Role of DNA methylation in common disease: analysis of two asthma-associated regions
Bibliographic record
Abstract
Two chromosomal regions, 5q31 and 17q21, are both among the best replicated asthma-associated regions from genome-wide association studies (GWAS) and share certain characteristics.They are among the highest genome-wide significance allele-specific expression differences: in the 17q region, the childhood asthma-associated allele shows increased expression of gasdermin B (GSDMB) and ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) genes and in the 5q31 region the asthma-associated allele shows increased expression of the solute carrier family 22 (organic 3 cation/carnitine transporter) member 5 (SLC22A5) genes. This suggests that cis-regulatory mechanisms may influence disease development in these regions. Among children, the prevalence of asthma is higher in boys than girls, 5q31 and 17q21 regions show sex specificity of genetic association: the association with asthma is stronger in males than females, and both are associated with several autoimmune disorders such as asthma and Crohn’s disease, among different populations. We hypothesize that variation in DNA methylation at regulatory elements within asthma-associated genomic regions 5q31 and 17q21 may acts as a modifier of the effect of genotype on phenotype. To better understand the relationship between genetic variation in these regions, DNA methylation, and predisposition to asthma, we established DNA methylation profiles of 13 genes. We used sodium bisulfite sequencing methylation assay to examine the effects that genotype has on DNA methylation in the peripheral blood cells from individuals in the Saguenay-Lac-Saint-Jean (SLSJ) asthma familial collection and lymphoblastoid cell lines (LCLs). We found a single regulatory region, the zona pellucida binding protein 2 (ZPBP2) promoter, which showed a statistically significantly higher methylation level in females compared to males. The local genotype influenced methylation levels of SLC22A5, ZPBP2 and gasdermin A (GSDMA) promoter regions. The genotype had a dominant effect on SLC22A5, ZPBP2 and GSDMA methylation, with lower methylation levels in individuals that carry the asthma-predisposing alleles. To understand whether the moderate change in DNA methylation leads to a change in gene expression levels in 5q31 and 17q21, the effect of treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) on expression and promoter methylation of genes in 5q31 and 17q21 in the human airway epithelium cell line, NuLi-1 and embryonic kidney epithelium cell line, HEK293T/17 was assessed. We found that SLC22A5 and GSDMA were upregulated after 5-aza-dC treatment in both cell lines. ZPBP2 expression was increased in NuLi-1 but remained silent in HEK293T/17, while ORMDL3 showed upregulation in HEK293T/17 but not NuLi-1. Increased2expression of ZPBP2 and GSDMA was accompanied by a reduction in promoter methylation, whereas no change in SLC22A5 promoter methylation levels was observed. Furthermore, we noticed modification in allelic expression of ZPBP2 and ORMDL3, suggesting that each region may react in uniquely to 5-aza-dC.We hypothesized that sex-specific differences in DNA methylation levels at the ZPBP2 promoter resulted from the dosage of the sex chromosomes. Thus, ZPBP2 DNA methylation was analyzed using the sodium bisulfite sequencing assay in DNA samples from fibroblast cell lines derived from individuals with different sex phenotypes and sex chromosome dosages. No significant influence of the sex phenotype was detected. However, a significant positive correlation was found between ZPBP2 methylation levels and the number of X chromosomes. Our results suggest that the presence of more than one X in the absence of the sex-determining region Y (SRY) gene is associated with higher methylation levels.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".