Benjamin A. Eghan

A genome-wide scan for quantitative trait loci linked to obesity phenotypes among West Africans

OBJECTIVE:To identify quantitative trait loci (QTL) for three obesity phenotypes: body mass index (BMI), fat mass (FM) and percent body fat (PBF) in West Africans with type 2 diabetes (T2DM).DESIGN:An affected sibling pair (ASP) design, in which both siblings had T2DM. Obesity was analyzed as a quantitative trait using a variance components approach.SUBJECTS:Sib-pairs affected with T2DM from the Africa America Diabetes Mellitus (AADM) study, comprising 321 sibling pairs and 36 half-sibling pairs.MEASUREMENTS:Weight was measured on an electronic scale to the nearest 0.1 kg, and height was measured with a stadiometer to the nearest 0.1 cm. Body composition was estimated using bioelectric impedance analysis (BIA). Genotyping was carried out at the Center for Inherited Disease Research (CIDR) with a panel of 390 trinucleotide and tetranucleotide repeats.RESULTS:The obesity-related phenotype showing the strongest linkage evidence was PBF on chromosome 2 (LOD 3.30 at 72.6 cM, marker D2S739). Suggestive linkage to FM was found on chromosomes 2 (LOD 2.56 at 80.4 cM) and 5 (LOD 2.25 at 98 cM, marker D5S1725). The highest LOD score for BMI was 1.68 (chromosome 4, 113.8 cM). The areas of linkage for the three phenotypes showed some clustering as all three phenotypes were linked to the same regions of 2p13 and 5q14, and our study replicated linkage evidence for several regions previously reported in other studies.CONCLUSION:We obtained evidence for several QTLs on chromosome 2, 4 and 5 to three obesity phenotypes. This study provides data on the genetics of obesity in populations that are currently under represented in the global effort directed at understanding the pathophysiology of excess adiposity in free living individuals.

Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans

Objective:The role of the central melanocortin system in the development of obesity has been extensively studied. Single-nucleotide polymorphisms (SNPs) within several candidate genes have been associated with food intake and obesity-related phenotypes; however, few of these associations have been replicated. SNPs in the agouti-related protein (AGRP) gene coding (Ala67Thr, 199G/A) and promoter (−38C/T) have been reported to be associated with body mass index (BMI), fat mass (FM) and percent body fat, in populations of European and African descent. In this study, we evaluated the association between the functional AGRP −38C/T promoter SNP and weight-related traits, namely BMI, FM and fat-free mass (FFM), as well as diabetes status.Design:An association study of the AGRP −38C/T SNP and indices of obesity and diabetes status.Subjects:A well-characterized population of 538 West Africans from Ghana and Nigeria recruited in the AADM (Africa America Diabetes Mellitus) study (mean age 52 years, 41.3% males, 71% diabetic).Measurements:Genotyping of the AGRP −38C/T SNP, BMI, FM, FFM and fasting plasma glucose.Results:Women carrying two copies of the variant T allele had significantly lower BMI (OR=0.47; 95% CI, 0.25–0.87). Also, men with at least one copy of the variant T allele were over two times less likely to be diabetic than other men (OR=0.44; 95% CI, 0.22–0.89).Conclusion:Our results replicate previous findings and implicate the AGRP −38C/T SNP in the regulation of body weight in West Africans.

Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans

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.

Variation in APOL1 Contributes to Ancestry-Level Differences in HDLc-Kidney Function Association

Low levels of high-density cholesterol (HDLc) accompany chronic kidney disease, but the association between HDLc and the estimated glomerular filtration rate (eGFR) in the general population is unclear. We investigated the HDLc-eGFR association in nondiabetic Han Chinese (HC, n = 1100), West Africans (WA, n = 1497), and African Americans (AA, n = 1539). There were significant differences by ancestry: HDLc was positively associated with eGFR in HC (β = 0.13, P < 0.0001), but negatively associated among African ancestry populations (WA: −0.19, P < 0.0001; AA: −0.09, P = 0.02). These differences were also seen in nationally-representative NHANES data (among European Americans: 0.09, P = 0.005; among African Americans −0.14, P = 0.03). To further explore the findings in African ancestry populations, we investigated the role of an African ancestry-specific nephropathy risk variant, rs73885319, in the gene encoding HDL-associated APOL1. Among AA, an inverse HDLc-eGFR association was observed only with the risk genotype (−0.38 versus 0.001; P = 0.03). This interaction was not seen in WA. In summary, counter to expectation, an inverse HDLc-eGFR association was observed among those of African ancestry. Given the APOL1 × HDLc interaction among AA, genetic factors may contribute to this paradoxical association. Notably, these findings suggest that the unexplained mechanism by which APOL1 affects kidney-disease risk may involve HDLc.

Survival pattern of hemodialysis patients in Kumasi, Ghana: a summary of forty patients initiated on hemodialysis at a new hemodialysis unit.

To evaluate the survival pattern of hemodialysis patients at a dialysis unit in Kumasi, Ghana, through a retrospective (observational) study. Patients who were placed on hemodialysis at the dialysis unit at Komfo Anokye teaching hospital from October 25, 2006 to December 2007. The patients were followed from initiation of dialysis until December 31, 2007. The overall mortality was 14 (35.9%) on the incident population for the period and that for the first 90 days was 12 (32.4%) patients. Chronic glomerulonephritis was the underlying kidney disease in 35.9%. This was followed by hypertension (19.1%) and diabetes mellitus (15.4%), respectively. Cardiovascular diseases accounted for 42% of mortality. This was followed by septicemia (25%) from the access site and anemia (25%). Fifty percent of the patients were able to afford 20 sessions of hemodialysis before stopping. The most powerful predictors of survival were the duration of hemodialysis (P=0.05) and the number of hemodialysis sessions (P=0.02). Age at initiation of hemodialysis was not significant. First 90‐day mortality of patients on hemodialysis is high in poor African countries. This is due partially to the late referral of patients and also the cost of the dialysis treatment. Efforts will have to be made to reduce the cost of the dialysis treatment. Reuse technology (of dialyzer, etc.) should be introduced to cut down the cost of hemodialysis. Peritoneal dialysis should also be introduced for highly motivated patients. Efforts should also be made to reduce the increasing incidence of kidney disease, and finally third‐world countries should consider establishing kidney transplantation, that is cost effective.

Evaluation of Genome Wide Association Study Associated Type 2 Diabetes Susceptibility Loci in Sub Saharan Africans.

Genome wide association studies (GWAS) for type 2 diabetes (T2D) undertaken in European and Asian ancestry populations have yielded dozens of robustly associated loci. However, the genomics of T2D remains largely understudied in sub-Saharan Africa (SSA), where rates of T2D are increasing dramatically and where the environmental background is quite different than in these previous studies. Here, we evaluate 106 reported T2D GWAS loci in continental Africans. We tested each of these SNPs, and SNPs in linkage disequilibrium (LD) with these index SNPs, for an association with T2D in order to assess transferability and to fine map the loci leveraging the generally reduced LD of African genomes. The study included 1775 unrelated Africans (1035 T2D cases, 740 controls; mean age 54 years; 59% female) enrolled in Nigeria, Ghana, and Kenya as part of the Africa America Diabetes Mellitus (AADM) study. All samples were genotyped on the Affymetrix Axiom PanAFR SNP array. Forty-one of the tested loci showed transferability to this African sample (p < 0.05, same direction of effect), 11 at the exact reported SNP and 30 others at SNPs in LD with the reported SNP (after adjustment for the number of tested SNPs). TCF7L2 SNP rs7903146 was the most significant locus in this study (p = 1.61 × 10−8). Most of the loci that showed transferability were successfully fine-mapped, i.e., localized to smaller haplotypes than in the original reports. The findings indicate that the genetic architecture of T2D in SSA is characterized by several risk loci shared with non-African ancestral populations and that data from African populations may facilitate fine mapping of risk loci. The study provides an important resource for meta-analysis of African ancestry populations and transferability of novel loci.

Circulating Adiponectin Is Associated with Renal Function Independent of Age and Serum Lipids in West Africans

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.

Genome-wide analysis identifies an african-specific variant in SEMA4D associated with body mass index.

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.

Frequency and determinants of thyroid autoimmunity in Ghanaian type 2 diabetes patients: a case-control study

BackgroundThe link between type 1 diabetes and thyroid autoimmunity is well described. The same cannot be said for type 2 diabetes where results have been mixed so far. We investigated the prevalence and determinants of thyroid autoimmunity among Ghanaian type 2 diabetes patients.MethodsThis was a case-control study involving 302 type 2 diabetes patients and 310 non - diabetic controls aged 40–80 years. Anthropometric and blood pressure measurements were obtained. Fasting samples were analyzed for glucose, thyroid function, and antibodies to thyroglobulin and thyroid peroxidase.ResultsThe prevalence of thyroid autoimmunity was significantly higher among T2DM subjects (12.2% vs. 3.9%, p = 0.0004). Among T2DM subjects, 44 (14.7%) tested positive for TPOAb, 5 (1.7%) tested positive for TGAb and 15 (5.0%) tested positive for both autoantibodies. Females T2DM subjects showed a 3-fold increased risk of thyroid autoimmunity compared to males (OR:3.16, p =0.004), T2DM subjects with hyperthyroidism had a 41% increased risk of thyroid autoimmunity (OR: 1.41, p < 0.001), sub-clinical hyperthyroidism increased the risk of thyroid autoimmunity by 2 fold, (OR:2.19, p < 0.001), subclinical hypothyroidism increased the risk of autoimmunity by 4-fold, (OR:3.57 95% p < 0.0001), and hypothyroidism was associated with a 61% increased risk of thyroid autoimmunity (OR: 1.61,1.35–2.23). Dyslipidaemia was associated with a 44% increased risk of thyroid autoimmunity (OR: 1.44, p = 0.01) and a percentage increase in HbA1c was associated with 46% increased risk of thyroid autoimmunity (OR:1.46, p < 0.0001).ConclusionWe observed a high prevalence of thyroid autoimmunity in Ghanaian T2DM subjects compared to the general population. Thyroid autoimmunity in T2DM subjects was significantly associated with female gender, thyroid dysfunction, dyslipidaemia and poor glycemic control.

Impact of Type 2 Diabetes on Impaired Kidney Function in Sub-Saharan African Populations.

Background Diabetes is a leading risk factor for impaired kidney function, an indicator of chronic kidney disease. The aim of this study was to examine the association between type 2 diabetes (T2D) and impaired kidney function among adults in sub-Saharan Africa (SSA). Methods Participants were enrolled from Ghana, Kenya, and Nigeria. Impaired kidney function was based on an estimated glomerular filtration rate <60 ml/min/1.73 m2. Using logistic regression models, we conducted case–control analyses to estimate the multivariate-adjusted association of T2D and kidney function. Results We used data from 4815 participants for whom the mean (SD) age was 48 (15) years, 41% were male and 46% had T2D. Those with T2D were more likely to have impaired kidney function [13.4% (95% CI: 11.9–14.7)] compared to those without T2D [4.8% (95% CI: 4.0–5.6)], p-value <0.001. The multivariate odds ratio of impaired kidney function among those with type 2 diabetes was 1.50 (95% CI: 1.17–1.91) p-value = 0.001, compared to those without T2D. Also, individuals with T2D who were at least 60 years old, obese, hypertensive or dyslipidemic were more likely to have impaired kidney function compared to those without T2D. Conclusion T2D was associated with 50% increased risk of impaired kidney function in this sample of adults from SSA. Interventions targeted at prevention, early diagnosis, and management of T2D are likely to reduce the burden of kidney disease in SSA.