[Show abstract][Hide abstract] ABSTRACT: 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.
Molecular Genetics and Metabolism 05/2014; · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pharmacogenomically relevant markers of drug response and adverse drug reactions are known to vary in frequency across populations. We examined minor allele frequencies (MAFs), genetic diversity (FST) and population structure of 1156 genetic variants (including 42 clinically actionable variants) in 212 genes involved in drug absorption, distribution, metabolism and excretion (ADME) in 19 populations (n=1478). There was wide population differentiation in these ADME variants, reflected in the range of mean MAF (ΔMAF) and FST. The largest mean ΔMAF was observed in African ancestry populations (0.10) and the smallest mean ΔMAF in East Asian ancestry populations (0.04). MAFs ranged widely, for example, from 0.93 for single-nucleotide polymorphism (SNP) rs9923231, which influences warfarin dosing to 0.01 for SNP rs3918290 associated with capecitabine metabolism. ADME genetic variants show marked variation between and within continental groupings of populations. Enlarging the scope of pharmacogenomics research to include multiple global populations can improve the evidence base for clinical translation to benefit all peoples.The Pharmacogenomics Journal advance online publication, 9 July 2013; doi:10.1038/tpj.2013.24.
The Pharmacogenomics Journal 07/2013; · 5.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.
Journal of the American Society of Nephrology 04/2013; · 8.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10-11) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10-10). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10-8). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10-7), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
[Show abstract][Hide abstract] ABSTRACT: High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 x 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
The American Journal of Human Genetics 01/2013; 93(3):545-54. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Muscle biopsy is a minor surgical procedure that has been conducted over several decades in clinical practice. Over the years, the technique to implement this procedure has been modified to make it easier to perform and more tolerable for the patient. This study aimed to assess the feasibility of muscle biopsy as an office based procedure, by using a vacuum Assisted Biopsy System.
The procedure was successfully carried out on 57 individuals with/without diabetes, currently involved in the African American Diabetes Mellitus Study. One specimen was collected percutaneously from the vastus lateralis, under local anesthesia. A 16-gauge needle was used.
Muscle biopsies were successfully carried out on all study participants. The study participants reported no complications after the procedure.
The findings from our study show that muscle biopsy can be feasibly implemented as an office based procedure, involving minimal muscle invasion, less trauma, hospital stay time, and expenses.
African journal of medicine and medical sciences 09/2012; 41(3):313-6.
[Show abstract][Hide abstract] ABSTRACT: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs.
We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ±250 kb around each EuA SNP in AfAs.
Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r ( 2 ) < 0.2), suggesting allelic heterogeneity for association with FG at these loci.
Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.
Human Molecular Genetics 07/2012; 21(20):4530-6. · 7.69 Impact Factor
New England Journal of Medicine 03/2012; HLA class II locus and susceptibility to podoconiosis. Tekola Ayele F, Adeyemo A, Finan C, Hailu E, Sinnott P, Burlinson ND, Aseffa A, Rotimi CN, Newport MJ, Davey G. N Engl J Med. 2012 Mar 29;366(13):1200-8.(366). · 51.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathway-focused association approach offers a hypothesis driven alternative to the agnostic genome-wide association study. Here we apply the pathway-focused approach to an association study of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in 1614 Nigerians with genome-wide data.
Testing of 28 pathways with biological relevance to hypertension, selected a priori, containing a total of 101 unique genes and 4,349 unique single-nucleotide polymorphisms (SNPs) showed an association for the adrenergic alpha 1 (ADRA1) receptor pathway with hypertension (p<0.0009) and diastolic blood pressure (p<0.0007). Within the ADRA1 pathway, the genes PNMT (hypertension P(gene)<0.004, DBP P(gene)<0.004, and SBP P(gene)<0.009, and ADRA1B (hypertension P(gene)<0.005, DBP P(gene)<0.02, and SBP P(gene)<0.02) displayed the strongest associations. Neither ADRA1B nor PNMT could be the sole mediator of the observed pathway association as the ADRA1 pathway remained significant after removing ADRA1B, and other pathways involving PNMT did not reach pathway significance.
We conclude that multiple variants in several genes in the ADRA1 pathway led to associations with hypertension and DBP. SNPs in ADRA1B and PNMT have not previously been linked to hypertension in a genome-wide association study, but both genes have shown associations with hypertension through linkage or model organism studies. The identification of moderately significant (10(-2)>p>10(-5)) SNPs offers a novel method for detecting the "missing heritability" of hypertension. These findings warrant further studies in similar and other populations to assess the generalizability of our results, and illustrate the potential of the pathway-focused approach to investigate genetic variation in hypertension.
PLoS ONE 01/2012; 7(5):e37145. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adiponectin, a protein secreted by adipose tissue, has been associated with renal dysfunction. However, these observations have not been adequately investigated in large epidemiological studies of healthy individuals in general and in African populations in particular. Hence, we designed this study to evaluate the relationship between adiponectin and renal function in a large group of nondiabetic West Africans. Total adiponectin was measured in 792 participants. MDRD and Cockroft-Gault (CG-) estimated GFR were used as indices of renal function. Linear and logistic regression models were used to determine the relationship between adiponectin and renal function. Adiponectin showed an inverse relationship with eGFR in univariate (Beta(MDRD) = -0.18, Beta(CG) = -0.26) and multivariate (Beta(MDRD) = -0.10, Beta(CG) = -0.09) regression analyses. The multivariate models that included age, sex, BMI, hypertension, smoking, HDL-C, LDL-C, triglycerides, and adiponectin explained 30% and 55.6% of the variance in GFR estimated by MDRD and CG methods, respectively. Adiponectin was also a strong predictor of moderate chronic kidney disease (defined as eGFR < 60 mL/min/1.73 m(2)). We demonstrate that adiponectin is associated with renal function in nondiabetic West Africans. The observed relationship is independent of age and serum lipids. Our findings suggest that adiponectin may have clinical utility as a biomarker of renal function.
International journal of nephrology. 01/2012; 2012:730920.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have been successful in detecting common genetic variants underlying common traits and diseases. Despite the GWAS success stories, the percent trait variance explained by GWAS signals, the so called "missing heritability" has been, at best, modest. Also, the predictive power of common variants identified by GWAS has not been encouraging. Given these observations along with the fact that the effects of rare variants are often, by design, unaccounted for by GWAS and the availability of sequence data, there is a growing need for robust analytic approaches to evaluate the contribution of rare variants to common complex diseases. Here we propose a new method that enables the simultaneous analysis of the association between rare and common variants in disease etiology. We refer to this method as SCARVA (simultaneous common and rare variants analysis). SCARVA is simple to use and is efficient. We used SCARVA to analyze two independent real datasets to identify rare and common variants underlying variation in obesity among participants in the Africa America Diabetes Mellitus (AADM) study and plasma triglyceride levels in the Dallas Heart Study (DHS). We found common and rare variants associated with both traits, consistent with published results.
Bioinformatics and biology insights 01/2012; 6:1-9.
[Show abstract][Hide abstract] ABSTRACT: Adult height is a classic polygenic trait of high heritability (h(2) approximately 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 approximately10% 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10(-5)). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10(-7) for SBP and 7.52 × 10(-7) for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.
Human Molecular Genetics 03/2011; 20(11):2285-95. · 7.69 Impact Factor