Ellis Owusu-Dabo

Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2

We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 × 10−9, odds ratio = 1.19, 95% CI = 1.13–1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.

Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains

The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens in vitro. This includes Mycobacterium tuberculosis, which is in agreement with findings indicating that M. tuberculosis translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied IRGM gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS6110 fingerprinting and genotyping of the pks1/15 deletion. The IRGM genotype -261TT was negatively associated with TB caused by M. tuberculosis (OR 0.66, CI 0.52-0.84, P(nominal) 0.0009, P(corrected) 0.0045) and not with TB caused by M. africanum or M. bovis (OR 0.95, CI 0.70-1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to M. tuberculosis strains with a damaged pks1/15 gene which is characteristic for the Euro-American (EUAM) subgroup of M. tuberculosis (OR 0.63, CI 0.49-0.81, P(nominal) 0.0004, P(corrected) 0.0019). Our results, including those of luciferase reporter gene assays with the IRGM variants -261C and -261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis EUAM clades. Moreover, they support in vitro findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact pks1/15 gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the IRGM -261TT genotype may have contributed to the establishment of M. africanum as a pathogen in the West African population.

Factors associated with hypertension awareness, treatment, and control in Ghana, West Africa

Hypertension is rapidly becoming a major public health burden in sub-Saharan/Africa but awareness, treatment, and control is lagging behind. We analysed cross-sectional data from Ghana (West-Africa) to examine factors associated with awareness, treatment, and control of hypertension. The overall prevalence of hypertension was 29.4%. Of these, 34% were aware of their condition, 28% were receiving treatment, and 6.2% were controlled below SBP/DBP <140/90 mmHg. Multivariate analysis showed that old age was independently associated with higher hypertension awareness: 35–49-year-olds (odds ratio (OR)=2.57, 95% (confidence interval) CI: 1.26–5.22), ⩾50-year-olds (OR=6.14, CI: 2.98–12.64) compared with 16–34-year-olds. Old age: ⩾50-year-olds (OR: 6.25, 95% CI: 2.87–13.62), trading (OR=2.46, 95% CI: 1.17–5.17), and overweight (OR=1.85, 95% CI: 1.02, 3.34) were independently associated with pharmacological treatment of hypertension. Trading (OR=2.51, 95% CI: 1.03–7.40) was independently associated with adequate blood pressure (BP) control but old age: ⩾50-year-olds (OR=0.11, 95% CI: 0.01–0.60) was independently associated with inadequate BP control. The identified factors provide important information for improving BP control among this population. Given the high cost of hypertension medication relative to income, increasing awareness and simple preventive measures such as promotion of physical activity, normalising body weight and reduction of salt intake, present the best hope for reducing the impact of hypertension on morbidity and mortality.

Common variants at 11p13 are associated with susceptibility to tuberculosis

After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10−9). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10−11.

Overweight and obesity among Ghanaian residents in The Netherlands: how do they weigh against their urban and rural counterparts in Ghana?

OBJECTIVE To investigate differences in overweight and obesity between first-generation Dutch-Ghanaian migrants in The Netherlands and their rural and urban counterparts in Ghana. DESIGN Cross-sectional study. SUBJECTS A total of 1471 Ghanaians (rural Ghanaians, n 532; urban Ghanaians, n 787; Dutch-Ghanaians, n 152) aged > or = 17 years. MAIN OUTCOME MEASURES Overweight (BMI > or = 25 kg/m2) and obesity (BMI > or = 30 kg/m2). RESULTS Dutch-Ghanaians had a significantly higher prevalence of overweight and obesity (men 69.1%, women 79.5%) than urban Ghanaians (men 22.0%, women 50.0%) and rural Ghanaians (men 10.3%, women 19.0%). Urban Ghanaian men and women also had a significantly higher prevalence of overweight and obesity than their rural Ghanaian counterparts. In a logistic regression analysis adjusting for age and education, the odds ratios for being overweight or obese were 3.10 (95% CI 1.75, 5.48) for urban Ghanaian men and 19.06 (95% CI 8.98, 40.43) for Dutch-Ghanaian men compared with rural Ghanaian men. Among women, the odds ratios for being overweight and obese were 3.84 (95% CI 2.66, 5.53) for urban Ghanaians and 11.4 (95% CI 5.97, 22.07) for Dutch-Ghanaians compared with their rural Ghanaian counterparts. CONCLUSION Our current findings give credence to earlier reports of an increase in the prevalence of overweight/obesity with urbanization within Africa and migration to industrialized countries. These findings indicate an urgent need to further assess migration-related factors that lead to these increases in overweight and obesity among migrants with non-Western background, and their impact on overweight- and obesity-related illnesses such as diabetes among these populations.

Blood pressure patterns in rural, semi-urban and urban children in the Ashanti region of Ghana, West Africa

BackgroundHigh blood pressure, once rare, is rapidly becoming a major public health burden in sub-Saharan/Africa. It is unclear whether this is reflected in children. The main purpose of this study was to assess blood pressure patterns among rural, semi-urban, and urban children and to determine the association of blood pressure with locality and body mass index (BMI) in this sub-Saharan Africa setting.MethodsWe conducted a cross-sectional survey among school children aged 8–16 years in the Ashanti region of Ghana (West-Africa). There were 1277 children in the study (616 boys and 661 females). Of these 214 were from rural, 296 from semi-urban and 767 from urban settings.ResultsBlood pressure increased with increasing age in rural, semi-urban and urban areas, and in both boys and girls. The rural boys had a lower systolic and diastolic blood pressure than semi-urban boys (104.7/62.3 vs. 109.2/66.5; p < 0.001) and lower systolic blood pressure than urban boys (104.7 vs. 107.6; p < 0.01). Girls had a higher blood pressure than boys (109.1/66.7 vs. 107.5/63.8; p < 0.01). With the exception of a lower diastolic blood pressure amongst rural girls, no differences were found between rural girls (107.4/64.4) and semi-urban girls (108.0/66.1) and urban girls (109.8/67.5). In multiple linear regression analysis, locality and BMI were independently associated with blood pressure in both boys and girls.ConclusionThese findings underscore the urgent need for public health measures to prevent increasing blood pressure and its sequelae from becoming another public health burden. More work on blood pressure in children in sub-Saharan African and other developing countries is needed to prevent high blood pressure from becoming a major burden in many of these countries.

MCP-1 promoter variant −362C associated with protection from pulmonary tuberculosis in Ghana, West Africa

Current endeavour focuses on human genetic factors that contribute to susceptibility to or protection from tuberculosis (TB). Monocytes are crucial in containing Mycobacterium tuberculosis infection, and the monocyte chemoattractant protein-1 (MCP-1) cytokine plays a role in their recruitment to the site of infection. The G allele of the MCP-1 promoter polymorphism at position -2581 relative to the ATG transcription start codon has been described to be associated in Mexican and Korean TB patients with increased susceptibility to TB. We genotyped this and additional MCP-1 variants in sample collections comprising more than 2000 cases with pulmonary TB and more than 2300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and more than 1400 TB patients and more than 1500 controls from Russia. In striking contrast to previous reports, MCP-1 -2581G was significantly associated with resistance to TB in cases versus controls [odds ratio (OR) 0.81, corrected P-value (P(corr)) = 0.0012] and nuclear families (OR 0.72, P(corr) = 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P = 0.86). Our and other results do not support an association of MCP-1 -2581 with TB. In the Ghanaian population, eight additional MCP-1 polymorphisms were genotyped. MCP-1 -362C was associated with resistance to TB in the case-control collection (OR 0.83, P(corr) = 0.00017) and in the affected families (OR 0.7, P(corr) = 0.004). Linkage disequilibrium (LD) and logistic regression analyses indicate that, in Ghanaians, the effect results exclusively from the MCP-1 -362 variant, whereas the effect of -2581 may in part be explained by its LD with -362.

No associations of human pulmonary tuberculosis with Sp110 variants

Background: After a recent report on the role of the Ipr1 gene in mediating innate immunity in a mouse model of Mycobacterium tuberculosis infection, the human Ipr1 homologue, Sp110, was considered a promising candidate for an association study in human tuberculosis. Methods: In a sample of >1000 sputum positive, HIV negative West African patients with pulmonary tuberculosis and >1000 exposed, apparently healthy controls, we have genotyped 21 Sp110 gene variants that were either available from public databases, including HapMap data, or identified by DNA re-sequencing. Results: No significant differences in the frequencies of any of the 21 variants were observed between patients and controls. This applied also for HapMap tagging variants and the corresponding haplotypes, when including sliding window analyses with three adjacent variants, and when stratifying controls for positivity and negativity according to the results of intradermal tuberculin (purified protein derivative, PPD) skin tests. DNA re-sequencing revealed 13 novel Sp110 variants in the 5′-UTR, exons, and adjacent intronic regions. Conclusions: Based on the results obtained in this case-control study, the hypothesis that Sp110 variants and haplotypes might be associated with distinct phenotypes of human M tuberculosis infection is doubtful.

Variant G57E of Mannose Binding Lectin Associated with Protection against Tuberculosis Caused by Mycobacterium africanum but not by M. tuberculosis

Structural variants of the Mannose Binding Lectin (MBL) cause quantitative and qualitative functional deficiencies, which are associated with various patterns of susceptibility to infectious diseases and other disorders. We determined genetic MBL variants in 2010 Ghanaian patients with pulmonary tuberculosis (TB) and 2346 controls and characterized the mycobacterial isolates of the patients. Assuming a recessive mode of inheritance, we found a protective association between TB and the MBL2 G57E variant (odds ratio 0.60, confidence interval 0.4–0.9, P 0.008) and the corresponding LYQC haplotype (P corrected 0.007) which applied, however, only to TB caused by M. africanum but not to TB caused by M. tuberculosis. In vitro, M. africanum isolates bound recombinant human MBL more efficiently than did isolates of M. tuberculosis. We conclude that MBL binding may facilitate the uptake of M. africanum by macrophages, thereby promoting infection and that selection by TB may have favoured the spread of functional MBL deficiencies in regions endemic for M. africanum.

IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB.

Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions −2849 , −1082 , −819 , and −592 and reconstructed the haplotypes. The IL10 low-producer haplotype −2849A/−1082A/−819C/−592C, compared to the high-producer haplotype −2849G/−1082G/−819C/−592C, occurred less frequent among PPD-negative controls than among cases (OR 2.15, CI 1.3–3.6) and PPD-positive controls (OR 2.09, CI 1.2–3.5). Lower IL-10 plasma levels in homozygous −2849A/−1082A/−819C/−592C carriers, compared to homozygous −2849G/−1082G/−819C/−592C carriers, were confirmed by a IL-10 ELISA (p = 0.016). Although we did not observe differences between the TB patients and all controls, our results provide evidence that a group of individuals exposed to M. tuberculosis transmission is genetically distinct from healthy PPD positives and TB cases. In these PPD-negative individuals, higher IL-10 production appears to reflect IL-10-dependent suppression of adaptive immune responses and sustained long-term specific anergy.