Zhou Zijun, Jie Youkun, Hu Xianyue, Chen Guange, Bao Yanjing, OuYang Zhenbo, Wu Liangzhi, Gao Tianyang, Zhang Qiushi, Hua Wenfeng
Department of Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China.
Department of Gynecology and Obstetrics, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China.
Front Genet. 2025 Jan 3;15:1460216. doi: 10.3389/fgene.2024.1460216. eCollection 2024.
Endometriosis, a prevalent chronic gynecological condition, is frequently associated with infertility and pelvic pain. Despite numerous studies indicating a correlation between epigenetic regulation and endometriosis, its precise genetic etiology remains elusive. Methyltransferase-like 14 (METTL14), a crucial component of the N6-methyladenosine (mA) RNA methyltransferase complex and an RNA binding scaffold, is known to play a pivotal role in various human diseases. The possibility that single nucleotide polymorphisms (SNPs) in the METTL14 gene contribute to susceptibility of endometriosis has not been thoroughly investigated.
We assessed the genotype frequencies of five potential functional METTL14 SNPs (rs298982 G>A, rs62328061A>G, rs9884978G>A, rs4834698C>T, and rs1064034A>T) in a Chinese population consisting of 458 patients with ovarian endometriosis and 462 healthy controls. We employed unconditional logistic regression and stratified analyses to evaluate their genotypic associations with the risk of ovarian endometriosis.
Among the five SNPs examined, we found that the rs298982 A allele was significantly associated with increased risk, whereas the rs62328061 G allele was linked to a decreased risk of ovarian endometriosis. Individuals harboring two unfavorable genotypes demonstrated a significantly elevated risk of ovarian endometriosis (adjusted odds ratio (AOR) = 1.57, 95% confidence interval (CI) = 1.16-2.13, = 0.004) compared with those with no risk genotypes. Stratified analysis revealed the risk effect of rs298982 GA/AA genotypes in the gravidity≤1, parity≤1, rASRM stage I, and rASRM stage II + III + IVsubgroups. Haplotype analysis showed that individuals with the GATAA haplotype were at higher risk of ovarian endometriosis (AOR = 5.54, 95% CI = 1.63-18.87, = 0.006), whereas the AGTTG haplotype exhibited protective effects (AOR = 0.55, 95% CI = 0.31-0.97, = 0.039) compared with wild-type GACAG haplotype carriers. Additionally, Bayesian false discovery probability and false positive report probability analysis confirmed the robustness of the significant findings. Expression quantitative trait loci analysis revealed a significant association between the rs9884978 GA/AA genotypes and elevated METTL14 mRNA levels in fibroblasts and adrenal gland. Conversely, the rs298982 GA/GG genotypes were significantly associated with reduced METTL14 mRNA levels in the nucleus accumbens and frontal cortex.
Our results demonstrate that METTL14 polymorphisms are associated with susceptibility to ovarian endometriosis among Chinese women.
子宫内膜异位症是一种常见的慢性妇科疾病，常与不孕和盆腔疼痛相关。尽管众多研究表明表观遗传调控与子宫内膜异位症之间存在关联，但其确切的遗传病因仍不清楚。甲基转移酶样蛋白14（METTL14）是N6-甲基腺苷（m⁶A）RNA甲基转移酶复合物的关键组成部分和RNA结合支架，已知在多种人类疾病中起关键作用。METTL14基因中的单核苷酸多态性（SNP）是否导致子宫内膜异位症易感性尚未得到充分研究。
我们在中国人群中评估了5个潜在功能性METTL14 SNP（rs298982 G>A、rs62328061 A>G、rs9884978 G>A、rs4834698 C>T和rs1064034 A>T）的基因型频率，该人群包括458例卵巢子宫内膜异位症患者和462例健康对照。我们采用非条件逻辑回归和分层分析来评估它们与卵巢子宫内膜异位症风险的基因型关联。
在检测的5个SNP中，我们发现rs298982的A等位基因与风险增加显著相关，而rs62328061的G等位基因与卵巢子宫内膜异位症风险降低有关。与无风险基因型的个体相比，携带两种不利基因型的个体患卵巢子宫内膜异位症的风险显著升高（调整优势比（AOR）=1.57，95%置信区间（CI）=1.16 - 2.13，P = 0.004）。分层分析揭示了rs298982的GA/AA基因型在妊娠≤1、产次≤1、rASRM I期和rASRM II + III + IV亚组中的风险效应。单倍型分析表明，与野生型GACAG单倍型携带者相比，携带GATAA单倍型的个体患卵巢子宫内膜异位症的风险更高（AOR = 5.54，95% CI = 1.63 - 18.87，P = 0.006），而AGTTG单倍型具有保护作用（AOR = 0.55，95% CI = 0.31 - 0.97，P = 0.039）。此外，贝叶斯错误发现概率和假阳性报告概率分析证实了显著发现的稳健性。表达数量性状位点分析显示，rs9884978的GA/AA基因型与成纤维细胞和肾上腺中METTL14 mRNA水平升高显著相关。相反，rs298982的GA/GG基因型与伏隔核和额叶皮质中METTL14 mRNA水平降低显著相关。
我们的结果表明，METTL14基因多态性与中国女性卵巢子宫内膜异位症易感性相关。
