allele at any of these three SNPs was associated with a reduction of 0.012 mmol/L in fasting glucose levels ( p = 8.0×10 −28 ), and this association was replicated in trans-ethnic analysis of 14,303 individuals ( p = 2.2×10 −16 ). The three SNPs were jointly associated with significantly reduced T2D risk, with an odds ratio (95% CI) of 0.93 (0.88, 0.98) per protective allele. Our findings implicate additive effects across pathophysiological pathways involved in type 2 diabetes, including glycolysis, gluconeogenesis, and insulin secretion. Since none of the individuals homozygous for the alternate alleles at all three loci has T2D, it might be possible to use a genetic predictor of fasting glucose levels to identify individuals at low vs . high risk of developing type 2 diabetes.

Gut dysbiosis has been associated with several disease outcomes including diabetes in human populations. Currently, there are no studies of the gut microbiome composition in relation to type 2 diabetes (T2D) in Africans. Here, we describe the profile of the gut microbiome in non-diabetic adults (controls) and investigate the association between gut microbiota and T2D in urban West Africans. Gut microbiota composition was determined in 291 Nigerians (98 cases, 193 controls) using fecal 16S V4 rRNA gene sequencing done on the Illumina MiSeq platform. Data analysis of operational taxonomic units (OTU) was conducted to describe microbiome composition and identify differences between T2D and controls. The most abundant phyla were , and . , and were significantly lower in cases than controls ( < 0.001). Feature selection analysis identified a panel of 18 OTUs enriched in cases that included . A panel of 17 OTUs that was enriched in the controls included , and . OTUs with strain-level annotation showing the largest fold-change included (log FC = -3.1; = 4.2 × 10 ), (log FC = -2.5; = 0.005), (log FC = -1.76; = 0.01), all lower in cases. These findings are notable because supplementation with and has been shown to improve hyperglycemia and reduce insulin resistance in murine models. This first investigation of gut microbiome and diabetes in urban Africans shows that T2D is associated with compositional changes in gut microbiota highlighting the possibility of developing strategies to improve glucose control by modifying bacterial composition in the gut.

Background X chromosome inactivation (XCI) refers to silencing of genes on one copy of the X chromosome in XX females, resulting in dosage compensation between XX females and XY males. Genes can escape this silencing, potentially leading to sex-based differences in disease. Results Across three primary tissue types, we determined XCI status by integrating whole-genome sequencing with bulk RNA-Seq data to assess allele-specific expression (ASE) at heterozygous SNPs. Across all genes and tissues, the average percentage of individuals showing escape was 4.7%. We show that models of full dosage compensation and no dosage compensation are strongly correlated over most parameter space. For G6PD deficiency, we illustrate that in G6PD*B/G6PD*A- heterozygotes, even if silencing is complete and escape is not associated with disease risk, the allele that is expressed can affect mRNA abundance. Conclusions With respect to studies of the genetic architecture of complex traits, our results suggest that a model of full dosage compensation, although not strictly correct for much of chromosome X, is more appropriate than a model of no dosage compensation. We conclude that uncertainty about the model of dosage compensation should not be an impediment to analysis of chromosome X in genetic epidemiology studies.

Aims/hypothesisGenome-wide association studies (GWAS) for type 2 diabetes have uncovered >400 risk loci, primarily in populations of European and Asian ancestry. Here, we aimed to discover additional type 2 diabetes risk loci (including African-specific variants) and fine-map association signals by performing genetic analysis in African populations.MethodsWe conducted two type 2 diabetes genome-wide association studies in 4347 Africans from South Africa, Nigeria, Ghana and Kenya and meta-analysed both studies together. Likely causal variants were identified using fine-mapping approaches.ResultsThe most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10−13). Fine-mapping of the TCF7L2 locus suggested one type 2 diabetes association signal shared between Europeans and Africans (indexed by rs7903146) and a distinct African-specific signal (indexed by rs17746147). We also detected one novel signal, rs73284431, near AGMO (p = 5.2 × 10−9, minor allele frequency [MAF] = 0.095; monomorphic in most non-African populations), distinct from previously reported signals in the region. In analyses focused on 100 published type 2 diabetes risk loci, we identified 21 with shared causal variants in African and non-African populations.Conclusions/interpretationThese results demonstrate the value of performing GWAS in Africans, provide a resource to larger consortia for further discovery and fine-mapping and indicate that additional large-scale efforts in Africa are warranted to gain further insight in to the genetic architecture of type 2 diabetes.

Elevated triglycerides (TG) are a risk factor for cardiometabolic disorders. There are limited data on lipidomics profiles associated with serum triglycerides concentrations, although these could advance our understanding of the mechanisms underlying these associations. We conducted a lipidomics study of 308 Nigerians with replication in 199 Kenyans. Regression models were used to assess the association of TG with 480 lipid metabolites. Association and mediation analyses were conducted to determine the relationship among TG, metabolites, and several cardiometabolic traits. Ninety-nine metabolites were significantly associated with TG, and 91% of these associations replicated. Overrepresentation analysis identified enrichment of diacylglycerols, monoacylglycerols, diacylglycerophosphoethanolamines, monoacylglycerophosphocholines, ceramide phosphocholines, and diacylglycerophosphocholines. TG-cardiometabolic trait associations were largely mediated by TG-associated metabolites. Associations with type 2 diabetes, waist circumference, body mass index, total cholesterol, and low-density lipoprotein cholesterol concentration were independently mediated by metabolites in multiple subpathways. This lipidomics study in sub-Saharan Africans demonstrated that TG is associated with several non-TG lipids classes, including phosphatidylethanolamines, phosphatidylcholines, lysophospholipids, and plasmalogens, some of which may mediate the effect of TG as a risk factor for cardiometabolic disorders. The study identifies metabolites that are more proximal to cardiometabolic traits, which may be useful for understanding the underlying biology as well as differences in TG-trait associations across ancestries.

ApolipoproteinL1 (APOL1) protects humans and some primates against several African trypanosomes. APOL1 genetic variants strongly associated with kidney disease in African Americans have additional trypanolytic activity against Trypanosoma brucei rhodesiense , the cause of acute African sleeping sickness. We combined genetic, physiological, and biochemical studies to explore coevolution between the APOL1 gene and trypanosomes. We analyzed the APOL1 sequence in modern and archaic humans and baboons along with geographic distribution in present day Africa to understand how the kidney risk variants evolved. Then, we tested Old World monkey, human, and engineered APOL1 variants for their ability to kill human infective trypanosomes in vivo to identify the molecular mechanism whereby human trypanolytic APOL1 variants evade T. brucei rhodesiense virulence factor serum resistance-associated protein (SRA). For one APOL1 kidney risk variant, a two-residue deletion of amino acids 388 and 389 causes a shift in a single lysine residue that mimics the Old World monkey sequence, which augments trypanolytic activity by preventing SRA binding. A second human APOL1 kidney risk allele, with an amino acid substitution that also restores sequence alignment with Old World monkeys, protected against T. brucei rhodesiense due in part to reduced SRA binding. Both APOL1 risk variants induced tissue injury in murine livers, the site of transgenic gene expression. Our study shows that both genetic variants of human APOL1 that protect against T. brucei rhodesiense have recapitulated molecular signatures found in Old World monkeys and raises the possibility that APOL1 variants have broader innate immune activity that extends beyond trypanosomes.

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1 , was downregulated in cases (q = 3.26 × 10 −9 ) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response ( CEACAM5 ; p = 9.62 × 10 −16 and CPA3 ; p = 2.39 × 10 −14 ) and wound healing ( FN1 ; p = 7.63 × 10 −9 ). Multi-omic analysis identifies FKBP5 , a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora. Here, the authors suggest that molecular dysregulation on three axes may play a critical role in asthma within the African Diaspora. RNASeq and DNA methylation data are generated from nasal epithelium including cases and controls from seven different geographic sites.

Adiponectin has been associated with cardiometabolic traits in observational studies across populations, yet it is unclear if these associations are causal. We performed Mendelian randomization (MR) analysis to assess the relationship between adiponectin and cardiometabolic traits in sub-Saharan Africans. We constructed a polygenic risk score (PRS) for adiponectin levels across 3354 unrelated sub-Saharan Africans. The PRS was used as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, Type 2 Diabetes (T2D), and hypertension. The adiponectin PRS was causally related with LDL (β = 0.55, 95%CI 0.07–1.04, P- value = 0.024) but not the other traits. This association was observed in both overweight/obese and normal weight individuals, but only reached statistical significance among overweight/obese individuals (β = 0.55, 95%CI 0.01–1.08, P -value = 0.045). In normal weight individuals, the adiponectin PRS was associated with T2D (OR = 0.13, 95%CI 0.02–0.73, P -value = 0.021), and in men with HDL (β = 1.03, 95%CI 0.14–1.92, P-value  = 0.023). The findings of this first MR study in sub-Saharan Africans support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. These observations add to the small but growing literature on adiponectin MR studies.

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12–q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations. The burden of asthma varies between ancestries, but GWAS have so far focused on mainly European ancestry populations. Here, Daya et al. perform GWAS for asthma in 14,654 individuals of African ancestry and, besides confirming previously known loci, identify two potentially African ancestry-specific loci.

Background In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses. Methods We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals ( n  = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones). Results Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β  =  − 0.67, P -value = 1.88 × 10 −6 and HOMA-B β  = 0.59, P -value = 1.88 × 10 −5 ; IL-1RA ~ HOMA-S  β  =  − 0.51,  P -value = 8.49 × 10 −5 and HOMA-B β  = 0.48,  P -value = 5.71 × 10 −4 ). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P -value = 9.79 × 10 −6 ), though these associations were not consistent in all sensitivity analyses. Conclusions The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.