M. Gené

Meta- and Pooled Analysis of GSTP1 Polymorphism and Lung Cancer: A HuGE-GSEC Review

Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.

Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk

Two polymorphic sites of the microsomal epoxide hydrolase gene (EPHX1, 113Tyr-->113His, 139His-->139Arg) and four glutathione S-transferase genes (GSTM1, GSTM3, GSTP1, GSTT1) were genotyped in a group of patients with larynx cancer (N=204) and in a group of healthy controls (N=203), all Spanish caucasians. After adjusting for gender, age, and tobacco smoking, none of the polymorphisms alone were found to be associated with larynx cancer risk. The analysis of EPHX1/GST combinations, however, showed a significant over-representation of patients with a combination of 113Tyr/113Tyr EPHX1 and 105Ile/105Ile GSTP1 (adjusted odds ratio (OR): 1.95; 95% confidence interval (CI): 1.02-3.78). The calculation of the predicted epoxide hydrolase (EH) activity also showed an increased risk for the individuals with both predicted high activity EH and 105Ile/105Ile GSTP1 (OR: 2.90; 95% CI: 1.10-7.67). These results on larynx cancer tend to confirm a former study on lung cancer (Cancer Lett. 173 (2001) 155) suggesting the existence of an interaction between variants of EH and GSTpi, both enzymes being involved in the metabolism of aromatic hydrocarbons, that may increase susceptibility to tobacco-related cancers.

Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1

Human microsomal epoxide hydrolase (mEH) catalyzes a key step in the biotransformation of benzo[a]pyrene that yields the highly mutagenic (+)-anti-7,8-diol-9,10 epoxide (BPDE). Two polymorphisms have been described in the coding region of the mEH gene (EPHX1) that produce two protein variants: 113Tyr-->113His (exon 3) and 139His-->139Arg (exon 4). We performed a case-control study among Northwestern Mediterranean Caucasians to investigate a possible association between these EPHX1 variants and lung cancer risk. Both EPHX1 polymorphisms were analyzed in a group of lung cancer patients (n=176) and in a control group of healthy smokers (n=187). The results showed a significantly decreased risk for the rare homozygous 113His/113His (adjusted odds ratio (OR): 0.44, 95% confidence interval (CI): 0.27-0.71) and 139Arg/139Arg (adjusted OR: 0.55, 95% CI: 0.33-0.91) compared with the major wild-types 113Tyr/113Tyr and 139His/139His, respectively, as the references. Thereafter, we analyzed the EPHX1 variants in combination with three glutathione S-transferase polymorphic genes (GSTM1, GSTT1, and GSTP1) and we found a significant overepresentation of cancer patients with a combination of exon 3 113Tyr/113Tyr EPHX1 and exon 5 105Ile/105Ile GSTP1 (adjusted OR: 2.34, 95% CI: 1.21-4.52). The polymorphic site within the exon 5 of GSTP1 results in a Ile-->Val substitution, and the isoleucine GSTpi isoform has been found in vitro to be less active than the valine isoform towards the conjugation of BPDE. The 113 Tyr/Tyr EPHX1 encodes for a high-activity mEH. Our results agree with these observations in vitro and suggest that a genetically determined combination of a high-activity mEH and a low-activity GSTpi may increase lung cancer risk among smokers.

Haplotype frequencies of eight Y-chromosome STR loci in Barcelona (North-East Spain)

Abstract Haplotype frequencies for eight Y-chromosomal short tandem repeat (STR) loci were determined in ¶a population sample from Barcelona (NE Spain). After PCR amplification and denaturing PAGE electrophoresis, DYS19, DYS388, DYS389 I/II, DYS390, DYS391, DYS392 and DYS393 loci were typed. Complete eight ¶Y-chromosomal STRs haplotypes could be formed for 223 subjects, among which 137 different haplotypes were observed. The most common haplotype was shared by 13% of the sample, while 108 haplotypes were unique. The discrimination capacity was 61.5% and the gene diversity was 0.978. From the forensic point of view the combined polymorphisms provide a high diagnostic efficiency.

Characterisation of three Amerindian populations from Hidalgo State (Mexico) by 15 STR-PCR polymorphisms

The purpose of this study is to report allele frequency data of three ethnic Amerindian population samples: the Otomi (Hña-hñu) from eastern Sierra Madre and Ixmiquilpan valley and the Huasteco from La Huasteca. These groups were characterised by 15 STR-PCR polymorphisms (HumTH01, HumvWA, D18S51, HumTPOX, D19S433, D16S539, D13S317, D8S1179, D7S820, D5S818, HumFGA, CSF1PO, D2S1338, D3S1358 and D21S11). No significant deviations in observed allelic frequencies from Hardy-Weinberg equilibrium were found for all the studied systems. From the forensic point of view, the heterozygosity value, power of discrimination and the a priori chance of exclusion were calculated.

Population genetics of the D12S391, CSF1PO and TPOX loci in Catalonia (Northeast Spain)

Abstract Allele and genotype frequencies for three short tandem repeat loci were determined in a population sample from Catalonia (NE Spain). After denaturing PAGE electrophoresis, 11 alleles were identified for D12S391 (n = 167), 9 alleles for CSF1pO (n = 282) and 6 alleles for TPOX (n = 283). No deviation from Hardy-Weinberg equilibrium was found. The allele frequencies observed are similar to those of other compared European populations.

Population study of the HUMTH01, HUMVWA31A, HUMF13A1, and HUMFES/FPS STR polymorphisms in the north of Portugal.

Allele and genotype frequencies of four short tandem-repeat loci were determined in a population sample from the North of Portugal using the polymerase chain reaction (PCR). After denaturing PAGE, 6 alleles were identified for HUMTH01 (n = 419), 9 alleles for HUMVWA31A (n = 376), 12 alleles for HUMF13A1 (n = 232), and 5 alleles for HUMFES/FPS (n = 409). No deviation from Hardy-Weinberg equilibrium was found. The allele frequencies observed are similar to those of the European populations compared. The combined power of discrimination is 0.999.

Genetic Diversity of 15 STRs in Choles From Northeast of Chiapas (Mexico)

Allele frequencies for 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D19S433, HUMVWA31A, HUMTPOX, D18S51, D3S1358, HUMTHO1, D13S317, D16S539, D2S1338, D5S818, and HUMFGA) were analyzed in a Mexican population: Choles from Chiapas State. The aim of the study was to obtain accurate allele frequencies data and other genetic parameters of forensic interest on the Amerindian ethnic groups from Mexico, using an automatic method and commercial amplification kit. The agreement with HWE (Hardy-Weinberg equilibrium) was confirmed for all loci (based on the X2-test).

The Fang population of Equatorial Guinea characterised by 15 STR-PCR polymorphisms

Allele frequencies for 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D19S433, HUMVWA31A, HUMTPOX, D18S51, D3S1358, HUMTHO1, D13S317, D16S539, D2S1338, D5S818 and HUMFGA) were analysed in the Fang population of Bioko Island, Equatorial Guinea. No deviation from Hardy-Weinberg equilibrium was found for all loci. Statistical parameters demonstrated the forensic utility of the analysed systems.

Catalonian population study of the tetranucleotide repeat loci D3S1358, D8S1179, D18S51 and D19S253

Abstract Allele frequencies for four short tandem repeat loci were determined in a population sample from Catalonia (NE Spain). After denaturing PAGE electrophoresis, 8 alleles were identified for D3S1358 (n = 201), 10 alleles for D8S1179 (n = 198), 13 alleles for D18S51 (n = 197) and 11 alleles for D19S253 (n = 201). No deviation from Hardy-Weinberg equilibrium was found. Complete and relative uniformity in Caucasoid populations has been observed for D18S51 and D8S1179 respectively. Pronounced differences were found between different ethnic groups for both systems. Catalonia and Portugal do not differ for D3S1358 locus. Multiplex PCR amplifications of three loci (D3S1358, D18S51 and D19S253) without overlapping fragment size ranges could be interesting for monochrome automated laser fluorescence devices.