Glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based systematic HuGE review and meta-analysis.

Multiple genes have been studied for potential associations with lung cancer. The gene most frequently associated with increased risk has been glutathione S-transferase M1 (GSTM1). The glutathione S-transferase enzyme family is known to catalyze detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. In this review, the authors summarize the available evidence associating lung cancer with the GSTM1 gene. They describe results from an updated meta-analysis of 98 published genetic association studies investigating the relation between the GSTM1 null variant and lung cancer risk including 19,638 lung cancer cases and 25,266 controls (counting cases and controls in each study only once). All studies considered, the GSTM1 null variant was associated with an increased risk of lung cancer (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14, 1.30), but no increase in risk was seen (OR = 1.01, 95% CI: 0.91, 1.12) when only the five largest studies (>500 cases each) were considered. Furthermore, while GSTM1 null status conferred a significantly increased risk of lung cancer to East Asians (OR = 1.38, 95% CI: 1.24, 1.55), such a genotype did not confer increased risk to Caucasians. More data regarding the predictive value of GSTM1 genetic testing are needed before population-based testing may be reasonably considered.

Inducible nitric oxide synthase gene (NOS2A) haplotypes and the outcome of hepatitis C virus infection.

Inducible nitric oxide synthase (iNOS) is an important molecule involved in the host defense against infectious agents. iNOS is encoded by the NOS2A gene and well-defined haplotypes exist with respect to this gene. We examined whether these haplotypes were associated with the outcome of hepatitis C virus (HCV) infection in 619 Caucasian patients from seven European liver centres. We observed five major haplotypes: (-277A)+(-1026G)+(-1659C): haplotype 1; (-277G)+(-1026T)+(-1659C): haplotype 2; (-277G)+(-1026G)+(-1659C): haplotype 3; (-277G)+(-1026T)+(-1659T): haplotype 4; and (-277A)+(-1026T)+(-1659C): haplotype 5. Distributions of these haplotypes are comparable with those of previous studies. Homozygotes for haplotype 2 or those with haplotypes 2/4 were more likely than those with the 1/1 (wild type) combination to have self-limiting infections (odds ratios (OR)=3.43; 95% confidence intervals (95% CI): 1.10-8.0; P=0.0206 and OR=5.15; 95% CI: 1.32-14.32; P=0.0018, respectively). Conversely, carriage of haplotype 1 was associated with the lack of self-limiting disease (OR=0.48; 95% CI: 0.27-0.83; P=0.009). The effect was mainly among males (OR=0.41; 95% CI: 0.182-0.942; P=0.031 for males, and OR=0.55; 95% CI: 0.24-1.37; P=0.136 for women). Carriage of haplotype 1 was not associated with initial response (P=0.268) or sustained response (P>0.171). Combinations of haplotypes 1/4 were more likely to respond to interferon monotherapy in comparison of initial responders to nonresponders (OR=2.25; 95% CI: 1.05-5.68; P=0.0275).

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR.

Interferon stimulates the expression of a number of genes encoding enzymes with antiviral activities, including myxovirus resistance-1 (MxA), 2-5-oligoadenylate synthetase 1 (OAS-1) and double-stranded RNA-dependent protein kinase (PKR). We examined whether polymorphisms in these genes influenced the outcome of hepatitis C virus (HCV) infection. We observed a lower frequency of the GG genotype at position -88 in the MxA gene promoter in self-limiting HCV infection (OR=0.56; 95% CI: 0.35-0.8; P=0.010) and in nonresponders to therapy (OR=0.49; 95% CI: 0.25-0.95; P=0.020). This genotype predominantly influenced the outcome of treatment in patients with viral genotype 1 (OR=0.22 95% CI: 0.07-0.67; P=0.002). A polymorphism in the 3'-untranslated region of the OAS-1 gene was associated with outcome of infection (GG genotype less frequent in self-limiting infection: OR=0.43; 95% CI: 0.21-0.86; P=0.010). A polymorphism at position -168 in the promoter region of the PKR gene was associated with self-limiting infection (CT genotype: OR=2.75; 95% CI: 1.45-5.24; P=0.002). Further associations were found with a CGG trinucleotide repeat in the 5'UTR region of the PKR gene. Polymorphisms in the interferon-induced genes, MxA, OAS-1 and PKR appear thus associated with HCV outcome.

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection.

The low-density lipoprotein receptor (LDLR) has been proposed to promote hepatitis C virus endocytosis and the cell membrane protein CD81 may also promote HCV host cell entry. The CD81 gene was sequenced to screen for novel polymorphisms, but no SNPs were identified. Polymorphisms within the LDLR gene are associated with the pathogenesis of familial hypercholesterolemia, atherosclerosis and obesity. We therefore studied genetic variation within the LDLR gene and clinical features of hepatitis C infection. An amino acid change in exon 8 was associated with severity of fibrosis; a SNP in exon 10 correlated with viral clearance and overall inflammation, and a SNP in the 3'UTR appeared to influence treatment response. There were no other significant associations between any of the SNPs studied and the clinical measures of hepatitis C infection. We furthermore report on linkage disequilibrium within the gene and haplotype frequencies in our population. Our findings support a possible role for the LDLR in the modulation of disease progression by affecting immune responses, rather than functioning as receptor for HCV.