8 research outputs found
Metabolomic biomarkers of habitual B vitamin intakes unveil novel differentially methylated positions in the human epigenome
Background:
B vitamins such as folate (B9), B6, and B12 are key in one carbon metabolism, which generates methyl donors for DNA methylation. Several studies have linked differential methylation to self-reported intakes of folate and B12, but these estimates can be imprecise, while metabolomic biomarkers can offer an objective assessment of dietary intakes. We explored blood metabolomic biomarkers of folate and vitamins B6 and B12, to carry out epigenome-wide analyses across up to three European cohorts. Associations between self-reported habitual daily B vitamin intakes and 756 metabolites (Metabolon Inc.) were assessed in serum samples from 1064 UK participants from the TwinsUK cohort. The identified B vitamin metabolomic biomarkers were then used in epigenome-wide association tests with fasting blood DNA methylation levels at 430,768 sites from the Infinium HumanMethylation450 BeadChip in blood samples from 2182 European participants from the TwinsUK and KORA cohorts. Candidate signals were explored for metabolite associations with gene expression levels in a subset of the TwinsUK sample (n = 297). Metabolomic biomarker epigenetic associations were also compared with epigenetic associations of self-reported habitual B vitamin intakes in samples from 2294 European participants.
Results:
Eighteen metabolites were associated with B vitamin intakes after correction for multiple testing (Bonferroni-adj. p < 0.05), of which 7 metabolites were available in both cohorts and tested for epigenome-wide association. Three metabolites — pipecolate (metabolomic biomarker of B6 and folate intakes), pyridoxate (marker of B6 and folate) and docosahexaenoate (DHA, marker of B6) — were associated with 10, 3 and 1 differentially methylated positions (DMPs), respectively. The strongest association was observed between DHA and DMP cg03440556 in the SCD gene (effect = 0.093 ± 0.016, p = 4.07E−09). Pyridoxate, a catabolic product of vitamin B6, was inversely associated with CpG methylation near the SLC1A5 gene promoter region (cg02711608 and cg22304262) and with SLC7A11 (cg06690548), but not with corresponding changes in gene expression levels. The self-reported intake of folate and vitamin B6 had consistent but non-significant associations with the epigenetic signals.
Conclusion:
Metabolomic biomarkers are a valuable approach to investigate the effects of dietary B vitamin intake on the human epigenome
The inactive X chromosome accumulates widespread epigenetic variability with age
Abstract Background Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women. Methods We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age. Results In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37). Conclusions Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability
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Red reflex examination in reproductive and child health clinics for early detection of paediatric cataract and ocular media disorders: cross-sectional diagnostic accuracy and feasibility studies from Kilimanjaro, Tanzania
Funder: Queen Elizabeth Diamond Jubilee Trust [grant code: ITCRZC6813]Abstract: Background/objectives: Late presentation of congenital cataract in the developing world has led to poor outcomes such that cataract is the leading cause of childhood blindness. Our hypothesis was that, sensitivity of red-reflex testing is greater than sensitivity of torchlight examination. We aimed to compare sensitivity of new red reflex screening tools and assess the feasibility of Arclight red reflex screening in the community. Subject/methods: We compared the diagnostic accuracy of four different screening tools for cataract and retinoblastoma performed by ophthalmic nurses, using a clinic based enriched sample of 41 positives and 60 negatives. We then conducted a separate feasibility study, training non-specialist community nurses. Following the training, community nurses examined 2827 children <5 years with Arclight who were attending their clinics for growth monitoring and immunisation. Findings: Diagnostic accuracy study: estimated sensitivities were 97.6% for Catcam, 92.7% for Arclight, 90.2% for PEEK retina and 7.3% for torchlight. Estimated specificities were above 90% for Catcam, Arclight and torchlight and 87% for PEEK retina. Feasibility study: twenty-four out of 2728 children screened failed community screening, seven were true positive (six cataract, one retinoblastoma). Prevalence of bilateral cataract was 1.5/1000 (95% CI: 0.40–3.75 per 1000). Conclusions: Arclight and CatCam have higher sensitivity than torchlight, are easy to learn and use by primary health care nurses. Red reflex testing should be recommended in the WHO guidelines instead of torchlight examination to help early detection of potential blinding causes including congenital cataract and retinoblastoma
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Red reflex examination in reproductive and child health clinics for early detection of paediatric cataract and ocular media disorders: cross-sectional diagnostic accuracy and feasibility studies from Kilimanjaro, Tanzania.
Funder: Queen Elizabeth Diamond Jubilee Trust [grant code: ITCRZC6813]BACKGROUND/OBJECTIVES: Late presentation of congenital cataract in the developing world has led to poor outcomes such that cataract is the leading cause of childhood blindness. Our hypothesis was that, sensitivity of red-reflex testing is greater than sensitivity of torchlight examination. We aimed to compare sensitivity of new red reflex screening tools and assess the feasibility of Arclight red reflex screening in the community. SUBJECT/METHODS: We compared the diagnostic accuracy of four different screening tools for cataract and retinoblastoma performed by ophthalmic nurses, using a clinic based enriched sample of 41 positives and 60 negatives. We then conducted a separate feasibility study, training non-specialist community nurses. Following the training, community nurses examined 2827 children <5 years with Arclight who were attending their clinics for growth monitoring and immunisation. FINDINGS: Diagnostic accuracy study: estimated sensitivities were 97.6% for Catcam, 92.7% for Arclight, 90.2% for PEEK retina and 7.3% for torchlight. Estimated specificities were above 90% for Catcam, Arclight and torchlight and 87% for PEEK retina. Feasibility study: twenty-four out of 2728 children screened failed community screening, seven were true positive (six cataract, one retinoblastoma). Prevalence of bilateral cataract was 1.5/1000 (95% CI: 0.40-3.75 per 1000). CONCLUSIONS: Arclight and CatCam have higher sensitivity than torchlight, are easy to learn and use by primary health care nurses. Red reflex testing should be recommended in the WHO guidelines instead of torchlight examination to help early detection of potential blinding causes including congenital cataract and retinoblastoma
Epigenome-wide association study of dietary fatty acid intake
Abstract Background Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS). Results DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p < 7.17 × 10–8), we identified two differentially methylated positions (DMPs) associated with PUFA intake in the KORA study. The DMP cg19937480, annotated to gene PRDX1, was positively associated with docosahexaenoic acid (DHA) in model 1 (beta: 2.00 × 10–5, 95%CI: 1.28 × 10–5-2.73 × 10–5, P value: 6.98 × 10–8), while cg05041783, annotated to gene MARK2, was positively associated with docosapentaenoic acid (DPA) in our fully adjusted model (beta: 9.80 × 10–5, 95%CI: 6.25 × 10–5-1.33 × 10–4, P value: 6.75 × 10–8). In the meta-analysis, we identified the CpG site (cg15951061), annotated to gene CDCA7L below Bonferroni correction (1.23 × 10–7) associated with eicosapentaenoic acid (EPA) intake in model 1 (beta: 2.00 × 10–5, 95% CI: 1.27 × 10–5–2.73 × 10–5, P value = 5.99 × 10–8) and we confirmed the association of cg19937480 with DHA in both models 1 and 2 (beta: 2.07 × 10–5, 95% CI: 1.31 × 10–5–2.83 × 10–5, P value = 1.00 × 10–7 and beta: 2.19 × 10–5, 95% CI: 1.41 × 10–5–2.97 × 10–5, P value = 5.91 × 10–8 respectively). Conclusions Our study identified three CpG sites associated with PUFA intake. The mechanisms of these sites remain largely unexplored, highlighting the novelty of our findings. Further research is essential to understand the links between CpG site methylation and PUFA outcomes