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

The association between an energy-adjusted dietary inflammatory index and inflammation in rural and urban Black South Africans

Objective: To quantify the inflammatory potential of the diet of rural and urban Black South Africans using an adapted energy-adjusted dietary inflammatory index (AE-DII) and to investigate its relationship with inflammatory and cardio-metabolic disease risk markers. Dietary inflammatory potential has not been investigated in African populations. Design: Cross-sectional investigation. Setting: Rural and urban sites in the North West province of South Africa. Participants: 1,885 randomly selected, apparently healthy Black South Africans older than 30 years. Results: AE-DII scores ranged from -3.71 to +5.08 with a mean of +0.37. AE-DII scores were significantly higher in men (0.47±1.19) than in women (0.32±1.29), and in rural (0.55±1.29) than urban participants (0.21±1.19). Apart from its dietary constituents, AE-DII scores primarily associated with age, rural-urban status and education. Contrary to the literature, alcohol consumption was positively associated with AE-DII scores. Of the four tested inflammatory and 13 cardio-metabolic biomarkers, the AE-DII was only significantly negatively associated with albumin and high-density lipoprotein cholesterol, and positively with waist circumference and fasting glucose, upon full adjustment. Conclusion: Rural men consumed the most pro-inflammatory diet, and urban women the least pro-inflammatory diet. The diet of the participants was not overtly pro- or anti-inflammatory and was not associated with measured inflammatory markers. The inflammatory potential of alcohol at different levels of intake requires further research. Understanding dietary inflammatory potential in the context of food insecurity, unhealthy lifestyle practices and lack of dietary variety remains limited

Epigenetic age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations:the population based cross-sectional RODAM study

BACKGROUND: African populations are experiencing health transitions due to rapid urbanization and international migration. However, the role of biological aging in this emerging burden of cardiometabolic diseases (CMD) among migrant and non-migrant Africans is unknown. We aimed to examine differences in epigenetic age acceleration (EAA) as measured by four clocks (Horvath, Hannum, PhenoAge and GrimAge) and their associations with cardiometabolic factors among migrant Ghanaians in Europe and non-migrant Ghanaians. METHODS: Genome-wide DNA methylation (DNAm) data of 712 Ghanaians from cross-sectional RODAM study were used to quantify EAA. We assessed correlation of DNAmAge measures with chronological age, and then performed linear regressions to determine associations of body mass index (BMI), fasting blood glucose (FBG), blood pressure, alcohol consumption, smoking, physical activity, and one-carbon metabolism nutrients with EAA among migrant and non-migrants. We replicated our findings among 172 rural-urban sibling pairs from India migration study and among 120 native South Africans from PURE-SA-NW study. FINDINGS: We found that Ghanaian migrants have lower EAA than non-migrants. Within migrants, higher FBG was positively associated with EAA measures. Within non-migrants, higher BMI, and Vitamin B9 (folate) intake were negatively associated with EAA measures. Our findings on FBG, BMI and folate were replicated in the independent cohorts. INTERPRETATION: Our study shows that migration is negatively associated with EAA among Ghanaians. Moreover, cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Our results call for context-based interventions for CMD among transitioning populations that account for effects of biological aging. FUNDING: European Commission

Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: independent and IL-6-interactive associations

Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ' fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB±rs7439150, rs1800789 (±1420G/A) and rs1800787 (±148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account

Pairwise LD structure of 14 fibrinogen SNPs, illustrated by D’ values on an r² colour scheme.

<p>Empty boxes indicate D’ values of 1.0. Increased numerical values indicate stronger evidence of LD. Image generated through Haploview software [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187712#pone.0187712.ref051" target="_blank">51</a>].</p

Genotype-IL-6 interactions modulating total fibrinogen concentrations.

<p>Genotype-IL-6 interactions modulating total fibrinogen concentrations.</p

Genotype-IL-6 interactions modulating clot properties.

<p>Genotype-IL-6 interactions modulating clot properties.</p

Fourteen polymorphisms spanning the fibrinogen gene cluster.

<p>Image generated through the Ensembl database [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187712#pone.0187712.ref050" target="_blank">50</a>].</p