CRP Genotypes Predict Increased Risk to Co-Present with Low Vitamin D and Elevated CRP in a Group of Healthy Black South African Women.

Low 25-hydroxyvitamin D (25(OH)D) and elevated C-reactive protein (CRP) concentrations are independently associated with adverse health outcomes, including cardiovascular disease (CVD). Although an inverse association between these factors has been described, the underlying mechanisms remain unknown. We postulate that environment-gene interactions, through which 25(OH)D interacts with single nucleotide polymorphisms (SNPs) within the CRP gene, modulate CRP; that certain CRP genotypes predispose individuals to a co-phenotype of low 25(OH)D and elevated CRP concentrations; and that this co-phenotype is associated with higher CVD risk. Twelve CRP SNPs were genotyped, and both 25(OH)D and CRP were quantified, in 505 black South African women. Alarmingly, 66% and 60% of the women presented with deficient/insufficient 25(OH)D and elevated CRP concentrations, respectively. CRP concentrations were higher in individuals with lower 25(OH)D concentrations. However, no 25(OH)D-CRP genotype interactions were evident. Several genotypes were associated with an altered risk of presenting with the co-phenotype, indicating a genetic predisposition. Women presenting with this co-phenotype had higher blood pressure and increased anthropometric measures, which may predispose them to develop CVD. We recommend increasing vitamin D fortification and supplementation efforts to reduce inflammation among black women with vitamin D deficiency, thereby possibly curbing diseases contingent on the co-phenotype described here.

Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry.

BACKGROUND: Large genome-wide association (GWA) studies of European ancestry individuals have identified multiple genetic variants influencing iron status. Studies on the generalizability of these associations to African ancestry populations have been limited. These studies are important given interethnic differences in iron status and the disproportionate burden of iron deficiency among African ancestry populations. METHODS: We tested the associations of 20 previously identified iron status-associated single nucleotide polymorphisms (SNPs) in 628 Kenyans, 609 Tanzanians, 608 South Africans and 228 African Americans. In each study, we examined the associations present between 20 SNPs with ferritin and haemoglobin, adjusting for age, sex and CRP levels. RESULTS: In the meta analysis including all 4 African ancestry cohorts, we replicated previously reported associations with lowered haemoglobin concentrations for rs2413450 (ß = -0.19, P = 0.02) and rs4820268 (ß = -0.16, P = 0.04) in TMPRSS6. An association with increased ferritin concentrations was also confirmed for rs1867504 in TF (ß = 1.04, P = <0.0001) in the meta analysis including the African cohorts only. CONCLUSIONS: In all meta analyses, we only replicated 4 of the 20 single nucleotide polymorphisms reported to be associated with iron status in large GWA studies of European ancestry individuals. While there is now evidence for the associations of a number of genetic variants with iron status in both European and African ancestry populations, the considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of iron status in ethnically diverse populations.

Common Variants and Haplotypes in the TF, TNF-α, and TMPRSS6 Genes Are Associated with Iron Status in a Female Black South African Population.

BACKGROUND: It is unknown whether single nucleotide polymorphisms (SNPs), associated with iron status in European and Asian populations, have the same relation within the African population. OBJECTIVES: We investigated associations of reported SNPs with iron markers in a South African cohort. METHODS: Hemoglobin concentration, serum ferritin (SF) and soluble transferrin receptor (sTfR) concentrations, and body iron (BI) stores were measured in women (n = 686; range, 32-86 y) who were part of the Prospective Urban and Rural Epidemiology study. Thirty-two SNPs in 12 genes were selected based on existing genome-wide association study data. RESULTS: In the transferrin (TF) gene, SF and BI were significantly lower in the heterozygote genotype (AG) of reference SNP (rs) 1799852 (P = 0.01 and 0.03, respectively) and sTfR concentrations were significantly higher (P = 0.004) than the homozygote minor allele genotype (AA), whereas transferrin receptor and BI concentrations were significantly lower in the heterozygote genotype (AG) of rs3811647 (both P = 0.03) than the homozygote wild-type (AA) and minor allele groups (GG). The chromosome 6 allele combination (AAA) consisting of rs1799964 and rs1800629 both in tumor necrosis factor-α (TNF-α) and rs2071592 in nuclear factor κB inhibitor-like protein 1 (NFKBIL1) was associated with higher odds for low SF concentrations (SF < 15 µg/L; OR: 1.86; 95% CI: 1.23, 2.79) than the allele combinations AGA, GGT, and AGT. The chromosome 22 allele combination (GG) consisting of rs228918 and rs228921 in the transmembrane protease serine 6 (TMPRSS6) gene was associated with lower odds for increased sTfR concentrations (sTfR > 8.3mg/L; OR: 0.79; 95% CI: 0.63, 0.98) than the allele combination AA. CONCLUSIONS: Various SNPs and allele combinations in the TF, TNF-α, and TMPRSS6 genes are associated with iron status in black South African women; however, these association patterns are different compared with European ancestry populations. This stresses the need for population-specific genomic data.

Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses.

Transmembrane protease, serine 6 (TMPRSS6), is likely to be involved in iron metabolism through its pleiotropic effect on hepcidin concentrations. Recently, genome-wide association studies have identified common variants in the TMPRSS6 gene to be linked to anaemia and low iron status. To get a more precise evaluation of identified TMPRSS6 single nucleotide polymorphism associations with iron status in cohorts of differing continental ancestry, we conducted a systematic review with meta-analyses. We searched the literature using HuGE Navigator, Pubmed and Scopus databases for primarily genome-wide association studies using TMPRSS6 as a free term. Fixed-effects meta-analysis was used to obtain summary estimates of associations. Eleven studies comprised Caucasian populations, four included an Asian population and one study included an African-American population. Differences in minor allele frequencies of 8 TMPRSS6 SNPs (rs855791, rs4820268, rs2111833, rs1421312, rs228921, rs228918, rs228919 and rs575620) across ethnic groups were observed, with the MAF of rs855791 significantly higher in Asian populations than in Caucasians (0.55 vs 0.42, P < 0.0001). In the meta-analysis, the A allele of rs855791 was associated with lower Hb and ferritin concentrations in all populations. This allele was also associated with increased serum transferrin receptor and transferrin concentrations. We observed similar associations for the G allele in rs4820268. Clear disparities in associations were found for the African-American population, although not statistically significant. Associations between TMPRSS6 SNPs and anaemia are consistent across Caucasian and Asian populations. This study highlights the need to conduct studies in African populations where iron deficiency is of utmost public health significance.

Interactions between C-reactive protein genotypes with markers of nutritional status in relation to inflammation.

Inflammation, as indicated by C-reactive protein concentrations (CRP), is a risk factor for chronic diseases. Both genetic and environmental factors affect susceptibility to inflammation. As dietary interventions can influence inflammatory status, we hypothesized that dietary effects could be influenced by interactions with single nucleotide polymorphisms (SNPs) in the CRP gene. We determined 12 CRP SNPs, as well as various nutrition status markers in 2010 black South Africans and analyzed their effect on CRP. Interactions were observed for several genotypes with obesity in determining CRP. Lipid intake modulated the pro-inflammatory effects of some SNPs, i.e., an increase in both saturated fatty acid and monounsaturated fatty acid intake in those homozygous for the polymorphic allele at rs2808630 was associated with a larger increase in CRP. Those harboring the minor alleles at rs3093058 and rs3093062 presented with significantly higher CRP in the presence of increased triglyceride or cholesterol intake. When harboring the minor allele of these SNPs, a high omega-6 to -3 ratio was, however, found to be anti-inflammatory. Carbohydrate intake also modulated CRP SNPs, as HbA1C and fasting glucose levels interacted with some SNPs to influence the CRP. This investigation highlights the impact that nutritional status can have on reducing the inherent genetic susceptibility to a heightened systemic inflammatory state.

Lack of Association of Glycated Haemoglobin with Blood Pressure and Subclinical Atherosclerosis in Black South Africans: a Five-Year Prospective Study

Objectives: Hypertension and diabetes are common in rapidly urbanising sub-Saharan African communities. However; lack of longitudinal data in these regions prevents adequate analysis of the link between measures of glycaemia and cardiovascular disease. Therefore; we examined the relationships of fasting glucose and glycated haemoglobin (HbA1c) with brachial and central blood pressure (BP); and measures of vascular structure and function after five years in black South Africans.Setting and subjects: Nine hundred and twenty-eight participants were included as part of the Prospective Urban Rural Epidemiological (PURE) study in the North West Province.Outcome measures: Fasting glucose; HbA1c and brachial BP at two time points were determined. Central BP; augmentation index (AI) and carotid intima-media thickness (CIMT) were taken at follow-up. Results: Fasting glucose [4.78 (3.50; 6.30) vs. 5 mmol/l (3.96; 6.42)]; HbA1c [5.6 (4.9; 6.3) vs. 5.9 (5.2; 6.9) and (37 vs. 41 mmol/mol)]; and BP (134/88.1 vs. 138/89.5 mmHg) increased significantly over five years (p-value 0.05). However; an association was absent between BP; AI or CIMT and either baseline or the five-year change in glucose or HbA1c. Multivariate analyses confirmed that neither glucose or HbA1c predicted changes in BP; CIMT or AI; but factors that did associate significantly were age; male gender; rural location; abdominal obesity; alcohol intake; total cholesterol to high-density lipoprotein ratio; C-reactive protein and antihypertensive medication (R2; ranging from 0.24-0.36).Conclusion: Although both BP and measures of glycaemia increased significantly over five years in black South Africans; glucose was not independently associated with BP or measures of large artery structure or function. We suggest that fasting glucose and HbA1c below the threshold of diagnosing diabetes should not be used in isolation to predict cardiovascular risk in African individuals

Gene-environment and gene-gene interactions of specific MTHFR, MTR and CBS gene variants in relation to homocysteine in black South Africans.

The methylenetetrahydrofolate reductase (MTHFR), cystathione-ß-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 µmol/L; p<0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 µmol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p=0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p=0.003 and=0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 TT genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations. Therefore, some of the investigated genotypes affected Hcy; residential area changed the way in which the CBS T833C/844ins68 SNPs influenced Hcy concentrations highlighting the importance of environmental factors; and gene-gene interactions allude to epistatic effects.

Nutritional genetics: the case of alcohol and the MTHFR C677T polymorphism in relation to homocysteine in a black South African population.

BACKGROUND/AIMS: It is unknown whether the effect of alcohol consumption on homocysteine (Hcy) is modulated by the methylenetetrahydrofolate reductase (MTHFR) C677T. We explored this hypothesized effect by analyzing cross-sectional data of 1,827 black South Africans. METHODS: Total Hcy concentrations were determined by fluorescence polarization immunoassay and the genotype through polymerase chain reaction-based RFLP analysis. RESULTS: Subjects harboring the 677 TT genotype had the highest Hcy. Among subjects harboring the 677 CC genotype, men had higher Hcy (p = 0.04). Age and gamma-glutamyltransferase (GGT) correlated best (r = 0.26 and r = 0.27; p < 0.05), while the percentage carbohydrate-deficient transferrin and the B vitamins correlated weakly (r < 0.1; p < 0.05) with Hcy. Hcy was positively associated with the reported alcohol intake (p ≤ 0.01). There was no interaction between alcohol consumption and the MTHFR 677 CC or CT genotypes (p > 0.05) for Hcy concentrations; however, an interaction was determined for GGT and the MTHFR genotype (p = 0.02). Age, GGT, gender, MTHFR and vitamin B6 explained 16.8% of the variation in Hcy (p < 0.01). CONCLUSION: The determined interactions might result in differences in the risk conveyed through Hcy with regard to disease development in those with unfavorable GGT concentrations.

Are behavioural risk factors to be blamed for the conversion from optimal blood pressure to hypertensive status in Black South Africans? A 5-year prospective study.

BACKGROUND: Longitudinal cohort studies in sub-Saharan Africa are urgently needed to understand cardiovascular disease development. We, therefore, explored health behaviours and conventional risk factors of African individuals with optimal blood pressure (BP) (≤ 120/80 mm Hg), and their 5-year prediction for the development of hypertension. METHODS: The Prospective Urban Rural Epidemiology study in the North West Province, South Africa, started in 2005 and included African volunteers (n = 1994; aged > 30 years) from a sample of 6000 randomly selected households in rural and urban areas. RESULTS: At baseline, 48% of the participants were hypertensive (≥ 140/90 mmHg). Those with optimal BP (n = 478) were followed at a success rate of 70% for 5 years (213 normotensive, 68 hypertensive, 57 deceased). Africans that became hypertensive smoked more than the normotensive individuals (68.2% vs 49.8%), and they also had a greater waist circumference [ratio of geometric means of 0.94 cm (95% CI: 0.86-0.99)] and greater amount of γ-glutamyltransferase [0.74 U/l (95% CI: 0.62-0.88)] at baseline. The 5-year change in BP was independently explained by baseline γ-glutamyltransferase [R(2) = 0.23, ß = 0.13 U/l (95% CI: 0.01-0.19)]. Alcohol intake also predicted central systolic BP and carotid cross-sectional wall area (CSWA) at follow-up. Waist circumference was another predictor of BP changes [ß = 0.18 cm (95% CI: 0.05-0.24)] and CSWA. HIV infection was inversely associated with increased BP. CONCLUSIONS: During the 5 years, 24% of Africans with optimal BP developed hypertension. The surge in hypertension in Africa is largely explained by modifiable risk factors. Public health strategies should focus aggressively on lifestyle to prevent a catastrophic burden on the national health system.

Protective effect against type 2 diabetes mellitus identified within the ACDC gene in a black South African diabetic cohort.

Type 2 diabetes mellitus (T2D) is currently one of the fastest growing noncommunicable diseases in the world. It is induced by the pathogenic interaction between insulin resistance and secretion. This group of clinically heterogeneous disorders currently affects approximately 4% of the general population, but it is rapidly increasing, especially in developing regions such as sub-Saharan Africa. During this investigation, a diabetic (n = 227) and control cohort (n = 226) of adult black South African individuals were screened for the reported single nucleotide polymorphisms, termed C-11377G and G-11391A, within the promoter of the adiponectin (ACDC) gene. Genotyping was achieved via a real-time polymerase chain reaction method. It was determined that the variant allele at G-11391A as well as the 12 haplotype was significantly associated with a protective factor with regard to T2D susceptibility. The low frequency of this variant within the cohorts investigated indicated a minor role in decreasing disease susceptibility. It may not be a significant disease risk factor in itself, but may assist in elucidating the mechanism of disease susceptibility. When compared to various non-African populations, it becomes apparent that the investigated single nucleotide polymorphisms have differential effects depending on the population investigated. This investigation therefore underscores the genetic heterogeneity at T2D susceptibility loci within the black South African population.