Association of COL4A2 indel polymorphism with the development of stomach adenocarcinoma in Chinese populations.

OBJECTIVE: The objective of the study was to assess the potential association between the indel polymorphism (rs34802628) located within the intron of the collagen type ⅳ alpha 2 gene (COL4A2) and the susceptibility to stomach adenocarcinoma (STAD) within a Chinese population. METHODS: Peripheral venous blood samples were collected from a total of 497 STAD patients and 804 healthy control individuals to extract genomic DNA. The genotyping of the COL4A2 rs34802628 polymorphism was carried out using a polymerase chain reaction assay. Additionally, statistical analyses were conducted on the expression levels of COL4A2 mRNA using the GEPIA database. Meanwhile, the expression of COL4A2 mRNA was also validated by Real-time PCR using STAD tissue samples. Then, based on an analysis of patient tumor RNA seq data available from the Cancer Genome Atlas (TCGA), we assessed the prognostic value of mRNA expression of the COL4A2 gene in STAD patients using K-M plotter. RESULTS: The study presented compelling evidence supporting an association between the rs34802628 polymorphism in the COL4A2 gene and susceptibility to STAD. Logistic regression analysis revealed that both the heterozygote and homozygote 4-bp del/del genotypes were significantly associated with a decreased risk of STAD, even after controlling for other variables (adjusted odds ratio [OR] = 0.663, 95% confidence interval [CI] 0.519-0.848, p = 0.037; OR = 0.422, 95% CI 0.290-0.614, p = 0.000005, respectively). Importantly, individuals carrying the 4-bp deletion allele demonstrated a notably lower risk of developing the disease (OR = 0.696, 95% CI 0.591-0.820, p = 0.000014). Furthermore, Genotype-phenotype correlation studies in human STAD tissue samples demonstrated that the higher mRNA expression levels of COL4A2 were associated with the ins allele of rs34802628. Bioinformatics analysis revealed that higher expression of the COL4A2 gene was significant with development and poor prognosis of STAD. CONCLUSION: The results of our study provide strong evidence indicating a potential involvement of genetic variants in the COL4A2 gene in the development of STAD. Nonetheless, to validate and consolidate these findings, additional investigations incorporating larger sample sizes and functional experiments are necessary.

Association of COL4A2 Gene Polymorphisms with Lacunar Stroke in Xinjiang Han Populations.

Recent studies have shown that variants in the COL4A2 genes are associated with sporadic cerebral small vessel disease. The aim of the study was to investigate the relationship between COL4A2 gene polymorphisms and lacunar stroke in Xinjiang Han populations. The improved multiple ligase detection reaction (iMLDR) method was used to analyze the genotypes of seven single-nucleotide polymorphisms (SNPs) in the COL4A2 gene (rs3803230, rs391859, rs4103, rs445348, rs76425569, rs7990383, rs9515185) in a case-control study of 406 lacunar stroke patients and 425 controls. The GG genotype of rs3803230 (adjusted OR = 1.303, 95% CI = 1.146-1.480, P < 0.001) and the GA/AA genotype of rs76425569 (adjusted OR = 1.744, 95% CI = 1.306-2.329, P < 0.001) showed significant increases in the risk of lacunar stroke. The G-A haplotype of rs3803230-rs76425569 carried a significant increase in the risk of lacunar stroke (OR = 1.616, 95% CI = 1.292-2.022, P < 0.001). Hypertension stratification analyses demonstrated that the GA/AA genotype of rs76425569 was significantly associated with lacunar stroke in the hypertensive group (adjusted OR = 1.316, 95% CI = 1.083-1.598, P = 0.006). In the non-hypertensive group, the GG genotype of rs3803230 (adjusted OR = 1.584, 95% CI = 1.257-1.997, P < 0.001) and GA/AA genotype of rs76425569 were significantly associated with lacunar stroke (adjusted OR = 1.312, 95% CI = 1.054-1.635, P = 0.015). The TT genotype of rs4103 was significantly associated with lacunar stroke in the non-hypertensive group (adjusted OR = 1.355, 95% CI = 1.152-1.594, P < 0.001). This study demonstrates that the COL4A2 gene could play a role in the pathogenesis of lacunar stroke in the Han population of China.

Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma.

Uterine leiomyoma (UL), the most common benign tumour found in females, is associated with many recurrent genetic aberrations, such as translocations, interstitial deletions and specific germline mutations. Among these, mutations affecting exon 2 of the mediator complex subunit 12 (MED12) gene are commonly detected in the majority of ULs. Mutational analysis of the MED12 gene, performed on 36 UL samples, revealed that 12 leiomyomas (33.4%) exhibited heterozygous missense mutations in codon 44 of exon 2 of the MED12 gene, four leiomyomas (11.1%) showed internal in-frame deletions, and two leiomyomas (5.5%) exhibited deletions involving intron 1-exon 2 junction, which caused a predicted loss of the splice acceptor. No mutations were detected in uterine myometrium (UM) and pseudocapsule (PC) samples, including those from women with a MED12 mutation in UL. These data showed that the PC is a healthy tissue that surrounds the UL to maintain UM integrity. Analysis of insulin-like growth factor 2 (IGF-2) and collagen type IV alpha 2 (COL4A2) mRNA expression levels in the same set of ULs revealed that only those with MED12 missense mutations expressed significantly higher levels of IGF-2 mRNA. In contrast, MED12 gene status does not appear to affect mRNA expression levels of the COL4A2 gene. On the basis of this finding, we suggest that the MED12 status stratifies the ULs into two mutually exclusive pathways of leiomyoma genesis, one with IGF-2 overexpression and the other with no IGF-2 activation. The occurrence of IGF-2 overexpression could be therapeutically targeted for the non-surgical treatment of leiomyomas.