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Background There is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. GRS for cardiometabolic traits were evaluated in sub-Saharan Africans in comparison with African Americans and European Americans. Methods We evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n = 5200), African Americans (AA; n = 9139) and European Americans (EUR; n = 9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and the increase in discriminatory ability over traditional risk factors [age, sex and body mass index (BMI)], with adjustment for ancestry-derived principal components. Results Across all traits, GRS showed up to a 5-fold and 20-fold greater predictive utility in EUR relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percentage increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EUR, 26.6% to 65.8% among AA and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EUR relative to AA and up to 44-fold greater in EUR relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EUR. Conclusions This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiple ethnic populations in genomic studies to ensure equitable clinical translation of GRS.

Significance HLA alleles have previously been implicated with scleroderma risk, but, in this study, using a European American ancestral cohort and a newly recruited large cohort of African Americans, we comprehensively define the HLA alleles and amino acid residues associated with scleroderma. Scleroderma is characterized by mutually exclusive and specific autoantibodies. We demonstrated ancestry-predominant HLA alleles that were much more strongly associated with autoantibody subsets of scleroderma than with the overall risk of SSc. We bioinformatically predicted immunodominant peptides of self-antigens and demonstrated homology of these peptides with viral protein sequences from Mimiviridae and Phycodnaviridae families. Our findings suggest the hypothesis that scleroderma-specific autoantibodies may arise through molecular mimicry, driven by the interaction of specific viral antigens with corresponding HLA α/β heterodimers., Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10−6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Background: Context-specific evidence of the spectrum of type 2 diabetes (T2D) burden is essential for setting priorities and designing interventions to reduce associated morbidity and mortality. However, there are currently limited data on the burden of T2D complications and comorbidity in sub-Saharan Africa (SSA). Here, we aimed to estimate the burden and risk factors for T2D complications and comorbidity in a large sample of sub-Saharan Africans. Methods: Using a standardized protocol, we documented and estimated the burden of T2D complications and comorbidities in 2,784 diabetes participants enrolled from tertiary health centers from Nigeria, Ghana and Kenya. T2D complications and comorbidities evaluated by study physicians and clinic staffs included cardiometabolic, ocular, neurological and renal characteristics. Using the same protocol, we contextualized the burden of these complications and comorbidities by evaluating them in a sample of 3,209 individuals without diabetes enrolled from the catchment communities where the cases originated. Logistic regression models were used to identify risk factors and to adjust estimates of risk. Results: The mean age of T2D participants was 56 (SD 11) years with a median duration of diabetes of 5 (interquartile range 2-10) years. The notable complications/comorbidities observed in this sample of T2D participants included hypertension (71%; 95% CI 69-73), obesity 27% (25-29) and hyperlipidemia 34% (32-36). Diabetic retinopathy was found in 15% (13-17) and cataracts in 32% (30-35). About 13% (12-15) had impaired renal function as assessed by eGFR, representing 1 in 8 participants. Erectile dysfunction was a complication in 35% (32-38) of men. Age, duration of T2D and body mass index were significant risk factors for most complications/comorbidities. Population-attributable fraction ranged between 6 and 64 percent for most comorbidities. Conclusion: We observed a substantial burden of diabetes complications and comorbidity in this sample of T2D participants from SSA. Given the reported association of these complications with increased burden of T2D morbidity and mortality we call for public health strategies that prioritise early detection, the maintenance of healthy blood pressure, weight and lipid levels, as well as strengthen health care system capacities to provide treatment and care for neurological and ophthalmological complications of diabetes. Funding Statement: The study was supported in part by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). Support for participant recruitment and initial genetic studies of the AADM study was provided by NIH grant No. 3T37TW00041-03S2 from the Office of Research on Minority Health. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study received ethical approval from the Institutional Review Board at each study site, Howard University and the United States National Institutes of Health.

Serum bilirubin is associated with several clinical outcomes, including hypertension, type 2 diabetes (T2D), and drug metabolism. Here, we describe findings from our genome-wide association studies (GWAS) of serum (TBIL) using a generalized linear mixed model in West Africans (n = 1127), with adjustment for age, sex, body mass index, T2D, significant principal components of population structure, and cryptic relatedness. Genome-wide conditional analysis and CAVIARBF were used to fine map significant loci. The causal effect of TBIL on hypertension was assessed by Mendelian randomization (MR) using the GWAS findings as instrumental variables (IVs) in African Americans (n = 3,067). The SNP rs887829 (UGT1A1) was significantly associated with TBIL levels (effect allele (T) frequency = 0.49, β (SE) = 0.59 (0.04), p = 9.13 × 10−54). Genome-wide conditional analysis and regional fine mapping pointed to rs887829 as a possible causal variant with a posterior inclusion probability of 0.99. The T allele of rs887829 is associated with lower hepatic expression of UGT1A1. Using rs887829 as an IV, two-stage least-squares MR showed a causal effect of bilirubin on hypertension (β = −0.76, 95% CI [−1.52, −0.01], p = 0.0459). Our finding confirms that UGT1A1 influences bilirubin levels. Notably, lower TBIL is causally associated with the increased risk of hypertension.

Aims The glycated hemoglobin (HbA1c) test can be unreliable in the presence of hemoglobinopathies. The co-existence of type 2 diabetes (T2D) with sickle cell anemia calls for alternative tests. Therefore, we established a reference interval for serum fructosamine and evaluated its utility as a potential glycemic biomarker that is not affected by abnormal hemoglobin. Methods The accuracies of serum fructosamine in monitoring and diagnosing T2D were evaluated using the Area under the Receiver Operating Characteristics and other measures in 618 Nigerians with or without sickle cell trait. The estimated diagnostic cut-off for serum fructosamine was then validated in an independent multi-ethnic cohort of 634 West Africans. Results Serum fructosamine was similar between individuals with or without sickle cell trait (median: 287 vs 275 umol/L, p = 0·11, respectively) despite statistically different HbA1c. Fructosamine was highly correlated with both HbA1c and fasting glucose independently of sickle cell trait. The areas under the curve (AUC) of serum fructosamine in identifying individuals with uncontrolled glycemia and individuals with T2D were similar and independent of sickle cell trait: 0·92 (95% confidence interval [95% CI ], 0·88-0·95 and 0.92 (95% CI, (0.89–0.95) respectively. Conclusions Serum fructosamine is a good alternative to HbA1c for monitoring and diagnosing T2D in the presence of sickle cell trait.

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Obese individuals without expected metabolic co-morbidities are referred to as metabolically healthy obese (MHO). The molecular mechanisms underlying this phenotype remain elusive. MicroRNAs may be involved in the MHO phenotype. To test this hypothesis, we screened 179 serum miRNAs in 20 African-American women (10 MHOs and 10 metabolically abnormal obese individuals -MAO). We identified 8 differentially expressed miRNAs (DEMs) with validation in an independent sample of 64 MHO and 34 MAO. Of the eight DEMs in the screening phase (p ≤ 0.05), miR-374a-5p remained significant (p = 0.04) with directional consistency in the validation sample. Ingenuity Pathway analysis revealed that miR-374a-5p putatively targeted 37 mRNAs (e.g. chemokines and transcription factors) which are members of canonical pathways involved in inflammation (IL-17A signaling) and lipid metabolism. Analysis restricted to adipocytes, the main source of circulating miRNAs in obesity, identified 3 mRNAs (CCL2, STEAP2, EN1) as the main target of miR-374a-5p. Evaluation of the 3 mRNAs in an independent sample showed that CCL2 was significantly downregulated (p = 0.0005). In summary, MiR-374a-5p is upregulated in MHO compared to MAO individuals and appears to show association with downregulation of pro-inflammatory markers that are linked to insulin resistance. Given the correlative nature of our findings, functional studies are needed.

Objective The prevalence of obesity varies between ethnic groups. No genome-wide association study (GWAS) for body mass index (BMI) has been conducted in continental Africans. Methods We performed a GWAS for BMI in 1,570 West Africans (WA). Replication was conducted in independent samples of WA (n = 1,411) and African Americans (AA) (n = 9,020). Results We identified a novel genome-wide significant African-specific locus for BMI (SEMA4D, rs80068415; minor allele frequency = 0.008, P = 2.10 × 10−8). This finding was replicated in independent samples of WA (P = 0.013) and AA (P = 0.017). Individuals with obesity had higher serum SEMA4D levels compared to those without obesity (P

Background: The glycosylated hemoglobin (HbA1c) test can be unreliable in the presence of hemoglobinopathies and remains cost-prohibited and impractical in many developing countries. The increasing burden of type 2 diabetes (T2D) in sub-Saharan Africa (SSA) where sickle cell anemia, the most common inherited hemoglobinopathy, is prevalent calls for alternative tests for the management of T2D. In the present study, we evaluated the utility of serum fructosamine (FRA) as a biomarker of glycemic control that is not affected by abnormal hemoglobin or red blood cell (RBC) turnover. Methods: The accuracy of FRA in monitoring and diagnosing T2D was evaluated using the Area under the Receiver Operating Characteristics (AUROC) and other measures in a training dataset of 618 Nigerians [155 (25·1%) carrying sickle cell trait (HbAS) and 463 (74·9%) without sickle cell trait (HbAA)]. The FRA’s diagnostic cut-off was validated in an independent cohort of 634 West Africans. Findings: FRA was similar between HbAS and HbAA participants (Median = 287 vs 275 umol/L, p=0·11) despite statistically different HbA1c median among the two groups. FRA was highly correlated with both HbA1c (r HbAA = 0·80, r HbAS =0·82, p

Recent advances in genomics provide opportunities for novel understanding of the biology of human traits with the goal of improving human health. Here, we review recent obesity and type 2 diabetes (T2D)–related genomic studies in African populations and discuss the implications of limited genomics studies on health disparity and precision medicine. Genome-wide association studies in Africans have yielded genetic discovery that would otherwise not be possible; these include identification of novel loci associated with obesity (SEMA-4D, PRKCA, WARS2), metabolic syndrome (CA-10, CTNNA3), and T2D (AGMO, ZRANB3). ZRANB3 was recently demonstrated to influence beta cell mass and insulin response. Despite these promising results, genomic studies in African populations are still limited and thus genomics tools and approaches such as polygenic risk scores and precision medicine are likely to have limited utility in Africans with the unacceptable possibility of exacerbating prevailing health disparities. African populations provide unique opportunities for increasing our understanding of the genetic basis of cardiometabolic disorders. We highlight the need for more coordinated and sustained efforts to increase the representation of Africans in genomic studies both as participants and scientists.

Proliferative diabetic retinopathy (PDR) is a sight-threatening complication of diabetes that is associated with longer duration of diabetes and poor glycemic control under a genetic susceptibility background. Although GWAS of PDR have been conducted in Europeans and Asians, none has been done in continental Africans, a population at increased risk for PDR. Here, we report a GWAS of PDR among Africans. PDR cases (n = 64) were T2D patients with neovascularization in the retina and/or retinal detachment. Controls (n = 227) were T2D patients without listed eye complications despite high risk (T2D duration ≥10 years and fasting blood glucose >169 mg/dl). Replication was assessed in African Americans enrolled in the ARIC study. We identified 4 significant loci: WDR72, HLA-B, GAP43/RP11-326J18.1, and AL713866.1. At WDR72 the most strongly associated SNPs were rs12906891 (MAF = 0.071; p = 9.68 × 10-10; OR = 1.46, 95% CI [1.30,1.64]) and rs11070992 (MAF = 0.14; p = 4.23 × 10−8; OR = 1.28, 95%CI [1.17–1.40]). rs11070992 replicated in African Americans (p = 0.04). Variants in this gene have been associated with diabetic retinopathy, glycemic control, revascularization, and kidney disease.

ObjectiveSerum uric acid is the end-product of purine metabolism and at high levels is a risk factor for several human diseases including gout and cardiovascular disease. Heritability estimates range from 0.32 to 0.63. Genome-wide association studies (GWAS) provide an unbiased approach to identify loci influencing serum uric acid. Here, we performed the first GWAS for serum uric acid in continental Africans, with replication in African Americans.MethodsAfricans (n = 4126) and African Americans (n = 5007) were genotyped on high-density GWAS arrays. Efficient mixed model association, a variance component approach, was used to perform association testing for a total of ~ 18 million autosomal genotyped and imputed variants. CAVIARBF was used to fine map significant regions.ResultsWe identified two genome-wide significant loci: 4p16.1 (SLC2A9) and 11q13.1 (SLC22A12). At SLC2A9, the most strongly associated SNP was rs7683856 (P = 1.60 × 10−44). Conditional analysis revealed a second signal indexed by rs6838021 (P = 5.75 × 10−17). Gene expression and regulatory motif data prioritized a single-candidate causal variant for each signal. At SLC22A12, the most strongly associated SNP was rs147647315 (P = 6.65 × 10−25). Conditional analysis and functional annotation prioritized the missense variant rs147647315 (R (Arg) > H (His)) as the sole causal variant. Functional annotation of these three signals implicated processes in skeletal muscle, subcutaneous adipose tissue and the kidneys, respectively.ConclusionsThis first GWAS of serum uric acid in continental Africans identified three associations at two loci, SLC2A9 and SLC22A12. The combination of weak linkage disequilibrium in Africans and functional annotation led to the identification of candidate causal SNPs for all three signals. Each candidate causal variant implicated a different cell type. Collectively, the three associations accounted for 4.3% of the variance of serum uric acid.

Aims/hypothesis Genome-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. Methods We 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. Results The 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/interpretation These 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. Electronic supplementary material The online version of this article (10.1007/s00125-019-4880-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background: Context-specific evidence of the spectrum of type 2 diabetes (T2D) burden is essential for setting priorities and designing interventions to reduce T2D morbidity and mortality. However, there are currently limited data on the burden of T2D complications and comorbidity in sub-Saharan Africa (SSA). Using a study of ~6,000 participants, we aimed to estimate the burden and risk factors for T2D complications and comorbidity in sub-Saharan Africans. Methods: Participants (2784 T2D, 3209 controls) were African men and women aged 18 years or older, enrolled from major academic medical centres and surrounding communities in Ghana, Nigeria and Kenya. T2D was defined according to the American Diabetes Association criteria. T2D complications and comorbidities evaluated included cardiometabolic, ocular, neurological and renal characteristics. Logistic regression models were used to identify risk factors and to adjust estimates of risk and prevalence for covariates. Results: T2D participants had a mean age of 56 [SD 11] years and a median duration of T2D of 5 (interquartile range 2-10) years. Among the T2D participants, notable associated complications/comorbidities included hypertension with a prevalence of 71% (95% CI 69-73), obesity 27% (25-29) and hyperlipidemia 34% (32-36). Diabetic retinopathy was found in 15% (13-17) and cataracts in 32% (30-35). About 13% (12-15) had impaired renal function as assessed by eGFR, representing 1 in 8 participants. Erectile dysfunction was a complication in 35% (32-38) of men. Age, duration of T2D and body mass index were significant risk factors for most complications/comorbidities. There was significant heterogeneity between sites in prevalence of most complications/comorbidities after adjusting for covariates. Population-attributable fraction ranged between 6 and 64 percent for most comorbidities. Conclusion: The burden of T2D complications and comorbidity is substantial among sub-Saharan Africans. Interventions to reduce T2D morbidity and mortality in SSA need to prioritise early detection, the maintenance of healthy blood pressure, weight and lipid levels, as well as strengthen health care system capacities to provide treatment and care for neurological and ophthalmological complications of T2D. Funding Statement: The study was supported in part by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). Support for participant recruitment and initial genetic studies of the AADM study was provided by NIH grant No. 3T37TW00041-03S2 from the Office of Research on Minority Health. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study received ethical approval from the Institutional Review Board at each study site, Howard University and the United States National Institutes of Health.

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., Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.

The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86 × 10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63 × 10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37 × 10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52 × 10(-8), Pmeta=7.82 × 10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.

Several clinical guidelines have been proposed to distinguish metabolically healthy obesity (MHO) from other subgroups of obesity but the molecular mechanisms by which MHO individuals remain metabolically healthy despite having a high fat mass are yet to be elucidated. We conducted the first whole blood transcriptomic study designed to identify specific sets of genes that might shed novel insights into the molecular mechanisms that protect or delay the occurrence of obesity-related co-morbidities in MHO. The study included 29 African-American obese individuals, 8 MHO and 21 metabolically abnormal obese (MAO). Unbiased transcriptome-wide network analysis was carried out to identify molecular modules of co-expressed genes that are collectively associated with MHO. Network analysis identified a group of 23 co-expressed genes, including ribosomal protein genes (RPs), which were significantly downregulated in MHO subjects. The three pathways enriched in the group of co-expressed genes are EIF2 signaling, regulation of eIF4 and p70S6K signaling, and mTOR signaling. The expression of ten of the RPs collectively predicted MHO status with an area under the curve of 0.81. Triglycerides/HDL (TG/HDL) ratio, an index of insulin resistance, was the best predictor of the expression of genes in the MHO group. The higher TG/HDL values observed in the MAO subjects may underlie the activation of endoplasmic reticulum (ER) and related-stress pathways that lead to a chronic inflammatory state. In summary, these findings suggest that controlling ER stress and/or ribosomal stress by downregulating RPs or controlling TG/HDL ratio may represent effective strategies to prevent or delay the occurrence of metabolic disorders in obese individuals., Defining the molecular basis of “healthy obesity” Decreased expression of genes encoding ribosomal proteins could be a hallmark of metabolically healthy obese (MHO) individuals. Amadou Gaye, Ayo P. Doumatey and colleagues at the National Institutes of Health in Bethesda examined the gene expression patterns in whole blood samples from 29 obese African Americans. Eight of the 29 individuals had been categorized as MHO—despite having a Body Mass Index that fell within the obese range they did not have metabolic complications commonly associated with obesity such as diabetes and hypertension. Eighteen ribosomal protein genes were under-expressed in these individuals compared with the 21 that had metabolic disorders. Ribosomal proteins are required for ribosome assembly and protein production and have been implicated in ribosomal stress, which triggers chronic inflammation. These findings reveal a protective mechanism that could prevent or delay obesity-related metabolic comorbidities.

Context. Low levels of systemic F2-isoprostanes (F2-IsoP) increase the risk of diabetes and weight gain and were found in African Americans. Low F2-IsoPs could reflect an unfavorable metabolic characteristic, namely, slow mitochondrial metabolism in individuals with African ancestry.Objective. To examine differences in plasma F2-IsoPs in three groups with a priori different proportion of African ancestry: non-Hispanic Whites (NHWs), US-born African Americans (AAs), and West African immigrants (WAI).Design. Cross-sectional study.Setting. Georgia residents recruited from church communities.Participants. 218 males and females 25–74 years of age, who are self-identified as NHW (n=83), AA (n=56), or WAI (n=79).Main Outcome Measure(s). Plasma F2-IsoPs quantified by gas chromatography-mass spectrometry.Results. After adjustment for age, gender, obesity, and other comorbidities, WAI had lower levels of plasma F2-IsoP than AA (beta-coefficient = −9.8,p<0.001) and AA had lower levels than NHW (beta-coefficient = −30.3,p<0.001). Similarly, among healthy nonobese participants, F2-IsoP levels were lowest among WAI, followed by AA, and the highest levels were among NHW.Conclusion. Plasma F2-IsoPs are inversely associated with African ancestry gradient. Additional studies are required to test whether optimization of systemic F2-IsoP levels can serve as means to improve race-specific lifestyle and pharmacological intervention targeted to obesity prevention and treatment.

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values5 × 10(-8). The lowest P-value was 1.7 × 10(-22) for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10(-11); this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r(2)≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations.

Aims/hypothesis Chronically elevated blood glucose (hyperglycaemia) is the primary indicator of type 2 diabetes, which has a prevalence that varies considerably by ethnicity in the USA, with African-Americans disproportionately affected. Genome-wide association studies (GWASs) have significantly enhanced our understanding of the genetic basis of diabetes and related traits, including fasting plasma glucose (FPG). However, the majority of GWASs have been conducted in populations of European ancestry. Thus, it is important to conduct replication analyses in populations with non-European ancestry to identify shared loci associated with FPG across populations. Methods We used data collected from non-diabetic unrelated African-American individuals (n = 927) who participated in the Howard University Family Study to attempt to replicate previously published GWASs of FPG. Of the 29 single nucleotide polymorphisms (SNPs) previously reported, we directly tested 20 in this study. In addition to the direct test, we queried a 500 kb window centred on all 29 reported SNPs for local replication of additional markers in linkage disequilibrium (LD). Results Using direct SNP and LD-based comparisons, we replicated multiple SNPs previously associated with FPG and strongly associated with type 2 diabetes in populations with European ancestry. The replicated SNPs included those in or near TCF7L2, SLC30A8, G6PC2, MTNR1B, DGKB-TMEM195 and GCKR. We also replicated additional variants in LD with the reported SNPs in ZMAT4 and adjacent to IRS1. Conclusions/interpretation We identified multiple GWAS variants for FPG in our cohort of African-Americans. Using an LD-based strategy we also identified SNPs not previously reported, demonstrating the utility of using diverse populations for replication analysis. Electronic supplementary material The online version of this article (doi:10.1007/s00125-010-2002-7) contains supplementary material, which is available to authorised users.

Context: Adiponectin, a hormone secreted by adipose tissue, has both metabolic and antiinflammatory properties. Although multiple studies have described the relationship between adiponectin and obesity in several human populations, no large studies have evaluated this relationship in Africans. Objective: We investigated the relationship between adiponectin and measures of obesity, serum lipids, and insulin resistance in a large African cohort. Design: Participants are from the Africa America Diabetes Mellitus (AADM) Study, a case-control study of genetic and other risk factors associated with development of type 2 diabetes in Africans. Setting: Patients were recruited from five academic medical centers in Nigeria and Ghana (Accra and Kumasi in Ghana and Enugu, Ibadan, and Lagos in Nigeria) over 10 yr. Main Outcome Measures: Circulating adiponectin levels were measured in 690 nondiabetic controls using an ELISA. The correlation between log-transformed circulating adiponectin levels and age, gender, measures of obesity (body mass index, waist circumference, and percent fat mass), and serum lipid levels was assessed. Linear regression was used to explore the association between adiponectin levels and measures of obesity, lipids, and insulin resistance as measured by homeostasis model assessment. Results: Significant negative associations were observed between log-adiponectin levels and measures of obesity after adjusting for age and gender. Similarly, log-adiponectin levels were significantly negatively associated with serum triglycerides and insulin resistance but positively associated with high-density lipoprotein-cholesterol and total cholesterol after adjusting for age, gender, and body mass index. Conclusions: Circulating adiponectin is significantly associated with measures of obesity, serum lipids, and insulin resistance in this study of West African populations.

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)-alpha), 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-alpha 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.

OBJECTIVE The FTO gene is one of the most consistently replicated loci for obesity. However, data from populations of African ancestry are limited. We evaluated genetic variation in the FTO gene and investigated associations with obesity in West Africans and African Americans. RESEARCH DESIGN AND METHODS The study samples comprised 968 African Americans (59% female, mean age 49 years, mean BMI 30.8 kg/m2) and 517 West Africans (58% female, mean age 54 years, mean BMI 25.5 kg/m2). FTO genetic variation was evaluated by genotyping 262 tag single nucleotide polymorphisms (SNPs) across the entire gene. Association of each SNP with BMI, waist circumference, and percent fat mass was investigated under an additive model. RESULTS As expected, both African-ancestry samples showed weaker linkage disequilibrium (LD) patterns compared with other continental (e.g., European) populations. Several intron 8 SNPs, in addition to intron 1 SNPs, showed significant associations in both study samples. The combined effect size for BMI for the top SNPs from meta-analysis was 0.77 kg/m2 (P = 0.009, rs9932411) and 0.70 kg/m2 (P = 0.006, rs7191513). Two previously reported associations with intron 1 SNPs (rs1121980 and rs7204609, r2 = 0.001) were replicated among the West Africans. CONCLUSIONS The FTO gene shows significant differences in allele frequency and LD patterns in populations of African ancestry compared with other continental populations. Despite these differences, we observed evidence of associations with obesity in African Americans and West Africans, as well as evidence of heterogeneity in association. More studies of FTO in multiple ethnic groups are needed.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Objective: Transferability of significantly associated loci or GWAS “hits” adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. Methods: Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an “exact” approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a “local” approach that examined all the regional SNPs in LD with the index SNP. Results: Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133-2.167], P = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149–4.013], P = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected P values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of IL33 were significantly associated with asthma. Conclusions: This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the IL33, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding.

Background Hyperuricemia and associated cardio-metabolic disorders are more prevalent in African Americans than in European Americans. We used genome-wide admixture mapping and association testing to identify loci with ancestry effects on serum uric acid levels. Methods We analyzed 1,976 African Americans from Washington, D.C, including 1,322 individuals from 328 pedigrees and 654 unrelated individuals, enrolled in the Howard University Family Study. We performed admixture mapping and genome-wide association testing using ~800 k autosomal single-nucleotide polymorphisms (SNPs). We performed fine mapping by dense genotyping. We assessed functionality by a combination of bioinformatic annotation, reporter gene assays, and gel shift experiments. We also analyzed 12,641 individuals enrolled in the National Health and Nutrition Examination Survey. Results We detected a genome-wide significant locus on chromosome 11p15.4 at which serum uric acid levels increased with increasing African ancestry, independent of kidney function. Fine-mapping identified two independent signals in the β-globin locus. The ancestral allele at SNP rs2855126, located upstream of the hemoglobin, gamma A gene HBG1, was associated with increased serum uric acid levels and higher expression of a reporter gene relative to the derived allele. Hyperuricemia was associated with increased risk of hypertension in 3,767 African Americans (Odds Ratio = 2.48, p = 2.71 × 10− 19). Conclusions Given that increased expression of γ-globin leads to increased levels of fetal hemoglobin which confers protection against malaria, we hypothesize that evolution in Africa of protection against malaria may have occurred at the cost of increased serum uric acid levels, contributing to the high rates of hyperuricemia and associated cardio-metabolic disorders observed in African Americans. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0249-z) contains supplementary material, which is available to authorized users.

There are scant data from African populations on the association between beta-cell function and response to treatment with oral hypoglycaemic agents in Type 2 diabetes mellitus (T2DM). Fasting plasma C-peptide (FCP) and glucagon-stimulated C-peptide (GSCP) levels were measured in 116 Nigerians with T2DM at a university teaching hospital. After 9 months of follow-up and treatment, they were categorized into three groups based on response to treatment: (A) good control but not on maximum sulphonylurea (SU) therapy, (B) inadequate control but not on maximum SU therapy and (C) on maximum SU therapy+/-insulin or biguanide. Logistic regression models were used to investigate how well C-peptide levels predicted the subjects belonging to Group C who are likely to require insulin. The mean FCP and mean GSCP levels of Group C were significantly lower than in the other groups (p=0.024; p=0.001 respectively). A GSCP cut-off value ofor =1.3 ng/mL predicted membership of Group C with 85% sensitivity and 89% specificity while a cut-off ofor =1.8 ng/mL was associated with 91% sensitivity and 66% specificity. In resource-poor settings where inadequate treatment are common, estimation of GSCP may be useful in predicting treatment response and should be weighed against the cost of inadequate therapy with higher morbidity and mortality.

Background: It has been suggested that adiponectin may offer protection against the adverse health effects of obesity. In this study, we determined the prevalence of paradoxically high adiponectin or paradoxical hyperadiponectinemia (PHA) among obese African Americans and investigated its relationship with the metabolically healthy obese (MHO) phenotype. Methods: Total adiponectin and metabolic markers including fasting glucose, insulin, serum lipids and obesity measures were determined in 822 unrelated participants from the Howard University Family Study (HUFS). Logistic regression models were used to evaluate the association between MHO phenotype and PHA while adjusting for relevant covariates. Results: Overall, men had significantly lower adiponectin levels than women. However, adiponectin level was associated with obesity measures, glucose, insulin and insulin resistance index in both men and women. Equal proportion of the obese male and female subjects (19.2%; 66 / 343) had PHA; these obese individuals with PHA had a healthier metabolic profile including higher HDL-cholesterol, lower insulin levels and smaller waist circumference and insulin levels compared to those without PHA. Also, 28% (96 / 343) of the study participants met the criteria of MHO phenotype. Interestingly, 42% (28 / 66) of the obese individuals with PHA also had the MHO phenotype. Finally, the MHO phenotype was associated with PHA in both men and women. Conclusions: These findings confirm the presence of MHO in African Americans and demonstrate the association of PHA with the MHO phenotype. In all, our findings along with other published results provide evidence for a more systematic investigation of the mechanisms underlying the protective function of adiponectin and its potential therapeutic applications in human metabolic disorders. doi:10.4021/jem95w

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 P5 × 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.

The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in APOL1 associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry vs. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans.

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 (BetaMDRD=-0.18,BetaCG=-0.26) and multivariate (BetaMDRD=-0.10,BetaCG=-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 m2). 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.

The aim of the study was to investigate the associations between IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, measures of obesity, and insulin resistance in African-Americans.Nondiabetic participants (n = 1025) of the Howard University Family Study were investigated for associations between serum IL (IL-1RA, IL-6, IL-10), measures of obesity, and insulin resistance, with adjustment for age and sex. Measures of obesity included body mass index, waist circumference, hip circumference, waist-to-hip ratio, and percent fat mass. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Data were analyzed with R statistical software using linear regression and likelihood ratio tests.IL-1RA and IL-6 were associated with measures of obesity and insulin resistance, explaining 4-12.7% of the variance observed (P values0.001). IL-1RA was bimodally distributed and therefore was analyzed based on grouping those with low vs. high IL-1RA levels. High IL-1RA explained up to 20 and 12% of the variance in measures of obesity and HOMA-IR, respectively. Among the IL, only high IL-1RA improved the fit of models regressing HOMA-IR on measures of obesity. In contrast, all measures of obesity improved the fit of models regressing HOMA-IR on IL. IL-10 was not associated with obesity measures or HOMA-IR.High IL-1RA levels and obesity measures are associated with HOMA-IR in this population-based sample of African-Americans. The results suggest that obesity and increased levels of IL-1RA both contribute to the development of insulin resistance.

Background: Although designed to predict cardiovascular disease and type 2 diabetes mellitus, the Metabolic Syndrome (MetSyn) under-predicts these conditions in African Americans (AA). Failure of MetSyn in AA is often attributed to their relative absence of hypertriglyceridemia. It is unknown if the African experience with MetSyn will be similar or different to that in AA. Focusing on the lipid profile, our goal was to determine in West Africans (WA) and AA the pattern of variables that leads to the diagnosis of the MetSyn.Methods: Cross-sectional analysis of 1296 subjects (364 WA, 44% male, 932 AA, 46% male). WA were from urban centers in Nigeria and Ghana and enrolled in the Africa America Diabetes Mellitus Study. AA lived in Washington, DC and participated in the Howard University Family Study.Results: The prevalence of MetSyn was different in WA women and men: 42% vs.19%, P < 0.001, and in AA women and men: 25% vs.17%, P < 0.01. The three variables that most often led to the diagnosis of MetSyn in WA and AA were: low HDL-C, central obesity and hypertension. Less than 40% of AA and less than 25% of WA with the MetSyn had hypertriglyceridemia.Conclusions: Elevated triglyceride levels were uncommon in both WA and AA with MetSyn. As the relative absence of hypertriglyceridemia is associated with a lack of efficacy of MetSyn in AA, caution is warranted in diagnosing MetSyn in WA, the ancestral population of AA. Prospective studies are necessary to determine if an ethnic-specific reformulation of the MetSyn scoring system for lipids might optimize risk identification in black populations.

C-peptide is a substance that the pancreas releases into the circulation in equimolar amounts to insulin and has demonstrated important physiological effects which relate to the vascular field, in particular the microcirculation. For this analysis, we included 321 full and 36 half sibling pairs affected with type 2 diabetes (T2D) from West Africa. A genome-wide panel of 390 tri-nucleotide and tetra-nucleotide repeats with an average distance of 8.9cM was performed on a total of 691 persons. Variance components based on multipoint linkage approach as implemented in SOLAR were performed for logC-peptide. Significant linkage evidences were observed on 10q23 at D10S2327 with a LOD score of 4.04 (nominal p -value=0.000008, empirical p -value=0.0004); and on 4p15 at D4S2632 with a LOD score of 3.48 (nominal p -value=0.000031, empirical p -value=0.0013). Other suggestive evidence of linkage were observed on 15q14 at D15S659 with a LOD score 2.41 (nominal p -value=0.000435, empirical p -value=0.0068), and on 18p11 near D18S976 with a LOD score 2.18 (nominal p -value=0.000771 and empirical p -value=0.0094). Interestingly, five positional candidate genes for diabetes and related complications are located in our linkage region (the pituitary adenylate cyclase activating polypeptide (PACAP in 18p11); the peroxisome proliferator-activated receptor gamma coactivator 1 (PPARGC1 in 4p15); PTEN, PPP1R5, and IDE located in 10q23. In conclusion, we identified four major genetic loci (10q23, 4p15, 15q14, and 18p11) influencing C-peptide concentration in West Africans with T2D.

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 9cM. 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.

High risk HPV (hrHPV) infection is a necessary cause of cervical cancer but the host genetic determinants of infection are poorly understood. We enrolled 267 women who presented to our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. We collected information on demographic characteristics, risk factors of cervical cancer and obtained samples of blood and cervical exfoliated cells from all participants. We used Roche Linear Array HPV Genotyping Test® to characterize the prevalent HPV according to manufacturer's instruction; Sequenom Mass Array to test 21 SNPs in genes/regions previously associated with hrHPV and regression models to examine independent factors associated with HPV infection. We considered a p

Purpose 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.

Background Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term. Results Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 × HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies. Conclusions Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1645-7) contains supplementary material, which is available to authorized users.