Browsing by Author "Adeyemo, A.A."
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Item Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans(International Journal of Obesity, 2006-04) Bonilla, C.; Panguluri, R.K.; Taliaferro-Smith, L.; Argyropoulos, G.; Chen, G.; Adeyemo, A.A.; Amoah, A.; Owusu, S.; Acheampong, J.; Agyenim-Boateng, K.; Eghan Jr., B.A.; Oli, J.; Okafor, G.; Abbiyesuku, F.; Johnson, T.; Rufus, T.; Fasanmade, O.; Chen, Y.; Collins, F.S.; Dunston, G.M.; Rotimi, C.; Kittles, R.A.Objective: The role of the central melanocortin system in the development of obesity has been extensively studied. Single-nucleotide polymorphisms (SNPs) within several candidate genes have been associated with food intake and obesity-related phenotypes; however, few of these associations have been replicated. SNPs in the agouti-related protein (AGRP) gene coding (Ala67Thr, 199G/A) and promoter (-38C/T) have been reported to be associated with body mass index (BMI), fat mass (FM) and percent body fat, in populations of European and African descent. In this study, we evaluated the association between the functional AGRP -38C/T promoter SNP and weight-related traits, namely BMI, FM and fat-free mass (FFM), as well as diabetes status. Design: An association study of the AGRP -38C/T SNP and indices of obesity and diabetes status. Subjects: A well-characterized population of 538 West Africans from Ghana and Nigeria recruited in the AADM (Africa America Diabetes Mellitus) study (mean age 52 years, 41.3% males, 71% diabetic). Measurements: Genotyping of the AGRP -38C/T SNP, BMI, FM, FFM and fasting plasma glucose. Results: Women carrying two copies of the variant T allele had significantly lower BMI (OR = 0.47; 95% CI, 0.25-0.87). Also, men with at least one copy of the variant T allele were over two times less likely to be diabetic than other men (OR = 0.44; 95% CI, 0.22-0.89). Conclusion: Our results replicate previous findings and implicate the AGRP -38C/T SNP in the regulation of body weight in West Africans.Item Evaluation of genome wide association study associated type 2 diabetes susceptibility loci in sub Saharan Africans(Frontiers in Genetics, 2015-11) Adeyemo, A.A.; Tekola-Ayele, F.; Doumatey, A.P.; Bentley, A.R.; Chen, G.; Huang, H.; Zhou, J.; Shriner, D.; Fasanmade, O.; Okafor, G.; Eghan, B.Jr.; Agyenim-Boateng, K.; Adeleye, J.; Balogun, W.; Elkahloun, A.; Chandrasekharappa, S.; Owusu, S.; Amoah, A.; Acheampong, J.; Johnson, T.; Oli, J.; Adebamowo, C.; Collins, F.; Dunston, G.; Rotimi, C.N.Genome wide association studies (GWAS) for type 2 diabetes (T2D) undertaken in European and Asian ancestry populations have yielded dozens of robustly associated loci. However, the genomics of T2D remains largely understudied in sub-Saharan Africa (SSA), where rates of T2D are increasing dramatically and where the environmental background is quite different than in these previous studies. Here, we evaluate 106 reported T2D GWAS loci in continental Africans. We tested each of these SNPs, and SNPs in linkage disequilibrium (LD) with these index SNPs, for an association with T2D in order to assess transferability and to fine map the loci leveraging the generally reduced LD of African genomes. The study included 1775 unrelated Africans (1035 T2D cases, 740 controls; mean age 54 years; 59% female) enrolled in Nigeria, Ghana, and Kenya as part of the Africa America Diabetes Mellitus (AADM) study. All samples were genotyped on the Affymetrix Axiom PanAFR SNP array. Forty-one of the tested loci showed transferability to this African sample (p < 0.05, same direction of effect), 11 at the exact reported SNP and 30 others at SNPs in LD with the reported SNP (after adjustment for the number of tested SNPs). TCF7L2 SNP rs7903146 was the most significant locus in this study (p = 1.61 × 10-8). Most of the loci that showed transferability were successfully fine-mapped, i.e., localized to smaller haplotypes than in the original reports. The findings indicate that the genetic architecture of T2D in SSA is characterized by several risk loci shared with non-African ancestral populations and that data from African populations may facilitate fine mapping of risk loci. The study provides an important resource for meta-analysis of African ancestry populations and transferability of novel loci. © 2015 Adeyemo, Tekola-Ayele, Doumatey, Bentley, Chen, Huang, Zhou, Shriner, Fasanmade, Okafor, Eghan, Agyenim-Boateng, Adeleye, Balogun, Elkahloun, Chandrasekharappa, Owusu, Amoah, Acheampong, Johnson, Oli, Adebamowo, Collins, Dunston and Rotimi.Item A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population(Atherosclerosis, 2005-08) Adeyemo, A.A.; Johnson, T.; Acheampong, J.; Oli, J.; Okafor, G.; Amoah, A.; Owusu, S.; Agyenim-Boateng, K.; Eghan Jr., B.A.; Abbiyesuku, F.; Fasanmade, O.; Rufus, T.; Doumatey, A.; Chen, G.; Zhou, J.; Chen, Y.; Furbert-Harris, P.; Dunston, G.; Collins, F.; Rotimi, C.Lipid abnormalities are strongly linked with coronary heart disease and are common in type 2 diabetes. However, little is known about the genetic determinants of serum lipids in African populations. An autosomal genome scan was performed for linkage to five plasma lipid phenotypes (total cholesterol, triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and VLDL-cholesterol (VLDL-C)) in the Africa-America Diabetes Mellitus (AADM) study. Two hundred and ninety-five affected sibling pairs with type 2 diabetes mellitus enrolled from Ghana and Nigeria were genotyped for 390 microsatellite markers with an average inter-marker distance of 9 cM. Multipoint variance components linkage analysis showed that HDL-C had a LOD score of 4.34 near marker D7S3061 and 3.00 near marker D7S513. Some clustering of linkage evidence to several lipid phenotypes was observed on chromosomes 5 (LDL-C, total cholesterol, VLDL-C), chromosome 7 (HDL-C, TG) and chromosome 19 (total cholesterol, LDL-C, TG). Principal component analysis of the five phenotypes yielded two factors, one (TG, HDL-C and VLDL) of which was linked to QTLs on chromosomes 2, 5 and 7, while the other (total cholesterol and LDL-C) was linked to a different set of QTLs on chromosomes 2, 5 and 18. Several of these regions have been reported to be linked to lipids in other studies. Follow up investigations are warranted in view of the central role serum lipids play in the aetiopathogenesis of cardiovascular disease. © 2005 Elsevier Ireland Ltd. All rights reserved.Item A genome-wide scan for quantitative trait loci linked to obesity phenotypes among West Africans(International Journal of Obesity, 2005-03) Chen, G.; Adeyemo, A.A.; Johnson, T.; Zhou, J.; Amoah, A.; Owusu, S.; Acheampong, J.; Agyenim-Boateng, K.; Eghan Jr., B.A.; Oli, J.; Okafor, G.; Abbiyesuku, F.; Dunston, G.M.; Chen, Y.; Collins, F.; Rotimi, C.OBJECTIVE: To identify quantitative trait loci (QTL) for three obesity phenotypes: body mass index (BMI), fat mass (FM) and percent body fat (PBF) in West Africans with type 2 diabetes (T2DM). DESIGN: An affected sibling pair (ASP) design, in which both siblings had T2DM. Obesity was analyzed as a quantitative trait using a variance components approach. SUBJECTS: Sib-pairs affected with T2DM from the Africa America Diabetes Mellitus (AADM) study, comprising 321 sibling pairs and 36 half-sibling pairs. MEASUREMENTS: Weight was measured on an electronic scale to the nearest 0.1 kg, and height was measured with a stadiometer to the nearest 0.1 cm. Body composition was estimated using bioelectric impedance analysis (BIA). Genotyping was carried out at the Center for Inherited Disease Research (CIDR) with a panel of 390 trinucleotide and tetranucleotide repeats. RESULTS: The obesity-related phenotype showing the strongest linkage evidence was PBF on chromosome 2 (LOD 3.30 at 72.6 cM, marker D2S739). Suggestive linkage to FM was found on chromosomes 2 (LOD 2.56 at 80.4 cM) and 5 (LOD 2.25 at 98 cM, marker D5S1725). The highest LOD score for BMI was 1.68 (chromosome 4, 113.8 cM). The areas of linkage for the three phenotypes showed some clustering as all three phenotypes were linked to the same regions of 2p13 and 5q14, and our study replicated linkage evidence for several regions previously reported in other studies. CONCLUSION: We obtained evidence for several QTLs on chromosome 2, 4 and 5 to three obesity phenotypes. This study provides data on the genetics of obesity in populations that are currently under represented in the global effort directed at understanding the pathophysiology of excess adiposity in free living individuals.Item A genome-wide search for linkage to renal function phenotypes in West Africans with type 2 diabetes(American Journal of Kidney Diseases, 2007-03) Chen, G.; Adeyemo, A.A.; Zhou, J.; Chen, Y.; Doumatey, A.; Lashley, K.; Huang, H.; Amoah, A.; Agyenim-Boateng, K.; Eghan Jr., B.A.; Okafor, G.; Acheampong, J.; Oli, J.; Fasanmade, O.; Johnson, T.; Rotimi, C.Background: Reduced renal function often is a major consequence of diabetes and hypertension. Although several indices of renal function (eg, creatinine clearance) are clearly heritable and show linkage to several genomic regions, the specific underlying genetic determinants are still being sought. The purpose of this study is to conduct a genome-wide search for regions linked to 3 renal function phenotypes, serum creatinine, creatinine clearance, and glomerular filtration rate (GFR), in persons with type 2 diabetes. Methods: A genome-wide panel of 372 autosomal short tandem repeat markers at an average spacing of 9 centimorgan were typed in 691 patients with type 2 diabetes (321 sib pairs and 36 half-sib pairs) in an affected sib pair study in West Africa. Linkage analysis was conducted with the 3 phenotypes by using a multipoint variance components linkage method. Results: Creatinine clearance showed higher logarithm of odds (LOD) score than the other 2 phenotypes. Linkage to creatinine clearance was observed on chromosomes 16 (marker D16S539, LOD score of 3.56, empirical P = 0.0001), 17 (D17S1298, LOD score of 2.08, empirical P = 0.0018), and 7 (D7S1818, LOD score of 1.84, nominal P = 0.00181, empirical P = 0.0022). Maximum LOD scores for serum creatinine were observed on chromosomes 10 (D10S1432, LOD score of 2.53, empirical P = 0.0001) and 3 (D3S2418, LOD score of 2.21, empirical P = 0.0003) and for GFR on chromosomes 6 (D6S1040, LOD score of 2.08, empirical P = 0.0001) and 8 (D8S256, LOD score of 1.80, empirical P = 0.0001). Several of these results are replications of significant findings from other genome scans. Conclusion: A genome-wide scan for serum creatinine, creatinine clearance, and GFR in a West African sample showed linkage regions that may harbor genes influencing variation in these phenotypes. Potential candidate genes in these regions that have been implicated in diabetic nephropathy and/or renal damage in models of hypertension include CYBA (or P22PHOX) (16q24), NOX1 (10q22), and NOX3 (6q25.1-q26)Item A Genome-Wide Search for Type 2 Diabetes Susceptibility Genes in West Africans: The Africa America Diabetes Mellitus (AADM) Study(Diabetes, 2004-04) Rotimi, C.N.; Chen, G.; Adeyemo, A.A.; Furbert-Harris, P.; Guass, D.; Zhou, J.; Berg, K.; Adegoke, O.; Amoah, A.; Owusu, S. et.al.The incidence of type 2 diabetes is growing rapidly, not only in developed countries but also worldwide. We chose to study type 2 diabetes in West Africa, where diabetes is less common than in the U.S., reasoning that in an environment where calories are less abundant, incident cases of type 2 diabetes might carry a proportionately greater genetic component. Through the Africa America Diabetes Mellitus (AADM) study, we carried out a genome-wide linkage analysis of type 2 diabetes in a cohort of 343 affected sibling pairs (691 individuals) enrolled from five West African centers in two countries (Ghana: Accra and Kumasi; Nigeria: Enugu, Ibadan, and Lagos). A total of 390 polymorphic markers were genotyped, and multipoint linkage analysis was conducted using the GENEHUNTER-PLUS and ASM programs. Suggestive evidence of linkage was observed in four regions on three chromosomes (12, 19, and 20). The two largest logarithm of odds scores of 2.63 and 1.92 for chromosomes 20q13.3 and 12q24, respectively, are particularly interesting because these regions have been reported to harbor diabetes susceptibility genes in several other populations and ethnic groups. Given the history of forced migration of West African populations during the slave trade, these results should have considerable relevance to the study of type 2 diabetes in African Americans.Item Genomewide scan and fine mapping of quantitative trait loci for intraocular pressure on 5q and 14q in West Africans.(Investigative Ophthalmology & Visual Science, 2006) Rotimi, C.N.; Chen, G.; Adeyemo, A.A.; L.S., Jones; Agyenim-Boateng, K.; Eghan, B.A. Jr.; Zhou, J.; Doumatey, A.; Lashley, K.; Huang, H.; Fasanmade, O.; Akinsola, F.B.; Ezepue, F.; Amoah, A.; Akafo, S.; Chen, Y.; Oli, J.; Johnson, T.High intraocular pressure (IOP) is a major risk factor for glaucoma, one of the leading causes of blindness worldwide. Because it has been demonstrated that African populations are at increased risk for glaucoma, the authors investigated the genetic basis of IOP in a sample of West Africans with type 2 diabetes (T2D) from Ghana and Nigeria. METHODS: Genomewide linkage analysis was conducted for loci linked to IOP (measured by applanation tonometry) in 244 affected sibling pairs with T2D using 372 autosomal short-tandem repeat markers at an average spacing of 9 cM. RESULTS: Multipoint variance components linkage analyses revealed suggestive linkage on chromosome 5 (5q22) with a logarithm of odds (LOD) score of 2.50 (nominal P = 0.0003; empiric P = 0.0004) and on chromosome 14 (14q22) with an LOD score of 2.95 (nominal P = 0.0001; empiric P = 0.0003). Fine mapping at a marker density of 2 cM in the 5q region confirmed the linkage signal, with an increase in peak LOD score to 4.91. CONCLUSIONS: The strong signal on chromosome 5 lies in the region in which a novel gene, WDR36, in the GLC1G locus was recently identified as causative for adult-onset primary open-angle glaucoma and provides additional evidence that chromosome 5 contains susceptibility loci for glaucoma in multiple human populations. The evidence provided in this study is particularly important given the evolutionary history of these West African populations and the recent ancestral relationship to African Americans-a population with one of the highest rates of diabetes and associated complications (including glaucoma) in the world.Item Relationships among obesity, inflammation, and insulin resistance in african americans and west africans(Obesity, 2010-03) Doumatey, A.P.; Lashley, K.S.; Huang, H.; Zhou, J.; Chen, G.; Amoah, A.; Agyenim-Boateng, K.; Oli, J.; Fasanmade, O.; Adebamowo, C.A.; Adeyemo, A.A.; Rotimi, C.N.Several research studies in different populations indicate that inflammation may be the link between obesity and insulin resistance (IR). However, this relationship has not been adequately explored among African Americans, an ethnic group with disproportionately high rates of obesity and IR. In this study, we conducted a comparative study of the relationship among adiposity, inflammation, and IR in African Americans and West Africans, the ancestral source population for African Americans. The associations between obesity markers (BMI and waist-to-hip ratio (WHR)), inflammatory markers (high-sensitivity C-reactive protein (hsCRP), haptoglobin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α), and IR (homeostasis model assessment of insulin resistance (HOMA IR)) were evaluated in 247 West Africans and 315 African Americans. In average, African Americans were heavier than the West Africans (by an average of 1.6 BMI units for women and 3 BMI units for men). Plasma hsCRP, haptoglobin, and IL-6 (but not TNF-α level) were higher in African Americans than in West Africans. In both populations, BMI was associated with markers of inflammation and with HOMA IR, and these associations remained significant after adjusting for sex and age. However, the pattern of associations between measured inflammatory markers and IR was different between the two groups. In West Africans, hsCRP was the only inflammatory marker associated with IR. In contrast, hsCRP, haptoglobin, and IL-6 were all associated with IR in African Americans. Interestingly, none of the associations between markers of inflammation and IR remained significant after adjusting for BMI. This finding suggests that in African Americans, the relationship between inflammatory markers and IR is mediated by adiposity.Item ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response(nature communications, 2019-06-11) Owusu, S.; Adeyemo, A.A.; Zaghloul, N.A.; Chen, G.; Doumatey, A.P.; Leitch, C.C.; Hostelley, T.L.; Nesmith, J.E.; Zhou, J.; Bentley, A.R.; Shriner, D.; Fasanmade, O.; Okafor, G.; Eghan, B.J.; Agyenim-Boateng, K.; Chandrasekharappa, S.; Adeleye, J.; Balogun, W.; Owusu, S.; Amoah, A.; Acheampong, J.; Johnson, T.; Oli, J.; Adebamowo, C.; Collins, F.; Dunston, G.; Rotimi, C.N.Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10−9). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.