Replication and expansion of epigenome-wide association literature in a black South African population

DNA methylation is associated with non-communicable diseases (NCDs) and related traits. Methylation data on continental African ancestries are currently scarce, even though there are known genetic and epigenetic differences between ancestral groups and a high burden of NCDs in Africans. Furthermore, the degree to which current literature can be extrapolated to the understudied African populations, who have limited resources to conduct independent large-scale analysis, is not yet known. To this end, this study examines the reproducibility of previously published epigenome-wide association studies of DNA methylation conducted in different ethinicities, on factors related to NCDs, by replicating findings in 120 South African Batswana men aged 45 to 88 years. In addition, novel associations between methylation and NCD-related factors are investigated using the Illumina EPIC BeadChip. Results Up to 86% of previously identified epigenome-wide associations with NCD-related traits (alcohol consumption, smoking, body mass index, waist circumference, C-reactive protein, blood lipids and age) overlapped with those observed here and a further 13% were directionally consistent. Only 1% of the replicated associations presented with effects opposite to findings in other ancestral groups. The majority of these inconcistencies were associated with population-specific genomic variance. In addition, we identified eight new 450K array CpG associations not previously reported in other ancestries, and 11 novel EPIC CpG associations with alcohol consumption. Conclusions The successful replication of existing EWAS findings in this African population demonstrates that blood-based 450K EWAS findings from commonly investigated ancestries can largely be extrapolated to ethnicities for which epigenetic data are not yet available. Possible population-specific differences in 14% of the tested associations do, however, motivate the need to include a diversity of ethnic groups in future epigenetic research. The novel associations found with the enhanced coverage of the Illumina EPIC array support its usefulness to expand epigenetic literatur

Education, smoking and CRP genetics in relation to C-Reactive Protein concentrations in black South Africans

Abstract: Because elevated circulating C-reactive protein (CRP) and low socio-economic status (SES), have both been implicated in cardiovascular disease development, we investigated whether SES factors associate with and interact with CRP polymorphisms in relation to the phenotype. Included in the study were 1569 black South Africans for whom CRP concentrations, 12 CRP single nucleotide polymorphisms (SNPs), cardiovascular health markers, and SES factors were known. None of the investigated SES aspects was found to associate with CRP concentrations when measured individually; however, in adjusted analyses, attaining twelve or more years of formal education resulted in a hypothetically predicted 18.9% lower CRP concentration. We also present the first evidence that active smokers with a C-allele at rs3093068 are at an increased risk of presenting with elevated CRP concentrations. Apart from education level, most SES factors on their own are not associated with the elevated CRP phenotype observed in black South Africans. However, these factors may collectively with other environmental, genetic, and behavioral aspects such as smoking, contribute to the elevated inflammation levels observed in this population. The gene-smoking status interaction in relation to inflammation observed here is of interest and if replicated could be used in at-risk individuals to serve as an additional motivation to quit

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

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

H-Type Hypertension among Black South Africans and the Relationship between Homocysteine, Its Genetic Determinants and Estimates of Vascular Function

Elevated homocysteine (Hcy) increases cardiovascular disease (CVD) risk. Our objective was to emphasize Hcy’s contribution in hypertension and CVD management by determining H-type hypertension (hypertension with Hcy ≥ 10 µmol/L) and associations between Hcy, blood pressure (BP) and estimates of vascular function among Black South Africans. We included 1995 adults (63% female). Plasma Hcy and cardiovascular measures (systolic and diastolic BP (SBP, DBP), pulse pressure, heart rate (HR), carotid-radialis pulse wave velocity (cr-PWV), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1) were quantified. Five Hcy-related polymorphisms (cystathionine β-synthase (CBS 844ins68, T833C, G9276A); methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase (MTR A2756G)) were genotyped. Hcy was >10 µmol/L in 41% (n = 762), and of the 47% (n = 951) hypertensives, 45% (n = 425) presented with H-type. Hcy was higher in hypertensives vs. normotensives (9.86 vs. 8.78 µmol/L, p < 0.0001, effect size 0.56) and correlated positively with SBP, DBP, cr-PWV and ICAM-1 (r > 0.19, p < 0.0001). Over Hcy quartiles, SBP, DBP, HR, cr-PWV and ICAM-1 increased progressively (all p-trends ≤ 0.001). In multiple regression models, Hcy contributed to the variance of SBP, DBP, HR, cr-PWV and ICAM-1. H-type hypertensives also had the lowest MTHFR 677 CC frequency (p = 0.03). Hcy is positively and independently associated with markers of vascular function and raised BP

Gene interactions observed with the HDL-c blood lipid, intakes of protein, sugar and biotin in relation to circulating homocysteine concentrations in a group of black South Africans

Background Elevated homocysteine (Hcy) is associated with several pathologies. Gene–diet interactions related to Hcy might be used to customize dietary advice to reduce disease incidence. To explore this possibility, we investigated interactions between anthropometry, biochemical markers and diet and single-nucleotide polymorphisms (SNPs) in relation to Hcy concentrations. Five SNPs of Hcy-metabolizing enzymes were analyzed in 2010 black South Africans. Results Hcy was higher with each additional methylenetetrahydrofolate reductase (MTHFR) C677T minor allele copy, but was lower in methionine synthase (MTR) 2756AA homozygotes than heterozygotes. Individuals harboring cystathionine β synthase (CBS) 833 T/844ins68 had lower Hcy concentrations than others. No interactive effects were observed with any of the anthropometrical markers. MTHFR C677T and CBS T833C/844ins68 homozygote minor allele carriers presented with lower Hcy as high density lipoprotein cholesterol (HDL-c) increased. Hcy concentrations were negatively associated with dietary protein and animal protein intake in the TT and TC genotypes, but positively in the CC genotype of CBS T833C/844ins68. Hcy was markedly higher in TT homozygotes of MTHFR C677T as added sugar intake increased. In CBS T833C/844ins68 major allele carriers, biotin intake was negatively associated with Hcy; but positively in those harboring the homozygous minor allele. Conclusions The Hcy–SNP associations are modulated by diet and open up the possibility of invoking dietary interventions to treat hyperhomocysteinemia. Future intervention trials should further explore the observed gene–diet and gene–blood lipid interaction