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.

Evolutionary forces in diabetes and hypertension pathogenesis in Africans.

Rates of type 2 diabetes (T2D) and hypertension are increasing rapidly in urbanizing sub-Saharan Africa (SSA). While lifestyle factors drive the increases in T2D and hypertension prevalence, evidence across populations shows that genetic variation, which is driven by evolutionary forces including a natural selection that shaped the human genome, also plays a role. Here we report the evidence for the effect of selection in African genomes on mechanisms underlying T2D and hypertension, including energy metabolism, adipose tissue biology, insulin action and salt retention. Selection effects found for variants in genes PPARA and TCF7L2 may have enabled Africans to respond to nutritional challenges by altering carbohydrate and lipid metabolism. Likewise, African-ancestry-specific characteristics of adipose tissue biology (low visceral adipose tissue [VAT], high intermuscular adipose tissue and a strong association between VAT and adiponectin) may have been selected for in response to nutritional and infectious disease challenges in the African environment. Evidence for selection effects on insulin action, including insulin resistance and secretion, has been found for several genes including MPHOSPH9, TMEM127, ZRANB3 and MC3R. These effects may have been historically adaptive in critical conditions, such as famine and inflammation. A strong correlation between hypertension susceptibility variants and latitude supports the hypothesis of selection for salt retention mechanisms in warm, humid climates. Nevertheless, adaptive genomics studies in African populations are scarce. More work is needed, particularly genomics studies covering the wide diversity of African populations in SSA and Africans in diaspora, as well as further functional assessment of established risk loci.

GWAS in Africans identifies novel lipids loci and demonstrates heterogenous association within Africa.

Serum lipids are biomarkers of cardiometabolic disease risk, and understanding genomic factors contributing to their distribution is of interest. Studies of lipids in Africans are rare, though it is expected that such studies could identify novel loci. We conducted a GWAS of 4317 Africans enrolled from Nigeria, Ghana and Kenya. We evaluated linear mixed models of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG) and TG/HDLC. Replication was attempted in 9542 African Americans (AA). In our main analysis, we identified 28 novel associations in Africans. Of the 18 of these that could be tested in AA, three associations replicated (GPNMB-TG, ENPP1-TG and SMARCA4-LDLC). Five additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG, PGBD5-HDLC, CD80-TG/HDLC, SLC44A1-CHOL 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. Among our novel findings are some loci with known connections to lipids pathways. For instance, rs147706369 (TLL2) alters a regulatory motif for sterol regulatory element-binding proteins, a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid and TG synthesis, and rs115749422 (SMARCA4), an independent association near the known LDLR locus that is rare or absent in populations without African ancestry. These findings demonstrate the utility of conducting genomic analyses in Africans for discovering novel loci and provide some preliminary evidence for caution against treating 'African ancestry' as a monolithic category.

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.

Inverse Association between Iron Deficiency and Glycated Hemoglobin Levels in Ghanaian Adults-the RODAM Study.

BACKGROUND: Glycated hemoglobin (HbA1c) is often used to diagnose type 2 diabetes (T2D), but studies show that iron deficiency (ID) is associated with elevated HbA1c in the absence of hyperglycemia. It is unknown whether ID prevalence varies between sub-Saharan African populations living in different locations and whether ID influences HbA1c levels in these populations. OBJECTIVES: We assessed the prevalence of ID among Ghanaian migrants in Europe and nonmigrant Ghanaians, and the influence of ID on HbA1c categories among Ghanaians without T2D. METHODS: We used the database from the cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study. This contained data on 3377 Ghanaian men and women aged 25-70 y living in urban and rural Ghana and Ghanaian migrants living in Amsterdam, London, and Berlin. ID was defined as ferritin < 15 ng/mL or, if C-reactive protein was ≥5 mg/mL, as ferritin < 30 ng/mL according to the WHO. We used binary logistic regression to assess differences in ID between sites and its association with clinically defined HbA1c categories (<5.5%, ≥5.5% to <6.5%, ≥6.5%). Men and women were analyzed separately. RESULTS: The prevalence of ID was higher in migrant [28.4%; adjusted OR (aOR): 3.08; 95% CI: 2.04, 4.65)] and urban (23.2%; aOR: 2.37; 95% CI: 1.56, 3.59) women than in rural women (11.9%). Among women, ID was associated with higher odds of HbA1c ≥ 5.5% to <6.5% in the absence of hyperglycemia (aOR: 1.43; 95% CI: 1.08, 1.87). This association was not found in men. CONCLUSIONS: Further research is needed to identify factors underlying the high prevalence of ID among urban and migrant Ghanaian women, and the association of ID with HbA1c ≥ 5.5% to <6.5% in women. In addition, our study reinforces the need to consider iron concentrations if interpreting HbA1c among African populations.

Hyperuricaemia and its association with 10-year risk of cardiovascular disease among migrant and non-migrant African populations: the RODAM study.

OBJECTIVE: In the advent of rapid urbanisation, migration and epidemiological transition, the extent to which serum uric acid (sUA) affects cardiovascular disease (CVD) risk among Africans is not well understood. We assessed differences in sUA levels and associations with CVD risk among migrant Ghanaians in Europe and non-migrant Ghanaians in rural and urban Ghana. METHODS: Baseline data from 633 rural, 916 urban and 2315 migrant participants (40-70 years) from the cross-sectional RODAM study were analysed. Hyperuricaemia was defined as sUA >7 mg/dl in men and >6 mg/dl in women. The 10-year risk of atherosclerotic cardiovascular disease (ASCVD) was calculated using the American College of Cardiology (ACC)/American Heart Association (AHA) risk score which takes into account ethnic minority populations. High CVD risk was defined as ASCVD risk scores ≥7.5%. Logistic regressions were used to assess associations between hyperuricaemia and CVD risk. RESULTS: Prevalence for hyperuricaemia in rural, urban and migrant participants was 17.4%, 19.1% and 31.7% for men, and 15.9%, 18.2% and 33.2% for women, respectively. Hyperuricaemia was positively associated with elevated CVD risk among rural residents (adjusted OR for men 3.28, 95% CI: 1.21-8.96, 6.36, 95% CI: 2.98-13.56 for women), urban residents (1.12, 95% CI: 0.45-2.81 for men, 2.11, 95% CI: 1.26-3.52 for women) and migrants (1.73, 95% CI: 1.01-2.96 for men, 4.61, 95% CI: 3.05-6.97 for women). CONCLUSION: Our study shows variations of sUA levels in different African contexts. Hyperuricaemia is associated with elevated 10-year CVD risk in both migrants and non-migrants. Further studies should identify factors driving associations between sUA and CVD risk in Africans.

OBJECTIF: Avec l'avènement de l'urbanisation rapide, de la migration et de la transition épidémiologique, la mesure dans laquelle l'acide urique sérique (AUs) affecte le risque de maladie cardiovasculaire (MCV) chez les Africains n'est pas bien comprise. Nous avons évalué les différences dans les niveaux d'AUs et les associations avec le risque de MCV chez les ghanéens migrants en Europe et non migrants dans les zones rurales et urbaines du Ghana. MÉTHODES: Les données de base de 633 participants ruraux, 916 urbains et 2.315 migrants, de 40 à 70 ans de l'étude transversale RODAM ont été analysées. L'hyperuricémie a été définie comme une AUs > 7 mg/dl chez les hommes et >6 mg/dl chez les femmes. Le risque sur 10 ans de MCV athérosclérosique (MCVAS) a été calculé en utilisant le score de risque de l'American College of Cardiology (ACC)/American Heart Association (AHA) qui prend en compte les populations des minorités ethniques. Un risque de MCV élevé était défini comme un score de risque MCVAS ≥7,5%. Des régressions logistiques ont été utilisées pour évaluer les associations entre l'hyperuricémie et le risque de MCV. RÉSULTATS: La prévalence de l'hyperuricémie chez les participants ruraux, urbains et migrants était de 17,4% ; 19,1% et 31,7% pour les hommes et 15,9%, 18,2% et 33,2% pour les femmes, respectivement. L'hyperuricémie était positivement associée à un risque élevé de MCV chez les résidents ruraux (OR ajusté 3,28 ; IC95%: 1,21-8,96 pour les hommes, 6,36, IC95%: 2,98-13,56 pour les femmes), les résidents urbains (1,12 ; IC95%: 0,45-2,81 pour les hommes, 2,11 ; IC95%: 1,26-3,52 pour les femmes) et les migrants (1,73 ; IC95%: 1,01-2,96 pour les hommes, 4,61 ; IC95%: 3,05-6,97 pour les femmes). CONCLUSION: Notre étude montre des variations des niveaux d'AUs dans différents contextes africains. L'hyperuricémie est associée à un risque élevé de MCV sur 10 ans chez les migrants et les non-migrants. Des études plus poussées devraient identifier les facteurs à l'origine des associations entre le risque d'AUs et de MCV chez les africains.

Prevalence of metabolic syndrome in sub-Saharan Africa: A systematic review and meta-analysis.

BACKGROUND AND AIMS: There are rising levels of cardiovascular diseases (CVDs) and diabetes in Sub-Saharan Africa (SSA). Metabolic syndrome (MS) is a precursor of these conditions, but the data on the prevalence of MS in SSA are fragmented. We conducted a systematic review and meta-analysis to estimate the prevalence of MS in SSA and determine the population groups that are most at risk. METHODS AND RESULTS: We systematically searched PubMed, Embase and African Journals Online for all published articles reporting MS prevalence in SSA populations. Random effects models were used to calculate the pooled prevalence overall and by major study-level characteristics. A total of 65 studies across fourteen different countries comprising 34,324 healthy participants aged ≥16 years were included in the meta-analysis. The overall prevalence of MS according to the different diagnostic criteria was: IDF: 18.0% (95%CI:13.3-23.3), IDF-ethnic: 16.0% (95%CI:11.3-21.4), JIS: 23.9% (95%CI: 16.5-32.3), NCEP-ATP III: 17.1% (95%CI:12.8-22.0) and WHO: 11.1% (95%CI:5.3-18.9). The prevalence of MS was higher in women than in men, and higher in (semi-)urban than in rural participants. The MS prevalence was highest in Southern Africa, followed by Eastern, Western and Central Africa. Substantial heterogeneity in the prevalence estimates across studies were not explained by major study-level characteristics, while apparent publication biases were likely artefactual. CONCLUSIONS: MS is not rare in SSA. The prevalence of MS was highest for women, populations in urban areas, and populations in Southern Africa. Public health intervention efforts are needed to prevent further increases in the burden of MS in the region.

Differential associations between psychosocial stress and obesity among Ghanaians in Europe and in Ghana: findings from the RODAM study.

PURPOSE: Psychosocial stress is associated with obesity in some populations, but it is unclear whether the association is related to migration. This study explored associations between psychosocial stress and obesity among Ghanaian migrants in Europe and non-migrant Ghanaians in Ghana. METHODS: Cross-sectional data from the RODAM study were used, including 5898 Ghanaians residing in Germany, the UK, the Netherlands, rural Ghana, and urban Ghana. Perceived discrimination, negative life events and stress at work or at home were examined in relation to body mass index (BMI) and waist circumference (WC). Linear regression analyses were performed separately for migrants and non-migrants stratified by sex. RESULTS: Perceived discrimination was not associated with BMI and WC in both migrants and non-migrants. However, negative life events were positively associated with BMI (ß = 0.78, 95% CI 0.34-1.22) and WC (ß = 1.96, 95% CI 0.79-3.12) among male Ghanaian migrants. Similarly, stress at work or at home was positively associated with BMI (ß = 0.28, 95% CI 0.00-0.56) and WC (ß = 0.84, 95% CI 0.05-1.63) among male Ghanaian migrants. Among non-migrant Ghanaians, in contrast, stress at work or at home was inversely associated with BMI and WC in both males (ß = - 0.66, 95% CI - 1.03 to - 0.28; ß = - 1.71 95% CI - 2.69 to - 0.73, respectively) and females (ß = - 0.81, 95% CI - 1.20 to - 0.42; ß = - 1.46, 95% CI - 2.30 to - 0.61, respectively). CONCLUSIONS: Negative life events and stress at work or at home are associated with increased body weight among male Ghanaians in European settings, whereas stress at work or at home is associated with reduced body weight among Ghanaians in Ghana. More work is needed to understand the underlying factors driving these differential associations to assist prevention efforts.

Dietary Patterns Are Associated with Predicted 10-Year Risk of Cardiovascular Disease Among Ghanaian Populations: the Research on Obesity and Diabetes in African Migrants (RODAM) Study.

BACKGROUND: Sub-Saharan African populations are disproportionately affected by cardiovascular disease (CVD). Although diet is an important lifestyle factor associated with CVD, evidence on the relation between dietary patterns (DPs) and CVD risk among sub-Saharan African populations is limited. OBJECTIVE: We assessed the associations of DPs with estimated 10-y atherosclerotic cardiovascular disease (ASCVD) risk in Ghanaian adults in Ghana and Europe. METHODS: Three DPs ('mixed'; 'rice, pasta, meat, and fish'; and 'roots, tubers, and plantain') were derived by principal component analysis (PCA) based on intake frequencies obtained by a self-administered Food Propensity Questionnaire in the multi-center, cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study. The 10-y ASCVD risk was estimated using the Pooled Cohort Equations (PCE) for 2976 subjects, aged 40-70 y; a risk score ≥7.5% was defined as 'elevated' ASCVD risk. The associations of DPs with 10-y ASCVD risk were determined using Poisson regression with robust variance. RESULTS: Stronger adherence to a 'mixed' DP was associated with a lower predicted 10-y ASCVD in urban and rural Ghana and a higher 10-y ASCVD in Europe. The observed associations were attenuated after adjustment for possible confounders with the exception of urban Ghana (prevalence ratio [PR] for Quintile 5 compared with 1: 0.70; 95% CI: 0.53, 0.93, P-trend = 0.013). The 'rice, pasta, meat, and fish' DP was inversely associated with 10-y ASCVD across all study sites, with the adjusted effect being significant only in urban Ghana. A 'roots, tubers, and plantain' DP was directly associated with increased 10-y ASCVD risk. CONCLUSIONS: Adherence to 'mixed' and 'rice, pasta, meat, and fish' DPs appears to reduce predicted 10-y ASCVD risk in adults in urban Ghana. Further investigations are needed to understand the underlying contextual-level mechanisms that influence dietary habits and to support context-specific dietary recommendations for CVD prevention among sub-Saharan African populations.

The prevalence of metabolic syndrome among Ghanaian migrants and their homeland counterparts: the Research on Obesity and type 2 Diabetes among African Migrants (RODAM) study.

BACKGROUND: Metabolic syndrome (MetSyn) is an important risk factor for cardiovascular diseases and type 2 diabetes. It is unknown whether the MetSyn prevalence differs within a homogenous population residing in different settings in Africa and Europe. We therefore assessed the prevalence of MetSyn among Ghanaians living in rural- and urban-Ghana and Ghanaian migrants living in Europe. METHODS: We used data from the cross-sectional multi-centre RODAM study that was conducted among Ghanaian adults aged 25-70 years residing in rural- and urban-Ghana and in London, Amsterdam and Berlin (n = 5659). MetSyn was defined according to the 2009 harmonized definition. Geographical locations were compared using age-standardized prevalence rates, and prevalence ratios (PRs), adjusted for age, education, physical activity, and smoking and stratified for sex. RESULTS: In men, the age-standardized prevalence of MetSyn was 8.3% in rural Ghana and showed a positive gradient through urban Ghana (23.6%, adjusted PR = 1.85, 95% confidence interval 1.17-2.92) to Europe, with the highest prevalence in Amsterdam (31.4%; PR = 4.45, 2.94-6.75). In women, there was a rural-to-urban gradient in age-standardized MetSyn prevalence (rural Ghana 25%, urban Ghana 34.4%, PR = 1.38, 1.13-1.68), but small differences in MetSyn prevalence between urban-Ghanaian and European-Ghanaian women (Amsterdam 38.4%; London 38.2%). CONCLUSION: MetSyn is highly prevalent in Ghana as well as in Ghanaian migrants in Europe. To assist prevention efforts, further research is needed to understand the mechanisms driving the geographical differences in MetSyn prevalence between migrant and non-migrant Ghanaians.

Chronic kidney disease burden among African migrants in three European countries and in urban and rural Ghana: the RODAM cross-sectional study.

Background: Chronic kidney disease (CKD) is a major burden among sub-Saharan African (SSA) populations. However, differences in CKD prevalence between rural and urban settings in Africa, and upon migration to Europe are unknown. We therefore assessed the differences in CKD prevalence among homogenous SSA population (Ghanaians) residing in rural and urban Ghana and in three European cities, and whether conventional risk factors of CKD explained the observed differences. Furthermore, we assessed whether the prevalence of CKD varied among individuals with hypertension and diabetes compared with individuals without these conditions. Methods: For this analysis, data from Research on Obesity & Diabetes among African Migrants (RODAM), a multi-centre cross-sectional study, were used. The study included a random sample of 5607 adult Ghanaians living in Europe (1465 Amsterdam, 577 Berlin, 1041 London) and Ghana (1445 urban and 1079 rural) aged 25-70 years. CKD status was defined according to severity of kidney disease using the combination of glomerular filtration rate (G1-G5) and albuminuria (A1-A3) levels as defined by the 2012 Kidney Disease: Improving Global Outcomes severity classification. Comparisons among sites were made using logistic regression analysis. Results: CKD prevalence was lower in Ghanaians living in Europe (10.1%) compared with their compatriots living in Ghana (13.3%) even after adjustment for age, sex and conventional risk factors of CKD [adjusted odds ratio (OR) = 0.70, 95% confidence interval (CI) 0.56-0.88, P = 0.002]. CKD prevalence was markedly lower among Ghanaian migrants with hypertension (adjusted OR = 0.54, 0.44-0.76, P = 0.001) and diabetes (adjusted OR = 0.37, 0.22-0.62, P = 0.001) compared with non-migrant Ghanaians with hypertension and diabetes. No significant differences in CKD prevalence was observed among non-migrant Ghanaians and migrant Ghanaians with no hypertension and diabetes. Among Ghanaian residents in Europe, the odds of CKD were lower in Amsterdam than in Berlin, while among Ghanaian residents in Ghana, the odds of CKD were lower in rural Ghana (adjusted OR = 0.68, 95% CI 0.53-0.88, P = 0.004) than in urban Ghana, but these difference were explained by conventional risk factors. Conclusion: Our study shows important differences in CKD prevalence among Ghanaians living in Europe compared with those living in Ghana, independent of conventional risk factors, with marked differences among those with hypertension and diabetes. Further research is needed to identify factors that might explain the observed difference across sites to implement interventions to reduce the high burden of CKD, especially in rural and urban Ghana.

Food variety, dietary diversity, and type 2 diabetes in a multi-center cross-sectional study among Ghanaian migrants in Europe and their compatriots in Ghana: the RODAM study.

PURPOSE: The importance of dietary diversification for type 2 diabetes (T2D) risk remains controversial. We investigated associations of between- and within-food group variety with T2D, and the role of dietary diversification for the relationships between previously identified dietary patterns (DPs) and T2D among Ghanaian adults. METHODS: In the multi-center cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) Study (n = 3810; Ghanaian residence, 56%; mean age, 46.2 years; women, 63%), we constructed the Food Variety Score (FVS; 0-20 points), the Dietary Diversity Score (DDS; 0-7 points), and the Diet Quality Index-International (DQI-I) variety component (0-20 points). The associations of these scores, of a "rice, pasta, meat and fish" DP, of a "mixed" DP, and of a "roots, tubers and plantain" DP with T2D were calculated by logistic regression. RESULTS: The FVS was inversely associated with T2D, adjusted for socio-demographic, lifestyle, and anthropometric factors [odds ratio (OR) for T2D per 1 standard deviation (SD) increase: 0.81; 95% confidence interval (CI) 0.71-0.93]. The DDS and the DQI-I variety component were not associated with T2D. There was no association of the "mixed" DP and the "roots, tubers and plantain" DP with T2D. Yet, the "rice, pasta, meat and fish" DP is inversely associated with T2D (OR for T2D per 1 SD increase: 0.82; 95% CI 0.71-0.95); this effect was slightly attenuated by the FVS. CONCLUSIONS: In this Ghanaian population, between-food group variety may exert beneficial effects on glucose metabolism and partially explains the inverse association of the "rice, pasta, meat and fish" DP with T2D.

Peripheral insulin resistance rather than beta cell dysfunction accounts for geographical differences in impaired fasting blood glucose among sub-Saharan African individuals: findings from the RODAM study.

AIMS/HYPOTHESIS: The aim of this study was to assess the extent to which insulin resistance and beta cell dysfunction account for differences in impaired fasting blood glucose (IFBG) levels in sub-Saharan African individuals living in different locations in Europe and Africa. We also aimed to identify determinants associated with insulin resistance and beta cell dysfunction among this population. METHODS: Data from the cross-sectional multicentre Research on Obesity and Diabetes among African Migrants (RODAM) study were analysed. Participants included Ghanaian individuals without diabetes, aged 18-96 years old, who were residing in Amsterdam (n = 1337), Berlin (n = 502), London (n = 961), urban Ghana (n = 1309) and rural Ghana (n = 970). Glucose and insulin were measured in fasting venous blood samples. Anthropometrics were assessed during a physical examination. Questionnaires were used to assess demographics, physical activity, smoking status, alcohol consumption and energy intake. Insulin resistance and beta cell function were determined using homeostatic modelling (HOMA-IR and HOMA-B, respectively). Logistic regression analysis was used to study the contribution of HOMA-IR and inverse HOMA-B (beta cell dysfunction) to geographical differences in IFBG (fasting glucose 5.6-6.9 mmol/l). Multivariate linear regression analysis was used to identify determinants associated with HOMA-IR and inverse HOMA-B. RESULTS: IFBG was more common in individuals residing in urban Ghana (OR 1.41 [95% CI 1.08, 1.84]), Amsterdam (OR 3.44 [95% CI 2.69, 4.39]) and London (OR 1.58 [95% CI 1.20 2.08), but similar in individuals living in Berlin (OR 1.00 [95% CI 0.70, 1.45]), compared with those in rural Ghana (reference population). The attributable risk of IFBG per 1 SD increase in HOMA-IR was 69.3% and in inverse HOMA-B was 11.1%. After adjustment for HOMA-IR, the odds for IFBG reduced to 0.96 (95% CI 0.72, 1.27), 2.52 (95%CI 1.94, 3.26) and 1.02 (95% CI 0.78, 1.38) for individuals in Urban Ghana, Amsterdam and London compared with rural Ghana, respectively. In contrast, adjustment for inverse HOMA-B had very minor impact on the ORs of IFBG. In multivariate analyses, BMI (ß = 0.17 [95% CI 0.11, 0.24]) and waist circumference (ß = 0.29 [95%CI 0.22, 0.36]) were most strongly associated with higher HOMA-IR, whereas inverse HOMA-B was most strongly associated with age (ß = 0.20 [95% CI 0.16, 0.23]) and excess alcohol consumption (ß = 0.25 [95% CI 0.07, 0.43]). CONCLUSIONS/INTERPRETATION: Our findings suggest that insulin resistance, rather than beta cell dysfunction, is more important in accounting for the geographical differences in IFBG among sub-Saharan African individuals. We also show that BMI and waist circumference are important factors in insulin resistance in this population.

Obesity and type 2 diabetes in sub-Saharan Africans - Is the burden in today's Africa similar to African migrants in Europe? The RODAM study.

BACKGROUND: Rising rates of obesity and type 2 diabetes (T2D) are impending major threats to the health of African populations, but the extent to which they differ between rural and urban settings in Africa and upon migration to Europe is unknown. We assessed the burden of obesity and T2D among Ghanaians living in rural and urban Ghana and Ghanaian migrants living in different European countries. METHODS: A multi-centre cross-sectional study was conducted among Ghanaian adults (n = 5659) aged 25-70 years residing in rural and urban Ghana and three European cities (Amsterdam, London and Berlin). Comparisons between groups were made using prevalence ratios (PRs) with adjustments for age and education. RESULTS: In rural Ghana, the prevalence of obesity was 1.3 % in men and 8.3 % in women. The prevalence was considerably higher in urban Ghana (men, 6.9 %; PR: 5.26, 95 % CI, 2.04-13.57; women, 33.9 %; PR: 4.11, 3.13-5.40) and even more so in Europe, especially in London (men, 21.4 %; PR: 15.04, 5.98-37.84; women, 54.2 %; PR: 6.63, 5.04-8.72). The prevalence of T2D was low at 3.6 % and 5.5 % in rural Ghanaian men and women, and increased in urban Ghanaians (men, 10.3 %; PR: 3.06; 1.73-5.40; women, 9.2 %; PR: 1.81, 1.25-2.64) and highest in Berlin (men, 15.3 %; PR: 4.47; 2.50-7.98; women, 10.2 %; PR: 2.21, 1.30-3.75). Impaired fasting glycaemia prevalence was comparatively higher only in Amsterdam, and in London, men compared with rural Ghana. CONCLUSION: Our study shows high risks of obesity and T2D among sub-Saharan African populations living in Europe. In Ghana, similarly high prevalence rates were seen in an urban environment, whereas in rural areas, the prevalence of obesity among women is already remarkable. Similar processes underlying the high burden of obesity and T2D following migration may also be at play in sub-Saharan Africa as a consequence of urbanisation.

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.

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.

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.

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.