Relevance of GSTM1, GSTT1, and GSTP1 gene polymorphisms to gastric cancer susceptibility and phenotype.

Human glutathione S-transferases (GSTs) are phase II metabolizing enzymes that play a key role in protecting against cancer by detoxifying numerous potentially cytotoxic/genotoxic compounds. The genes encoding the human GST isoenzymes GSTM(mu)1, GSTT(theta)1 and GSTP(pi)1 harbour polymorphisms, which have been considered important modifiers of the individual risk for environmentally induced cancers such as gastric cancer (GC). However, results are inconsistent among studies from different geographic areas and ethnic groups. Our goal was to perform a nationwide, case-control study in Spain to evaluate the relevance of several functional GST gene polymorphisms and environmental factors to GC risk and phenotype. DNA from 557 GC patients and 557 sex- and age-matched healthy controls (HC) was typed for two deletions in the GSTM1 and GSTT1 genes and two SNPs in the GSTP1 gene (rs1695 and rs1138272) using polymerase chain reaction-restriction fragment length polymorphism methods. Logistic regression analysis identified Helicobacter pylori infection with CagA strains [odds ratio (OR): 2.36; 95% confidence interval (CI): 1.78-3.15], smoking habit (OR: 2.10; 95% CI: 1.48-2.97) and family history of GC (OR: 3.2; 95% CI: 2.02-5.16) as independent risk factors for GC. No differences in the frequencies of GSTM1 or GSTT1 null genotypes were observed between cases and controls (GSTM1: 50.8% vs. 48%; GSTT1: 21.5% vs. 21%). Moreover, simultaneous carriage of both, the GSTM1 and the GSTT1 null genotypes, was almost identical in both groups (10.7% in GC vs. 10.6% in HC). In addition, no significant differences in GSTP1 Ile105Val (rs1695) and GSTP1 Val114Ala (rs1138272) genotype distribution were observed between GC patients and controls. Subgroup analysis for age, gender, Helicobacter pylori status, smoking habits, family history of GC, anatomic location and histological subtype revealed no significant association between GST variants and GC risk. Our results show that the GST polymorphisms evaluated in this study are not relevant when determining the individual susceptibility to GC or phenotype in a South-European population.

Gender-related association between the TGFB1+869 polymorphism and multiple sclerosis.

Our objective was to investigate whether polymorphisms and haplotypes in the TGFB1 gene are associated with susceptibility or disease characteristics of multiple sclerosis (MS). In 247 MS patients and 194 controls, single nucleotide polymorphisms (SNPs) at position +869 (Leu10Pro) and position +915 (Arg25Pro) in the signaling sequence of the TGFB1 gene were determined, and the distribution of alleles, genotypes, and haplotypes was related to clinical data. In addition, magnetic resonance imaging (MRI) data were studied in a subgroup of patients (n = 96). The allele distribution of the two polymorphisms studied was in Hardy-Weinberg equilibrium in patients and in controls. No association was found with any of the three haplotypes found in the Dutch population, denoted as haplotype 1 (TGFB1+869T-TGFB1+915G), haplotype 2 (TGFB1+869C-TGFB1+915G), and haplotype 3 (TGFB1+869C-TGFB1+915C). However, the TGFB1+869 genotype CC was significantly more frequent in patients (p = 0.031, chi2 test). The highest frequency of the TGFB1+869 genotype CC was observed in male patients (25.2% vs. 10.0% in controls, p = 0.004, chi2 test), and carriership of TGFB1+869 allele C was correspondingly increased in male patients (74.8% vs. 56.7%, p = 0.008, chi2 test, OR 2.27, 95% CI 1.23-4.17). Although there was no association with clinical markers of disease progression, patients homozygous for TGFB1+869 allele C showed a significantly higher annual increase in two MRI parameters: ventricular fraction (central atrophy) and T1-hypointense lesion load (matrix destruction). The TGFB1 T+869C (Leu10Pro) gene polymorphism is associated with MS susceptibility, especially in males, and with a more destructive course of the disease as illustrated by MRI.