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.

Background: 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 populationspecific 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 bloodbased 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 literature.

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Background African populations are going through health transitions due to rapid urbanisation and international migration. However, the role of biological ageing in the emerging burden of cardiometabolic diseases 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 residing in Europe and non-migrant Ghanaians residing in Ghana using cross-sectional data.Methods In this population-based cross-sectional RODAM substudy, recruitment of urban participants in Ghana was done in two cities (Kumasi and Obuasi), whereas recruitment in rural areas was done in 15 villages in the Ashanti region. In Europe, participants were recruited from the cities of Amsterdam (Netherlands), Berlin (Germany), and London (UK). The method and location of participant recruitment varied according to country and city. Participants were included in the RODAM study if they were older than 25 years, had completed the RODAM study questionnaire, were physically examined, and had blood samples taken. In the present subsample, data for DNA-methylation (DNAm) had to be available for the participants. We did not specify any exclusion criteria. We used genome-wide DNAm data from Ghanaians to quantify EAA. We assessed the correlation between DNAm-based age measures and chronological age, and then we did linear regressions to investigate the associations between EAA and body-mass index (BMI), fasting blood glucose (FBG), blood pressure, alcohol consumption, smoking status, physical activity, and one-carbon metabolism nutrients among migrant and non-migrant populations. We replicated our findings among rural-urban sibling pairs from the India Migration Study and among indigenous South Africans from the PURE-SA-NW study. FindingsBetween Feb 2, 2012, and Sept 30, 2014, 736 individuals participated in the RODAM epigenetics substudy, of which 12 (2%) were excluded during DNAm quality control, and a further 12 (2%) were excluded because of genotypic and phenotypic sex discordance. 712 (97%) of 736 participants were included in the analysis; 365 (51%) of these 712 participants were migrants and 347 (49%) were non-migrants. We found that migrant Ghanaians had lower EAA than non-migrant Ghanaians (intrinsic EAA Horvath -0•34 years vs 0•35 years; extrinsic EAA Hannum -0•86 years vs 0•90 years; PhenoAge acceleration -1•68 years vs 1•77 years; and GrimAge acceleration -0•18 years vs 0•19 years). Within migrant Ghanaians, higher FBG was positively associated with EAA measures, with the adjusted regression β for intrinsic EAA being 0•30 (95% CI 0•01 to 0•59) for migrants and 0•12 (-0•04 to 0•28) for non-migrants, for extrinsic EAA being 0•31 (0•05 to 0•56) for migrants and 0•08 (-0•06 to 0•22) for non-migrants, for PhenoAge acceleration being 0•39 (0•07 to 0•71) for migrants and 0•14 (-0•01 to 0•32) for non-migrants, and for GrimAge acceleration being 0•18 (0•01 t...

Purpose of reviewDementia is a public health challenge with no existing cure or early biomarkers. We review the evidence for blood-based measures of sphingomyelins and ceramides as potential novel biomarkers of dementia. Recent findingsIn recent years, lipids have been under investigation for their role in neurodegenerative diseases especially dementia and Alzheimer's disease. Increasing evidence from postmortem human brains suggests that alterations in the metabolism of sphingolipids could play a crucial part in dementia. Findings from epidemiological investigations of blood-based sphingomyelins and ceramides have been inconsistent.

Urbanization coincides with a complex change in environmental exposure and a rapid increase in noncommunicable diseases (NCDs). Epigenetics, including DNA methylation (DNAm), is thought to mediate part of the association between genetic/environmental exposure and NCDs. The urban–rural divide provides a unique opportunity to investigate the effect of the combined presence of multiple forms of environmental exposure on DNAm and the related increase in disease risk. This review evaluates the ability of three epidemiological study designs (migration, income-comparative and urban–rural designs) to investigate the role of DNAm in the association between urbanization and the rise in NCD prevalence. We also discuss the ability of each study design to address the gaps in the current literature, including the complex methylation-mediated risk attributable to the cluster of forms of exposure characterizing urban and rural living, while providing a platform for developing countries to leverage their demographic discrepancies in future research ventures.

Background C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.

Introduction Plant‐based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained. Methods We measured antioxidants in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow‐up. We measured baseline plasma levels of retinol, α‐, and γ‐tocopherol; zeaxanthin and lutein (combined); beta‐cryptoxanthin; cis‐lycopene; trans‐lycopene; α‐carotene; and trans‐β‐carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist‐adjudicated risks of all‐cause dementia and AD. Results Plasma retinol, α‐, and γ‐tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β‐carotene, or vitamin E supplements. Higher trans‐β‐carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans‐β‐carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α‐carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α‐carotene: 1.15; 95% CI: 1.02, 1.29). Discussion Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.