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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.

Background African Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study. Results We identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel—cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans. Conclusions The findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.

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.

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

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.

BackgroundSerum lipids are biomarkers of cardiometabolic disease risk, and understanding the genomic factors contributing to their distribution has been of considerable interest. Large genome-wide association studies (GWAS) have identified over 150 lipids loci; however, GWAS of Africans (AF) are rare. Given the genomic diversity among those of African ancestry, it is expected that a GWAS in Africans could identify novel lipids loci. While GWAS have been conducted in African Americans (AA), such studies are not proxies for studies in continental Africans due to the drastically different environmental context. Therefore, we conducted a GWAS of 4,317 Africans enrolled in the Africa America Diabetes Mellitus study.Methods and ResultsWe used linear mixed models of the inverse normal transformations of covariate-djusted residuals of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG), and TG/HDLC, with adjustment for three principal components and the random effect of relatedness. Replication of loci associated at p−8 was attempted in 9,542 AA. Meta-analysis of AF and AA was also conducted. We also conducted analyses that excluded the relatively small number of East Africans. We evaluated known lipids loci in Africans using both exact replication and “local” replication, which accounts for interethnic differences in linkage disequilibrium.In our main analysis, we identified 23 novel associations in Africans. Of the 14 of these that were able to be tested in AA, two associations replicated (GPNMB-TG and ENPP1-TG). Two additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG and TLL2-CHOL). Analyses considering only those with predominantly West African ancestry (Nigeria, Ghana, and AA) yielded new insights: ORC5-LDLC and chr20:60973327-CHOL.ConclusionsWhile functional work will be useful to confirm and understand the biological mechanisms underlying these associations, this study demonstrates the utility of conducting large-scale genomic analyses in Africans for discovering novel loci. The functional significance of some of these loci in relation to lipids remains to be elucidated, yet some have known connections to lipids pathways. For instance, rs147706369 (intronic, TLL2) alters a regulatory motif for sterol regulatory element-binding proteins (SREBPs), which are a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid, and triglyceride synthesis.

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.

Background - Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which GWAS consistently report variants within and near the coding gene ( RETN ). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing GWAS, whole-exome analysis, fine-mapping, Mendelian randomization and transcriptomic data analyses. Methods - GWAS and fine-mapping analyses for resistin were performed in 5621 African ancestry individuals, including 3754 continental Africans (AF) and 1867 African Americans (AA). Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modelling (HOMA) derived insulin resistance index, BMI and type 2 diabetes. Results - The lead variant (rs3219175, in the promoter region of RETN ) for the single locus detected was the same for AF ( P -value 5.0×10 -111 ) and for AA (9.5×10 -38 ), respectively explaining 12.1% and 8.5% of variance in circulating resistin. Fine-mapping analyses and functional annotation revealed this variant as likely causal affecting circulating resistin levels as a cis -eQTL increasing RETN expression. Additional variants regulating resistin levels were upstream of RETN with genes PCP2 , STXBP2 and XAB2 showing the strongest association using integrative analysis of GWAS with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, BMI or type 2 diabetes risk in African-ancestry populations. Conclusions - Taking advantage of the fine-mapping resolution power of African genomes, we identified a single variant (rs3219175) as the likely causal variant responsible for most of the variability in circulating resistin levels. In contrast to findings in some other ancestry populations, we showed that resistin does not seem to increase insulin resistance and related cardiometabolic traits in African-ancestry populations.

Given a lifetime risk of ~90% by the ninth decade of life, it is unknown if there are true controls for hypertension in epidemiological and genetic studies. Here, we use the Bayesian framework to compare logistic and time-to-event approaches to modeling hypertension. Using a proportional hazards model, we explored nonparametric and parametric models of the baseline hazard function, accounting for interval censoring. In the Howard University Family Study (HUFS), a population-based study of African Americans from Washington, D.C., the median age at hypertension was 48 years, baseline hazard rates increased with age until 55 years, and the probability of being free of hypertension at 85 years of age was 12.2%. In the nationwide NHANES study, the median age at hypertension was 42 years in African Americans, in contrast to 57 years in European Americans and 56 years in Mexican Americans. Baseline hazard rates increased with age until 58 years in African Americans, comparable to 60 years in European Americans and 58 years in Mexican Americans. The probability of being free of hypertension at 85 years of age was 8.4% in African Americans, in contrast to 21.4% in European Americans and 20.6% in Mexican Americans. In all four groups, baseline hazard rates decreased but did not reach zero, consistent with the nonexistence of controls. Model fits were comparable for a proportional hazards model based on gamma-distributed hazard rates under a correlated prior process and a logistic model adjusted for age and age2. Last, using an agnostic model screening approach of 38 potential covariates, we identified and replicated in all groups a model that included chloride, low-density lipoprotein cholesterol, uric acid, and weight. With age and age2, the variance explained by these covariates was 40.9% in African Americans, 34.8% in European Americans, and 28.3% in Mexican Americans. Taken together, modeling of the baseline hazard function of hypertension suggests that there are no true controls and that controls in logistic regression are cases with a late age of onset. These findings shed considerable insights into the design of genetic and epidemiological studies of hypertension with implications for ethnic health disparities.

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.

A deeper appreciation of the complex architecture of African genomes is critical to the global effort to understand human history, biology and differential distribution of disease by geography and ancestry. Here, we report on how the growing engagement of African populations in genome science is providing new insights into the forces that shaped human genomes before and after the Out-of-Africa migrations. As a result of this human evolutionary history, African ancestry populations have the greatest genomic diversity in the world, and this diversity has important ramifications for genomic research. In the case of pharmacogenomics, for instance, variants of consequence are not limited to those identified in other populations, and diversity within African ancestry populations precludes summarizing risk across different African ethnic groups. Exposure of Africans to fatal pathogens, such as Plasmodium falciparum, Lassa Virus and Trypanosoma brucei rhodesiense, has resulted in elevated frequencies of alleles conferring survival advantages for infectious diseases, but that are maladaptive in modern-day environments. Illustrating with cardiometabolic traits, we show that while genomic research in African ancestry populations is still in early stages, there are already many examples of novel and African ancestry-specific disease loci that have been discovered. Furthermore, the shorter haplotypes in African genomes have facilitated fine-mapping of loci discovered in other human ancestry populations. Given the insights already gained from the interrogation of African genomes, it is imperative to continue and increase our efforts to describe genomic risk in and across African ancestry populations.

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

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

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.

Author(s): Daya, Michelle; Rafaels, Nicholas; Brunetti, Tonya M; Chavan, Sameer; Levin, Albert M; Shetty, Aniket; Gignoux, Christopher R; Boorgula, Meher Preethi; Wojcik, Genevieve; Campbell, Monica; Vergara, Candelaria; Torgerson, Dara G; Ortega, Victor E; Doumatey, Ayo; Johnston, Henry Richard; Acevedo, Nathalie; Araujo, Maria Ilma; Avila, Pedro C; Belbin, Gillian; Bleecker, Eugene; Bustamante, Carlos; Caraballo, Luis; Cruz, Alvaro; Dunston, Georgia M; Eng, Celeste; Faruque, Mezbah U; Ferguson, Trevor S; Figueiredo, Camila; Ford, Jean G; Gan, Weiniu; Gourraud, Pierre-Antoine; Hansel, Nadia N; Hernandez, Ryan D; Herrera-Paz, Edwin Francisco; Jimenez, Silvia; Kenny, Eimear E; Knight-Madden, Jennifer; Kumar, Rajesh; Lange, Leslie A; Lange, Ethan M; Lizee, Antoine; Maul, Pissamai; Maul, Trevor; Mayorga, Alvaro; Meyers, Deborah; Nicolae, Dan L; O'Connor, Timothy D; Oliveira, Ricardo Riccio; Olopade, Christopher O; Olopade, Olufunmilayo; Qin, Zhaohui S; Rotimi, Charles; Vince, Nicolas; Watson, Harold; Wilks, Rainford J; Wilson, James G; Salzberg, Steven; Ober, Carole; Burchard, Esteban G; Williams, L Keoki; Beaty, Terri H; Taub, Margaret A; Ruczinski, Ingo; Mathias, Rasika A; Barnes, Kathleen C; CAAPA | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

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 the largest genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyzed ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. TCF7L2 rs7903156 was the most significant locus (p=7.288 × 10−13). We identified a novel genome wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP chr2:136064024, T allele frequency=0.034, p=2.831×10−9). Knockdown of the zebrafish ortholog resulted in reduction in pancreatic beta cell number in the developing organism, suggesting a potential mechanism for its effect on glucose hemostasis. We also showed transferability in our study of 32 established T2D loci. Our findings provide evidence of a novel candidate T2D locus and advance understanding of the genetics of T2D in non-European ancestry populations.

Objective The metabolically healthy obesity (MHO) phenotype is an important obesity subtype in which obesity is not accompanied by any metabolic comorbidity. However, the underlying molecular mechanisms remain elusive. In this study, a shotgun proteomics approach to identify circulating biomolecules and pathways associated with MHO was used. Methods The subjects were 20 African-American women: 10 MHO cases and 10 metabolically abnormal individuals with obesity (MAO) controls. Serum proteins were detected and quantified using label-free proteomics. Differential expression of proteins between the two groups was analyzed, and the list of differentially expressed proteins was analyzed to determine enriched biological pathways. Results Twenty proteins were differentially expressed between MHO and controls. These proteins included: hemoglobin subunits (HBA1, P = 6.00 × 10−18), haptoglobin-related protein (HPR, P = 1.2 × 10−15), apolipoproteins (APOB-100, P = 1.50 × 10−40; APOA4, P = 1.1 × 10−14), retinol-binding protein 4 (RBP4, P = 7.1 × 10−08), and CRP (P = 2.0 × 10−04). MHO was associated with lower levels of proinflammatory and higher levels of anti-inflammatory biomarkers when compared with MAO. Pathway analysis showed enrichment of lipids and inflammatory pathways, including LXR/RXR and FXR/RXR activation, and acute phase response signaling. Conclusions These findings suggested that protection from dysregulated inflammatory and lipid processes were primary molecular hallmarks of MHO. The candidate biomarkers (AHSG, RBP4, and APOA4) identified in this study are potential prognostic markers for MHO.

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.

Genome-wide association studies have identified over one hundred common genetic risk variants associated with type 2 diabetes (T2D). However, most of the heritability of T2D has not been accounted for. In this study, we investigated the contribution of rare and common variants to T2D susceptibility by analyzing exome array data in 1,908 Han Chinese genotyped with Affymetrix Axiom® Exome Genotyping Arrays. Based on the joint common and rare variants analysis of 57,704 autosomal SNPs within 12,244 genes using Sequence Kernel Association Tests (SKAT), we identified significant associations between T2D and 25 variants (9 rare and 16 common) in MUC5B, p-value 1.01×10-14. This finding was replicated (p = 0.0463) in an independent sample that included 10,401 unrelated individuals. Sixty-six of 1,553 possible haplotypes based on 25 SNPs within MUC5B showed significant association with T2D (Bonferroni corrected p values < 3.2×10-5). The expression level of MUC5B is significantly higher in pancreatic tissues of persons with T2D compared to those without T2D (p-value = 5×10-5). Our findings suggest that dysregulated MUC5B expression may be involved in the pathogenesis of T2D. As a strong candidate gene for T2D, MUC5B may play an important role in the mechanisms underlying T2D etiology and its complications.

Background The stability of biomarkers in stored biomedical samples is crucial, especially when storage is for extended periods of time. High-sensitivity CRP (Hs-CRP) is a biomarker of low grade inflammation that is extensively used to identify and study cardiovascular and/or inflammatory processes in clinical care and large epidemiologic studies. Therefore, assessing Hs-CRP stability in archived samples at a given temperature is important to ensure precision of measurements over time and the validity of studies using archived samples. Methods We evaluated the stability of Hs-CRP in 30 randomly selected human serum samples by measuring Hs-CRP concentrations in freshly collected sample [Hs-CRP (0)] and in the same set of samples after 7–11 years of storage at − 80 °C [Hs-CRP (LT)]. Results Hs-CRP did not significantly change up to 11 years of storage at − 80 °C as shown by a negligible median difference between Hs-CRP (0) and Hs-CRP (LT), delta(Hs-CRP (0)–Hs-CRP (LT)) = − 0.01, p = 0.45. There was a good concordance and agreement between Hs-CRP (0) and Hs-CRP (LT) as measured respectively by Lin's coefficient of correlation (ρC = 0.98) and Bland–Altman analysis (mean difference = − 0.02, 95% CI [− 0.04–0.0045] p = 0.107). In addition, the data also suggest that the time elapsed between collection and Hs-CRP measurement does not affect Hs-CRP stability over time when samples are kept under the appropriate conditions. Conclusions Long-term storage at − 80 °C for up to 11 years did not significantly affect the stability of serum Hs-CRP. Given the cost and time for collecting fresh samples, this observation represents an important finding for biomedical research and clinical care.

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.

C-reactive protein (CRP) is an acute phase reactant protein produced primarily by the liver. Circulating CRP levels are influenced by genetic and non-genetic factors, including infection and obesity. Genome-wide association studies (GWAS) provide an unbiased approach towards identifying loci influencing CRP levels. None of the six GWAS for CRP levels has been conducted in an African ancestry population. The present study aims to: (i) identify genetic variants that influence serum CRP in African Americans (AA) using a genome-wide association approach and replicate these findings in West Africans (WA), (ii) assess transferability of major signals for CRP reported in European ancestry populations (EA) to AA and (iii) use the weak linkage disequilibrium (LD) structure characteristic of African ancestry populations to fine-map the previously reported CRP locus. The discovery cohort comprised 837 unrelated AA, with the replication of significant single-nucleotide polymorphisms (SNPs) assessed in 486 WA. The association analysis was conducted with 2 366 856 genotyped and imputed SNPs under an additive genetic model with adjustment for appropriate covariates. Genome-wide and replication significances were set at P < 5 × 10−8 and P < 0.05, respectively. Ten SNPs in (CRP pseudogene-1) CRPP1 and CRP genes were associated with serum CRP (P = 2.4 × 10−09 to 4.3 × 10−11). All but one of the top-scoring SNPs associated with CRP in AA were successfully replicated in WA. CRP signals previously identified in EA samples were transferable to AAs, and we were able to fine-map this signal, reducing the region of interest from the 25 kb of LD around the locus in the HapMap CEU sample to only 8 kb in our AA sample.

Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p 5 × 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10(-6) to 1.75 × 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 × 10(-6) to 1.63 × 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.

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.