VTRNA2-1: Genetic Variation, Heritable Methylation and Disease Association

Dugue, PA; Yu, C; McKay, T; Wong, EM; Joo, JE; Tsimiklis, H; Hammet, F; Mahmoodi, M; Theys, D; kConFab; Hopper, JL; Giles, GG; Milne, RL; Steen, JA; Dowty, JG; Nguyen-Dumont, T; Southey, MC

Author(s): Dugue, PA; Yu, C; McKay, T; Wong, EM; Joo, JE; Tsimiklis, H; Hammet, F; Mahmoodi, M; Theys, D; kConFab; Hopper, JL; Giles, GG; Milne, RL; Steen, JA; Dowty, JG; Nguyen-Dumont, T; Southey, MC;
Details: Publication Year 2021-03-03,Volume 22,Issue #5,Page 2535
Journal Title: International Journal of Molecular Sciences
Publication Type: Research article
Abstract: VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants +/- 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 x 10(-4)); however, these explained little of the methylation variation (R(2) < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h(2) = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.
Keywords: Aged; Breast Neoplasms/genetics; Case-Control Studies; CpG Islands/genetics; DNA Methylation/*genetics; Female; Genome-Wide Association Study/methods; Humans; Male; MicroRNAs/*genetics; Middle Aged; Polymorphism, Single Nucleotide/*genetics; Prospective Studies; Quantitative Trait Loci/genetics
Department(s): Laboratory Research
PubMed ID: 33802562
Publisher's Version: https://doi.org/10.3390/ijms22052535
Open Access at Publisher's Site: https://doi.org/10.3390/ijms22052535
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-03 05:54:00

Last Modified: 2026-07-03 05:54:48