Untargeted metabolomic profiling reveals molecular signatures associated with type 2 diabetes in Nigerians.

BACKGROUND: Type 2 diabetes (T2D) has reached epidemic proportions globally, including in Africa. However, molecular studies to understand the pathophysiology of T2D remain scarce outside Europe and North America. The aims of this study are to use an untargeted metabolomics approach to identify: (a) metabolites that are differentially expressed between individuals with and without T2D and (b) a metabolic signature associated with T2D in a population of Sub-Saharan Africa (SSA). METHODS: A total of 580 adult Nigerians from the Africa America Diabetes Mellitus (AADM) study were studied. The discovery study included 310 individuals (210 without T2D, 100 with T2D). Metabolites in plasma were assessed by reverse phase, ultra-performance liquid chromatography and mass spectrometry (RP)/UPLC-MS/MS methods on the Metabolon Platform. Welch's two-sample t-test was used to identify differentially expressed metabolites (DEMs), followed by the construction of a biomarker panel using a random forest (RF) algorithm. The biomarker panel was evaluated in a replication sample of 270 individuals (110 without T2D and 160 with T2D) from the same study. RESULTS: Untargeted metabolomic analyses revealed 280 DEMs between individuals with and without T2D. The DEMs predominantly belonged to the lipid (51%, 142/280), amino acid (21%, 59/280), xenobiotics (13%, 35/280), carbohydrate (4%, 10/280) and nucleotide (4%, 10/280) super pathways. At the sub-pathway level, glycolysis, free fatty acid, bile metabolism, and branched chain amino acid catabolism were altered in T2D individuals. A 10-metabolite biomarker panel including glucose, gluconate, mannose, mannonate, 1,5-anhydroglucitol, fructose, fructosyl-lysine, 1-carboxylethylleucine, metformin, and methyl-glucopyranoside predicted T2D with an area under the curve (AUC) of 0.924 (95% CI: 0.845-0.966) and a predicted accuracy of 89.3%. The panel was validated with a similar AUC (0.935, 95% CI 0.906-0.958) in the replication cohort. The 10 metabolites in the biomarker panel correlated significantly with several T2D-related glycemic indices, including Hba1C, insulin resistance (HOMA-IR), and diabetes duration. CONCLUSIONS: We demonstrate that metabolomic dysregulation associated with T2D in Nigerians affects multiple processes, including glycolysis, free fatty acid and bile metabolism, and branched chain amino acid catabolism. Our study replicated previous findings in other populations and identified a metabolic signature that could be used as a biomarker panel of T2D risk and glycemic control thus enhancing our knowledge of molecular pathophysiologic changes in T2D. The metabolomics dataset generated in this study represents an invaluable addition to publicly available multi-omics data on understudied African ancestry populations.

Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of ß-cell function and insulin sensitivity in Africans without type 2 diabetes.

BACKGROUND: In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses. METHODS: We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and ß-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones). RESULTS: Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S ß = - 0.67, P-value = 1.88 × 10-6 and HOMA-B ß = 0.59, P-value = 1.88 × 10-5; IL-1RA ~ HOMA-S ß = - 0.51, P-value = 8.49 × 10-5 and HOMA-B ß = 0.48, P-value = 5.71 × 10-4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10-6), though these associations were not consistent in all sensitivity analyses. CONCLUSIONS: The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased ß-cell function. GIP's effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.

Associations between epigenome-wide DNA methylation and height-related traits among Sub-Saharan Africans: the RODAM study.

Human height and related traits are highly complex, and extensively research has shown that these traits are determined by both genetic and environmental factors. Such factors may partially affect these traits through epigenetic programing. Epigenetic programing is dynamic and plays an important role in controlling gene expression and cell differentiation during (early) development. DNA methylation (DNAm) is the most commonly studied epigenetic feature. In this study we conducted an epigenome-wide DNAm association analysis on height-related traits in a Sub-Saharan African population, in order to detect DNAm biomarkers across four height-related traits. DNAm profiles were acquired in whole blood samples of 704 Ghanaians, sourced from the Research on Obesity and Diabetes among African Migrants study, using the Illumina Infinium HumanMethylation450 BeadChip. Linear models were fitted to detect differentially methylated positions (DMPs) and regions (DMRs) associated with height, leg-to-height ratio (LHR), leg length, and sitting height. No epigenome-wide significant DMPs were recorded. However we did observe among our top DMPs five informative probes associated with the height-related traits: cg26905768 (leg length), cg13268132 (leg length), cg19776793 (height), cg23072383 (LHR), and cg24625894 (sitting height). All five DMPs are annotated to genes whose functions were linked to bone cell regulation and development. DMR analysis identified overlapping DMRs within the gene body of HLA-DPB1 gene, and the HOXA gene cluster. In this first epigenome-wide association studies of these traits, our findings suggest DNAm associations with height-related heights, and might influence development and maintenance of these traits. Further studies are needed to replicate our findings, and to elucidate the molecular mechanism underlying human height-related traits.

Serum Adiponectin and Leptin Among Ghanaian Migrants in Amsterdam and Their Compatriots in Rural and Urban Ghana: The RODAM Study.

Background: The rapidly rising cardiometabolic disease (CMD) burden in urbanizing sub-Saharan African populations and among sub-Saharan African migrants in Europe likely affects serum adiponectin and leptin levels, but this has not yet been quantified. Objectives: To compare the serum levels of adiponectin and leptin among migrant, and non-migrant (urban and rural) populations of Ghanaian descent. Methods: Cross-sectional analysis of serum leptin and adiponectin in the multi-centre Research on Obesity and Diabetes among African Migrants (RODAM) study. Logistic-regression models were used to examine the association between these adipocyte-derived hormones after stratification (sex, geographic area) and adjustments for potential confounders. Results: A total of 2518 Ghanaians were included. Rural participants had the highest serum adiponectin and lowest leptin levels compared to Amsterdam and urban Ghanaians (P < .001). In fully adjusted models, participants living in urban Ghana had significantly higher odds of hyperleptinemia compared to rural participants (women-odds ratio 2.88; 95% CI, 1.12-7.38, P = .028 and men 43.52, 95% CI, 4.84-391.25, P < .001). Urban Ghanaian men also had higher odds of elevated leptin: adiponectin ratio (6.29, 95% CI, 1.43-27.62, P = .015). The odds of hyperleptinemia were only higher in Amsterdam Ghanaian men (10.56; 95% CI, 1.11-100.85, P = .041), but not in women (0.85; 95% CI, 0.30-2.41, P = .759). There was no significant association between hypoadiponectinemia and geographical location in both sexes. Conclusion: Urbanization is associated with serum adiponectin and leptin levels after adjusting for confounding covariates in sub-Saharan Africans. These findings serve as a backdrop for further research on the role adipokines play in CMD epidemiology among Africans.

Validation of prevalent diabetes risk scores based on non-invasively measured predictors in Ghanaian migrant and non-migrant populations - The RODAM study.

Background: Non-invasive diabetes risk models are a cost-effective tool in large-scale population screening to identify those who need confirmation tests, especially in resource-limited settings. Aims: This study aimed to evaluate the ability of six non-invasive risk models (Cambridge, FINDRISC, Kuwaiti, Omani, Rotterdam, and SUNSET model) to identify screen-detected diabetes (defined by HbA1c) among Ghanaian migrants and non-migrants. Study design: A multicentered cross-sectional study. Methods: This analysis included 4843 Ghanaian migrants and non-migrants from the Research on Obesity and Diabetes among African Migrants (RODAM) Study. Model performance was assessed using the area under the receiver operating characteristic curves (AUC), Hosmer-Lemeshow statistics, and calibration plots. Results: All six models had acceptable discrimination (0.70 ≤ AUC <0.80) for screen-detected diabetes in the overall/combined population. Model performance did not significantly differ except for the Cambridge model, which outperformed Rotterdam and Omani models. Calibration was poor, with a consistent trend toward risk overestimation for screen-detected diabetes, but this was substantially attenuated by recalibration through adjustment of the original model intercept. Conclusion: Though acceptable discrimination was observed, the original models were poorly calibrated among populations of African ancestry. Recalibration of these models among populations of African ancestry is needed before use.

Macrovascular and renal microvascular complications in West Africans with intermediate hyperglycemia living in West Africa and Europe: The RODAM study.

Background: Metabolic conditions, including intermediate hyperglycemia (IH), affect migrants to a greater extent than the populations of origin. Evidence suggests that IH increases the risk of vascular complications, but it is unclear whether the differences in IH between the non-migrant and migrant populations translate to differences in vascular complications between the two populations. We compared the prevalence of macrovascular and renal microvascular complications among West Africans with IH living in West Africa and their migrant compatriots in Europe. Methods: Data from the multicenter Research on Obesity and Diabetes among African Migrants(RODAM) study were analyzed. Ghanaians with IH(524 non-migrant and 1439 migrants) were included. Logistic regression analyses were used to determine the associations between migrant status and macrovascular [coronary artery disease(CAD) and peripheral artery disease(PAD)] and renal microvascular[nephropathy] complications with adjustment for age, sex, socioeconomic status, smoking, systolic blood pressure, BMI, total cholesterol, HbA1c, C-reactive protein, and serum uric acid. Findings: The prevalence of microvascular/macrovascular complications was higher in non-migrants than in migrants(nephropathy 15.3vs.9.7%; PAD 3.1%vs.1.3%; and CAD 15.8% vs. 5.0%). The differences persisted in the fully adjusted model: nephropathy [odds ratio, 2.12; 95% CI(1.46-3.08); PAD, 4.44(1.87-10.51); CAD 2.35(1.64-3.37)]. Non-migrant females had higher odds of nephropathy[2.14(1.34-3.43)], PAD[7.47(2.38-23.40)] and CAD [2.10(1.34-3.27)] compared to migrant females. Non-migrant males had higher odds of nephropathy[2.54(1.30-4.97)] and CAD[2.85(1.48-5.50)], but not PAD[1.81(0.32-10.29)],than their migrant peers. Interpretation: Macrovascular and renal microvascular complications were more prevalent in non-migrants than in migrant West Africans with IH. Further studies are needed to identify factors that increase the risk to aid preventive/treatment strategies.

Subgroups of adult-onset diabetes: a data-driven cluster analysis in a Ghanaian population.

Adult-onset diabetes mellitus (here: aDM) is not a uniform disease entity. In European populations, five diabetes subgroups have been identified by cluster analysis using simple clinical variables; these may elucidate diabetes aetiology and disease prognosis. We aimed at reproducing these subgroups among Ghanaians with aDM, and establishing their importance for diabetic complications in different health system contexts. We used data of 541 Ghanaians with aDM (age: 25-70 years; male sex: 44%) from the multi-center, cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) Study. Adult-onset DM was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L, documented use of glucose-lowering medication or self-reported diabetes, and age of onset ≥ 18 years. We derived subgroups by cluster analysis using (i) a previously published set of variables: age at diabetes onset, HbA1c, body mass index, HOMA-beta, HOMA-IR, positivity of glutamic acid decarboxylase autoantibodies (GAD65Ab), and (ii) Ghana-specific variables: age at onset, waist circumference, FPG, and fasting insulin. For each subgroup, we calculated the clinical, treatment-related and morphometric characteristics, and the proportions of objectively measured and self-reported diabetic complications. We reproduced the five subgroups: cluster 1 (obesity-related, 73%) and cluster 5 (insulin-resistant, 5%) with no dominant diabetic complication patterns; cluster 2 (age-related, 10%) characterized by the highest proportions of coronary artery disease (CAD, 18%) and stroke (13%); cluster 3 (autoimmune-related, 5%) showing the highest proportions of kidney dysfunction (40%) and peripheral artery disease (PAD, 14%); and cluster 4 (insulin-deficient, 7%) characterized by the highest proportion of retinopathy (14%). The second approach yielded four subgroups: obesity- and age-related (68%) characterized by the highest proportion of CAD (9%); body fat-related and insulin-resistant (18%) showing the highest proportions of PAD (6%) and stroke (5%); malnutrition-related (8%) exhibiting the lowest mean waist circumference and the highest proportion of retinopathy (20%); and ketosis-prone (6%) with the highest proportion of kidney dysfunction (30%) and urinary ketones (6%). With the same set of clinical variables, the previously published aDM subgroups can largely be reproduced by cluster analysis in this Ghanaian population. This method may generate in-depth understanding of the aetiology and prognosis of aDM, particularly when choosing variables that are clinically relevant for the target population.

Ancestral and environmental patterns in the association between triglycerides and other cardiometabolic risk factors.

BACKGROUND: West Africans and African Americans with substantial (∼80%) West African ancestry are characterized by low levels of triglycerides (TG) compared to East Africans and Europeans. The impact of these varying TG levels on other cardiometabolic risk factors is unclear. We compared the strength of association between TG with hypertension, blood pressure, BMI, waist circumference, type 2 diabetes (T2D), and fasting glucose across West African (WA), East African (EA), and European (EU) ancestry populations residing in three vastly different environmental settings: sub-Saharan Africa, United States, and Europe. METHODS: We analysed data from four cross-sectional studies that included WA in sub-Saharan Africa (n = 7201), the U.S. (n = 4390), and Europe (n = 6436), EA in sub-Saharan Africa (n = 781), and EU in the U.S. (n = 8670) and Europe (n = 4541). Linear regression analyses were used to test the association between TG and cardiometabolic risk factors. FINDINGS: Higher adjusted regression coefficients were observed in EU compared with WA ancestry for TG on hypertension (EU ß [95% CI]: 0.179 [0.156, 0.203], WA ß [95% CI]: 0.102 [0.086, 0.118]), BMI (EU ß [95% CI]: 0.028 [0.027, 0.030], WA ß [95% CI]: 0.015 [0.014, 0.016]), and waist circumference (EU ß [95% CI]: 0.013 [0.013, 0.014], WA ß [95% CI]: 0.009 [0.008, 0.009) (all ancestry × trait interaction P-values <0.05), irrespective of environmental differences within ancestry groups. Less consistency was observed among EA. Associations of TG with T2D did not follow ancestry patterns, with substantial variation observed between environments. INTERPRETATION: TG may not be an equally strong associated with other established cardiometabolic risk factors in West and East Africans in contrast to European ancestry populations. The value of TG for identifying individuals at high risk for developing metabolic disorders needs to be re-evaluated for African ancestry populations. FUNDING: National Institutes of Health, European Commission, Dutch Heart Foundation, Netherlands Organization for Health Research and Development, Centers for Disease Control and Prevention.

Epigenome-wide association study of plasma lipids in West Africans: the RODAM study.

BACKGROUND: DNA-methylation has been associated with plasma lipid concentration in populations of diverse ethnic backgrounds, but epigenome-wide association studies (EWAS) in West-Africans are lacking. The aim of this study was to identify DNA-methylation loci associated with plasma lipids in Ghanaians. METHODS: We conducted an EWAS using Illumina 450k DNA-methylation array profiles of extracted DNA from 663 Ghanaian participants. Differentially methylated positions (DMPs) were examined for association with plasma total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, and triglycerides concentrations using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, and technical covariates. Findings were replicated in independent cohorts of different ethnicities. FINDINGS: We identified one significantly associated DMP with triglycerides (cg19693031 annotated to TXNIP, regression coefficient beta -0.26, false discovery rate adjusted p-value 0.001), which replicated in-silico in South African Batswana, African American, and European populations. From the top five DMPs with the lowest nominal p-values, two additional DMPs for triglycerides (CPT1A, ABCG1), two DMPs for LDL-cholesterol (EPSTI1, cg13781819), and one for TC (TXNIP) replicated. With the exception of EPSTI1, these loci are involved in lipid transport/metabolism or are known GWAS-associated loci. The top 5 DMPs per lipid trait explained 9.5% in the variance of TC, 8.3% in LDL-cholesterol, 6.1% in HDL-cholesterol, and 11.0% in triglycerides. INTERPRETATION: The top DMPs identified in this study are in loci that play a role in lipid metabolism across populations, including West-Africans. Future studies including larger sample size, longitudinal study design and translational research is needed to increase our understanding on the epigenetic regulation of lipid metabolism among West-African populations. FUNDING: European Commission under the Framework Programme (grant number: 278901).

Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI.

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.

Associations of psychosocial stress with type 2 diabetes and glycaemic control among Ghanaians: The RODAM study.

BACKGROUND: The extent to which psychosocial stress relates to type 2 diabetes among sub-Saharan Africans is not well understood. We assessed associations of psychosocial stresses with type 2 diabetes status and glycaemic control among Ghanaians. METHODS: We used data from Research on Obesity and Diabetes among African Migrants (RODAM) study. We performed logistic and linear regression models to assess association of psychosocial stresses with type 2 diabetes and HbA1c respectively with adjustments for age, sex, education and other stresses. We also assessed moderation effects of migration status (migrant Ghanaians vs. non-migrant Ghanaians), age, sex and education by adding interaction terms in models. RESULTS: Four thousand eight hundred and forty one Ghanaians were included with 44% resident in Ghana, 62% women, mean age of 46 years and 10% having type 2 diabetes. Psychosocial stress at home and at work were not associated with type 2 diabetes or HbA1c levels. Negative life events in past 12 months were negatively associated with type 2 diabetes (adjusted odds ratio = 0.93, 95% CI 0.87-0.99). Perceived discrimination was positively associated with type 2 diabetes (aOR = 1.01, 95% CI 1.004-1.03). Both associations were more pronounced in men. Perceived discrimination was also positively associated with HbA1c levels, especially among those with type 2 diabetes (adjusted ß = 0.01, 95% CI 0.007-0.02). CONCLUSIONS: Perceived discrimination and negative life events are associated with type 2 diabetes and glycaemic control among Ghanaians, especially in men. Further studies are needed to identify context-specific mechanisms underlying these associations.

Cohort profile: Research on Obesity and Diabetes among African Migrants in Europe and Africa Prospective (RODAM-Pros) cohort study.

PURPOSE: The Research on Obesity and Diabetes among African Migrants (RODAM) prospective (RODAM-Pros) cohort study was established to identify key changes in environmental exposures and epigenetic modifications driving the high burden of cardiovascular disease (CVD) risk among sub-Saharan African migrants. PARTICIPANTS: All the participants in the RODAM cross-sectional study that completed the baseline assessment (n=5114) were eligible for the follow-up of which 2165 participants (n=638 from rural-Ghana, n=608 from urban-Ghana, and n=919 Ghanaian migrants in Amsterdam, the Netherlands) were included in the RODAM-Pros cohort study. Additionally, we included a subsample of European-Dutch (n=2098) to enable a comparison to be made between Ghanaian migrants living in the Netherlands and the European-Dutch host population. FINDINGS TO DATE: Follow-up data have been collected on demographics, socioeconomic status, medical history, psychosocial environment, lifestyle factors, nutrition, anthropometrics, blood pressure, fasting blood, urine and stool samples. Biochemical analyses included glucose metabolism, lipid profile, electrolytes and renal function, liver metabolism and inflammation. In a subsample, we assessed DNA methylation patterns using Infinium 850K DNA Methylation BeadChip. Baseline results indicated that migrants have higher prevalence of CVD risk factors than non-migrants. Epigenome-wide association studies suggest important differences in DNA methylation between migrants and non-migrants. The follow-up study will shed further light on key-specific environmental exposures and epigenetic modifications contributing to the high burden of CVD risk among sub-Saharan African migrants. FUTURE PLANS: Follow-up is planned at 5-year intervals, baseline completed in 2015 and first follow-up completed in 2021.

An explorative epigenome-wide association study of plasma renin and aldosterone concentration in a Ghanaian population: the RODAM study.

BACKGROUND: The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). Here we report the first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations and the aldosterone-to-renin ratio (ARR). METHODS: Epigenome-wide DNA methylation was measured using the Illumina 450K array on whole blood samples of 68 Ghanaians. Differentially methylated positions (DMPs) were assessed for plasma renin concentration, aldosterone, and ARR using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, hypertension, and technical covariates. Additionally, we extracted methylation loci previously associated with hypertension, kidney function, or that were annotated to RAAS-related genes and associated these with renin and aldosterone concentration. RESULTS: We identified one DMP for renin, ten DMPs for aldosterone, and one DMP associated with ARR. Top DMPs were annotated to the PTPRN2, SKIL, and KCNT1 genes, which have been reported in relation to cardiometabolic risk factors, atherosclerosis, and sodium-potassium handling. Moreover, EWAS loci previously associated with hypertension, kidney function, or RAAS-related genes were also associated with renin, aldosterone, and ARR. CONCLUSION: In this first EWAS on RAAS hormones, we identified DMPs associated with renin, aldosterone, and ARR in a SSA population. These findings are a first step in understanding the role of DNA methylation in regulation of the RAAS in general and in a SSA population specifically. Replication and translational studies are needed to establish the role of these DMPs in the hypertension burden in SSA populations.

Mendelian randomization study reveals a causal relationship between adiponectin and LDL cholesterol in Africans.

Adiponectin has been associated with cardiometabolic traits in observational studies across populations, yet it is unclear if these associations are causal. We performed Mendelian randomization (MR) analysis to assess the relationship between adiponectin and cardiometabolic traits in sub-Saharan Africans. We constructed a polygenic risk score (PRS) for adiponectin levels across 3354 unrelated sub-Saharan Africans. The PRS was used as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, Type 2 Diabetes (T2D), and hypertension. The adiponectin PRS was causally related with LDL (ß = 0.55, 95%CI 0.07-1.04, P-value = 0.024) but not the other traits. This association was observed in both overweight/obese and normal weight individuals, but only reached statistical significance among overweight/obese individuals (ß = 0.55, 95%CI 0.01-1.08, P-value = 0.045). In normal weight individuals, the adiponectin PRS was associated with T2D (OR = 0.13, 95%CI 0.02-0.73, P-value = 0.021), and in men with HDL (ß = 1.03, 95%CI 0.14-1.92, P-value = 0.023). The findings of this first MR study in sub-Saharan Africans support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. These observations add to the small but growing literature on adiponectin MR studies.

An epigenome-wide association study of insulin resistance in African Americans.

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.

Hypertension determinants among Ghanaians differ according to location of residence: RODAM study.

OBJECTIVE: Hypertension prevalence is high among African migrants, but the determinants of hypertension in migrants in Europe in relation to the population in the country of origin still needs to be elucidated. Therefore, the aim of this study was to assess the determinants of hypertension in Ghanaians residing in Ghana and Europe. METHODS: The current study used baseline data of 5659 participants, aged 25-70 years, of the Research on Obesity and Diabetes among African Migrants study. Multivariate logistic regression analysis was used to assess sociodemographic, lifestyle, psychosocial, anthropometric and health factors independently associated with hypertension in Ghanaians living in rural and urban Ghana, and Ghanaian migrants living in Europe. RESULTS: Across all sites, older age (both sexes; odds ratio 1.07, 95% confidence interval 1.06-1.08) and diabetes (females only; 2.02, 1.54-1.67) were independently associated with hypertension. The other determinants of hypertension differed between geographical locations. Higher waist circumference (1.12, 1.05-1.20) was independently associated with hypertension in rural-Ghanaian males, as was higher body mass index (1.15, 1.03- 1.28) in urban-Ghanaian males, higher waist circumference (1.04, 1.01-1.07) and diabetes (1.75, 1.17-2.63) in European-Ghanaian males. In European-Ghanaian females, high alcohol intake (1.88, 1.01 -3.53) and waist circumference (1.04, 1.02- 1.06) were associated with hypertension, whereas in rural-Ghanaian females, a higher educational level (0.28, 0.08-0.98) was inversely associated with hypertension. CONCLUSION: The current study identified several modifiable determinants of hypertension in Ghanaians, with differences between populations residing in various geographical locations. This highlights the importance of development and implementation of context-specific interventions targeting these determinants to reduce the burden of hypertension among Ghanaian migrants and nonmigrants.

Psychosocial stressors among Ghanaians in rural and urban Ghana and Ghanaian migrants in Europe.

Psychosocial stressors have significant health and socio-economic impacts on individuals. We examined the prevalence and correlates of psychosocial stressors among non-migrant and migrant Ghanaians as there is limited research in these populations. The study was cross-sectional and quantitative in design. A majority of the study participants had experienced stress, discrimination and negative life events. Increased age, female sex, strong social support and high sense of mastery were associated with lower odds of experiencing psychosocial stressors in both populations. Interventions should be multi-level in design, focusing on the correlates which significantly influence the experience of psychosocial stressors.

C-reactive protein and hypertension among Ghanaian migrants and their homeland counterparts: the Research on Obesity and Diabetes among African Migrants study.

BACKGROUND: Hypertension (HTN) is a growing public health problem in sub-Saharan Africa (SSA) and SSA migrants in Europe. Elevated levels of inflammatory marker C-reactive protein (CRP) have been linked to HTN but the relationship of CRP and HTN among SSA populations has not been studied. To address this knowledge gap, we studied the association between CRP and HTN in migrant and nonmigrant SSA populations residing in different settings. METHODS: Cross-sectional data from the multicentre Research on Obesity and Diabetes among African Migrants (RODAM) study were analysed including 5683 Ghanaians aged at least 18 years, residing in rural and urban Ghana, and Europe. Multivariate logistic regression analyses were used to assess the association between high levels of CRP (≥3 mg/l) and HTN (SBP ≥140 mmHg and/or DBP ≥90 mmHg and/or use of antihypertensive medication) per geographical site and sex. RESULTS: The association between CRP levels and HTN varied by sex and geographical location. In age-adjusted models, there was an association between high CRP levels and HTN in urban-Ghanaian women (odds ratio 1.50, 95% confidence interval 1.10-2.03), and European-Ghanaian men (1.68, 1.16-2.43) and women (1.63, 1.28-2.07). However, these associations were attenuated after adjustment for conventional risk factors, especially BMI. No association was found in rural-Ghanaians or urban-Ghanaian men. CONCLUSION: Our findings show an association between CRP and HTN among Ghanaian migrants and urban-Ghanaian women, however, this was largely explained by conventional risk factors. Thus, prevention of conventional risk factors, in particular obesity, may help to reduce the potentially low-grade inflammatory mechanism underlying HTN.

Serum potassium concentration and its association with hypertension among Ghanaian migrants and non-migrants: The RODAM study.

BACKGROUND AND AIMS: Low serum potassium concentration is associated with hypertension, but whether the same association can be found in African origin populations, is unknown. We assessed serum potassium concentration, and its association with hypertension among Ghanaians living in different geographical locations. METHODS: Baseline data of 962 rural, 1420 urban, and 2947 migrant Ghanaians from the Research on Obesity and Diabetes among African Migrants study were analysed. Mean serum potassium concentration was compared between the groups, and the association between serum potassium and hypertension was assessed using multivariate regression analyses. RESULTS: Mean serum potassium concentration was higher in rural Ghana (4.28, 95% confidence interval 4.25-4.32 mmol/L) than in Ghanaians living in Amsterdam (3.90, 3.88-3.92 mmol/L) and London (4.11, 4.07-4.14 mmol/L), but lower than in Ghanaians living in urban Ghana (4.38, 4.34-4.42 mmol/L) and Berlin (4.57, 4.51-4.62 mmol/L) in both sexes. In the age-adjusted analyses, serum potassium was associated with hypertension in urban- (odds ratio 0.44, 0.23-0.82), London- (0.34, 0.17-0.64) and Amsterdam-Ghanaian males (0.41, 0.20-0.86), and in rural- (0.49, 0.28-0.84), London- (0.29, 0.17-0.49) and Amsterdam-Ghanaian females (0.33, 0.17-0.64). However, after adjustment for demographic, lifestyle, and health factors, serum potassium was associated with hypertension in Amsterdam-Ghanaian males only (0.12, 0.02-0.59). CONCLUSIONS: This study shows differences in mean serum potassium among Ghanaian populations living in different locations in Europe and Ghana, and different associations with hypertension between sites. Further research should focus on elucidating the mechanism underlying potassium handling and blood pressure regulation in African populations, in order to mitigate the burden of hypertension among these populations.