2 research outputs found
<i>GPX3</i> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy
Current data suggest that aristolochic acid (AA) exposure is a putative cause of Balkan endemic nephropathy (BEN), a chronic kidney disease strongly associated with upper tract urothelial carcinoma. The cellular metabolism of AA is associated with the production of reactive oxygen species, resulting in oxidative distress. Purpose: Therefore, the aim of this study was to analyze individual, combined and cumulative effect of antioxidant gene polymorphisms (Nrf2 rs6721961, KEAP1 rs1048290, GSTP1AB rs1695, GSTP1CD rs1138272, GPX3 rs8177412 and MDR1 rs1045642), as well as GSTP1ABCD haplotypes with the risk for BEN development and associated urothelial cell carcinoma in 209 BEN patients and 140 controls from endemic areas. Experimental method: Genotyping was performed using polymerase chain reaction (PCR) and PCR with confronting two-pair primers (PCR-CTTP) methods. Results: We found that female patients carrying both variant GPX3 rs8177412 and MDR1 rs1045642 genotypes in combination exhibited significant risk towards BEN (OR 1 = 3.34, 95% CI = 1.16–9.60, p = 0.025; OR 2 = 3.79, 95% CI = 1.27–11.24, p = 0.016). Moreover, significant association was determined between GPX3rs8174412 polymorphism and risk for urothelial carcinoma. Carriers of variant GPX3*TC + CC genotype were at eight-fold increased risk of BEN-associated urothelial tumors development. There was no individual or combined impact on BEN development and BEN-associated tumors among all examined polymorphisms. The haplotype consisting of variant alleles for both polymorphisms G and T was associated with 1.6-fold increased risk although statistically insignificant (OR = 1.64; 95% CI = 0.75–3.58; p = 0.21). Conclusions: Regarding GPX3 rs8177412 polymorphism, the gene variant that confers lower expression is associated with significant increase in upper urothelial carcinoma risk. Therefore, BEN patients carrying variant GPX3 genotype should be more frequently monitored for possible upper tract urothelial carcinoma development
The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms
are shaped by serotonin acting centrally and peripherally. The serotonin
transporter gene SLC6A4 has been implicated in IBS pathophysiology, but
the underlying genetic mechanisms remain unclear. We sequenced the
alternative P2 promoter driving intestinal SLC6A4 expression and
identified single nucleotide polymorphisms (SNPs) that were associated
with IBS in a discovery sample. Identified SNPs built different
haplotypes, and the tagging SNP rs2020938 seems to associate with
constipation-predominant IBS (IBS-C) in females. rs2020938 validation
was performed in 1978 additional IBS patients and 6,038 controls from
eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128
controls confirmed the association with female IBS-C. Expression
analyses revealed that the P2 promoter drives SLC6A4 expression
primarily in the small intestine. Gene reporter assays showed a
functional impact of SNPs in the P2 region. In silico analysis of the
polymorphic promoter indicated differential expression regulation.
Further follow-up revealed that the major allele of the tagging SNP
rs2020938 correlates with differential SLC6A4 expression in the jejunum
and with stool consistency, indicating functional relevance. Our data
consolidate rs2020938 as a functional SNP associated with IBS-C risk in
females, underlining the relevance of SLC6A4 in IBS pathogenesis