m6A‑SNP: From genetics to epigenetics (Review)

Abstract

N 6 -methyladenosine (m 6 A), the most abundant RNA modification, can participate in various physiological functions and pathological processes by regulating the expression or structure of genes due to its involvement in all aspects of RNA metabolism. Thus, the genetic variant that influences m 6 A, such as m 6 A-associated single nucleotide polymorphism (m 6 A-SNP), which is in close proximity to or in the methylation site, may be related to various pathological processes by increasing or decreasing the m 6 A methylation level due to the alteration of the nucleotide. The present review summarizes the recent advances made in m 6 A-SNPs. Both the mining of genome-wide association studies and the combined analysis of the m6Avar database with expression quantitative trait loci datasets have identified functional variants and causal genes associated with various diseases and have provided new direction for future studies on disease pathogenesis. In particular, some studies have indicated that base change in m 6 A-sNps lead to alterations in m 6 A modification levels, a conversion from genetics to epigenetics, and the expression variation of corresponding genes, which may affect the biological behavior of cells and explain the association of m 6 A-SNPs with the risk or prognosis of diseases. In bladder cancer, colorectal cancer, coeliac disease, and pancreatic ductal adenocarcinoma, the overexpression of a specific allele alone can significantly modify the function of corresponding genes. On the whole, m 6 A-SNPs play a pivotal role in all stages of diseases. In the future, the identification of m 6 A-SNPs as disease biomarkers and ascertaining the functions of these m 6 A-SNPs may prove beneficial. This would help to identify susceptible individuals in a timely manner and clarify the roles of corresponding genes in the occurrence and progression of diseases, and would also aid in the development of novel treatment strategies, ultimately improving patients' survival. Contents 1. Introduction 2. Data mining of genome-wide association studies 3. Combined analysis of the m6Avar database and eQTLs 4. Effects and mechanisms of m 6 A sNps 5. Conclusion

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility

“…The variant inactivated DNA demethylation activity, but possibly demethylation of m 6 -modified mRNA was also inactive. The second category has received substantial recent attention in the form of SNPs inducing gain- or loss-of-function mutation of m 6 A sites, termed m 6 A-SNPs 69 . Two variants that generate pathologic m 6 A sites have been reported, both involving tumor suppressors.…”

“…In a second study, a G > A variant of ANKLE1 , a suppressor of colorectal cancer (CRC), induced m 6 A modification, increasing ANKLE1 expression and reducing CRC risk 71 . Several disease-associated m 6 A-SNPs that repress methylation have been identified by combined analysis of GWAS and eQTL data 69 . For example, a SNP in acyl‐CoA synthetase medium chain family member 5 ( ACSM5 ), a candidate gene for thyroid cancer, reduces m 6 A modification and ACSM5 expression in thyroid cancer tissues, and is associated with the poor prognosis 63 .…”