Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation

Husquin, Lucas T.; Rotival, Maxime; Fagny, Maud; Quach, Hélène; Zidane, Nora; McEwen, Lisa M.; MacIsaac, Julia L.; Kobor, Michæl S.; Aschard, Hugues; Patin, Étienne; Quintana-Murci, Lluı́s

doi:10.1186/s13059-018-1601-3

Cited by 111 publications

(85 citation statements)

References 111 publications

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“…As the sample numbers used for studies of DNA methylation, particularly epigenome-wide association studies (EWASs), continue to grow and the value of repeat sampling over time and exposures is recognised, so the logistical and financial issues surrounding whole blood sample collection and storage escalate. Moreover, population differences in DNA methylation 1– 4 highlight the need to profile DNA methylation around the world, including in low- and middle-income countries and rural settings, which might lack the required facilities for the low-temperature storage of EDTA blood collection tubes.…”

Section: Introductionmentioning

confidence: 99%

Assessment of dried blood spots for DNA methylation profiling

et al. 2019

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Background: DNA methylation reflects health-related environmental exposures and genetic risk, providing insights into aetiological mechanisms and potentially predicting disease onset, progression and treatment response. An increasingly recognised need for large-scale, longitudinally-profiled samples collected world-wide has made the development of efficient and straightforward sample collection and storage procedures a pressing issue. An alternative to the low-temperature storage of EDTA tubes of venous blood samples, which are frequently the source of the DNA used in such studies, is to collect and store at room temperature blood samples using purpose built filter paper, such as Whatman FTA® cards. Our goal was to determine whether DNA stored in this manner can be used to generate DNA methylation profiles comparable to those generated using blood samples frozen in EDTA tubes. Methods: DNA methylation profiles were obtained from matched EDTA tube and Whatman FTA® card whole-blood samples from 62 Generation Scotland: Scottish Family Health Study participants using the Infinium HumanMethylation450 BeadChip. Multiple quality control procedures were implemented, the relationship between the two sample types assessed, and epigenome-wide association studies (EWASs) performed for smoking status, age and the interaction between these variables and sample storage method. Results: Dried blood spot (DBS) DNA methylation profiles were of good quality and DNA methylation profiles from matched DBS and EDTA tube samples were highly correlated (mean r = 0.991) and could distinguish between participants. EWASs replicated established associations for smoking and age, with no evidence for moderation by storage method. Conclusions: Our results support the use of Whatman FTA® cards for collecting and storing blood samples for DNA methylation profiling. This approach is likely to be particularly beneficial for large-scale studies and those carried out in areas where freezer access is limited. Furthermore, our results will inform consideration of the use of newborn heel prick DBSs for research use.

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Section: Introductionmentioning

confidence: 99%

Assessment of dried blood spots for DNA methylation profiling

et al. 2019

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“…Next, we compared our results against all previously associated traits in EWASs (the EWAS atlas and the EWAS catalog) and GWASs (the GWAS catalog). One CpG (cg03995300) is mapped to ZNF232 and has been previously associated with prenatal maternal smoking, sex, and ancestry [56,91,92]. The ZNF232 locus was associated with a family history of Alzheimer’s disease in a GWA meta-analysis [93].…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

et al. 2019

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Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized (‘never‘ vs. ‘ever’). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10–8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

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“…Genetic mutants and epigenetic modi cations regulate immune gene expression [30]. Kuhmann et al (2011) reported that the methylation changes of TRAPPC9 are related to the regrowth of MCF-7 (human breast adenocarcinoma cell line) cells [22].…”

Section: Folic Acid Dose-dependently Prevents Mastitis and Increasesmentioning

confidence: 99%

Combined effects of intrinsic host gene (TRAPPC9) and extrinsic nutrient (folate) on resistance against S. aureus induced bovine mastitis

Mi¹,

Song²,

Dong³

et al. 2020

Preprint

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Background: Drug-resistance and immunological escape of Staphylococcus aureus and its “superbug”, methicillin-resistant S. aureus (MRSA), have become one of main causes of bacterial infection in both human and animals. In dairy cattle, elimination of bovine mastitis induced by S. aureus is of importance because S. aureus-infected cows normally are culled passively. Methods: Here, we investigated the beneficial effects of bovine trafficking protein particle complex 9 (TRAPPC9) gene and folic acid supplementation in the control of mastitis induced by S. aureus or MRSA by a series of in vivo and in vitro experiments. Results: The data showed that the genetic mutations and DNA methylation of TRAPPC9 were highly linked with the mastitis resistance of dairy cows. Additionally, knockdown of bovine TRAPPC9 was significantly involved in the mRNA expression levels of interleukin’s genes (increased IL-1β and IL-6), and down-regulated the protein level of NF-κB-P65 in the mastitis cell model induced by MRSA. Meanwhile, dose-dependent folic acid addition can inhibit the invasion of MRSA into Mac-T cells and improve TRAPPC9 expression in dairy cows. Conclusions: Altogether, our data suggest that an appropriate dose of folic acid can significantly reduce the inflammation caused by MRSA partially through TRAPPC9 mediated NF-κB pathway. These findings provide new insights to control the drug-resistant pathogens and to restrict the overuse of antibiotics through combined effects of the intrinsic host gene and extrinsic nutrient.

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Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation

Cited by 111 publications

References 111 publications

Assessment of dried blood spots for DNA methylation profiling

Assessment of dried blood spots for DNA methylation profiling

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

Combined effects of intrinsic host gene (TRAPPC9) and extrinsic nutrient (folate) on resistance against S. aureus induced bovine mastitis

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