Cytochrome P450 1A1 (CYP1A1) gene polymorphisms and ovarian cancer risk: a meta-analysis

This meta-analysis aims to examine whether the genotype status of MspI, Ile462Val, and Thr461Asn polymorphisms in Cytochrome P450 1A1 (CYP1A1) is associated with ovarian cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: October 2010). Pooled odds ratios (ORs) were appropriately derived from fixed effects or random effects models. Concerning MspI polymorphism, seven studies were eligible (1,051 cases and 1,613 controls); 11 studies were eligible (1,680 cases and 3,345 controls) for Ile462Val and three studies were eligible (349 cases and 785 controls) for Thr461Asn. Ile462Val polymorphism seemed to confer elevated ovarian cancer risk concerning homozygous carriers (pooled OR?=?2.65, 95?% CI: 1.40-5.03, p?=?0.003, fixed effects), as well as at the recessive model (pooled OR?=?2.10, 95?% CI: 1.13-3.92, p?=?0.020, fixed effects); these findings were replicated upon Caucasian subjects. MspI polymorphism was not associated with ovarian cancer risk (for heterozygous TC vs TT carriers pooled OR?=?1.10, 95?% CI: 0.91-1.34, p?=?0.329, fixed effects; for homozygous CC vs. TT carriers pooled OR?=?1.11, 95?% CI: 0.65-1.90, p?=?0.693, fixed effects). With respect to Thr461Asn polymorphism a finding of borderline statistical significance emerged, pointing to marginally elevated ovarian cancer risk in heterozygous Thr/Asn carriers (pooled OR?=?1.62, 95?% CI: 0.97-2.70, p?=?0.066, fixed effects), but not in homozygous Asn/Asn carriers (pooled OR?=?1.40, 95?% CI: 0.18-10.89, p?=?0.749, fixed effects). Ile462Val status seems to represent a meaningful risk factor for ovarian cancer in Caucasians. Additional case-control studies of high methodological quality are needed in order to further substantiate and enrich the present findings. Special attention should be paid upon the design of future studies; Asian and African populations should represent points of focus.     

Polymorphisms of cytochrome P450 1A1, glutathione s-transferases M1 and T1 genes in Ouangolodougou (Northern Ivory Coast)

In this study, the frequencies of CYP1A1, GSTM1, and GSTT1 gene polymorphisms were determined in 133 healthy individuals from Ouangolodougou, a small rural town situated in the north of the Ivory Coast. As appeared in several published studies, ethnic differences in these frequencies have been found to play an important role in the metabolism of a relevant number of human carcinogens. In the studied sample, the frequencies of Ile/Ile (wild type), Ile/Val (heterozygous variant), and Val/Val (homozygous variant) CYP1A1 genotypes were 0.271, 0.692, and 0.037, respectively. Frequencies of GSTM1 and GSTT1 null genotypes were 0.361 and 0.331, respectively. No significant differences were noted between men and women. In contrast to published data for Africans, CYP1A1 *Val Allele frequency (0.383) was significantly high (p < 0.001) in this specific population. For the GSTT1 null genotype, no differences were found between the studied and other African populations, the contrary to what occurred for the GSTM1 null genotype in relation to Gambia and Egypt.     

CYP1A1 Ile462Val Polymorphism Contributes to Lung Cancer Susceptibility among Lung Squamous Carcinoma and Smokers: A Meta-Analysis

Many studies have examined the association between the CYP1A1 Ile462Val gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. Ultimately, 43 case-control studies, comprising 19,228 subjects were included. A significantly elevated lung cancer risk was associated with 2 Ile462Val genotype variants (for Val/Val vs Ile/Ile: OR = 1.22, 95% CI = 1.08–1.40; for (Ile/Val +Val/Val) vs Ile/Ile: OR = 1.15, 95% CI = 1.07–1.23) in overall population. In the stratified analysis, a significant association was found in Asians, Caucasians and lung SCC, not lung AC and lung SCLC. Additionally, a significant association was found in smoker population and not found in non-smoker populations. This meta-analysis suggests that the Ile462Val polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility in Asian and Caucasian populations and there is an interaction with smoking status, but these associations vary in different histological types of lung caner.     

Inhibition of 17β-estradiol activation by CYP1A1: genotype- and regioselective inhibition by St. John's Wort and several natural polyphenols

Several epidemiological studies associate certain CYP1A1 genotypes, alone or in combination, with an increased risk of estrogen-related cancers. Previously we demonstrated that metabolic activation of estrogens by CYP1A1 is a genotype-dependent reaction with the CYP1A1.2 (Ile462Val) variant being the most efficient catalyst (Kisselev et al.). To answer the question whether genotype-dependent inhibition of activation of estrogens by CYP1A1 could also contribute, we studied the inhibition of hydroxylation activity of the most common allelic variants of human CYP1A1 towards 17β-estradiol. We expressed and purified CYP1A1.1 (wild-type), CYP1A1.2 (Ile462Val), and CYP1A1.4 (Thr461Asn) and performed inhibition assays by natural polyphenols of our diet and drugs of NADPH-dependent estradiol hydroxylation in reconstituted CYP1A1 systems. From the polyphenols studied, a St. John's Wort (Hypericum perforatum) extract, some of its main single constituents hypericin, pseudohypericin, and quercetin, as well as the flavonols kaempferol, myricetin and the phytoestrogens resveratrol and tetramethyl-stilbene exhibited strong inhibition. For the St. John's Wort extract and its single constituents hypericin, pseudohypericin, and quercetin, inhibition exhibited a remarkable dependency on the CYP1A1 genotype. Whereas (wild-type) CYP1A1.1 was most inhibited by the whole crude extract, the variant CYP1A1.2 (Ile462Val) was significantly stronger inhibited by the constituents in its pure form: IC?? values for 2-hydroxylation was more than two times lower compared with the wild-type enzyme and the variant CYP1A1.4 (Thr461Asn). Besides this, the inhibition exhibited a remarkable regioselectivity. The data suggest that risk of estrogen-mediated diseases might be not only influenced by CYP1A1 genotype-dependent activation but also its inhibition by natural polyphenols of our diet and drugs.     

Polymorphisms of Metabolizing Enzymes and Susceptibility to Ethmoid Intestinal-type Adenocarcinoma in Professionally Exposed Patients

Intestinal-type adenocarcinoma (ITAC) of ethmoid is a rare tumor associated with occupational exposure to wood and leather dusts. Polymorphisms in xenobiotic metabolizing enzymes play an important role in gene-environment interactions and may contribute to a high degree of variance in individual susceptibility to cancer risk. The aim of this study was to investigate by polymerase chain reaction the role of polymorphisms at CYP1A1 and GSTM1 genes in 30 ethmoid ITAC patients and 79 healthy donors. The distribution of Thr/Asn genotype at CYP1A1 codon 461 was significantly overrepresented among the patients (23.3%; P = .0422), whereas the Ile/Val genotype at CYP1A1 codon 462 was not significantly different between cases and controls (P = .76). The GSTM1 null genotype was not significantly different between cases and control (P = 1), but we observed that the combined codon 461 Thr/Asn and GSTM1 null genotype was overrepresented in the patient group (P = .0019). The results reveal that patients with CYP1A1 codon 461 polymorphism may be at high genetic risk of ITAC and that the risk increases in the presence of combined polymorphism of CYP1A1 and GSTM1 null genotype. This strongly suggests that CYP1A1 codon 461 and GSTM1 null genotype may be useful in selecting exposed individuals at risk for ethmoid ITAC.     

Cytochrome P450 1A1 (CYP1A1) gene polymorphisms and cervical cancer risk: a meta-analysis

This meta-analysis aims to examine whether the genotype status of MspI and Ile462Val polymorphisms in Cytochrome-P450 1A1 (CYP1A1) is associated with cervical cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: October 2010). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random effects models. Concerning MspI polymorphism, six studies were eligible (722 cases and 770 controls); four studies were eligible (350 cases and 519 controls) for Ile462Val. MspI polymorphism was associated with elevated cervical cancer risk (for heterozygous TC vs. TT carriers OR = 1.50, 95% CI: 0.93–2.42, random effects; for homozygous CC vs. TT carriers OR = 2.66, 95% CI: 1.14–6.19, random effects). Similarly, Ile462Val polymorphism was associated with elevated cervical cancer risk (for heterozygous Ile/Val vs. Ile/Ile carriers OR = 2.36, 95% CI: 1.10–5.08, random effects; for homozygous Val/Val vs. Ile/Ile carriers OR = 2.73, 95% CI: 1.21–6.15, fixed effects). The results were replicated upon Caucasian subjects, who represented the majority of existing data. The two examined CYP1A1 genotype polymorphisms seem to confer additional risk for cervical cancer. Accumulation of further data seems mandatory for future race-specific analyses and for the demonstration of CYP1A1-smoking interactions.     

MspI and Ile462Val Polymorphisms in CYP1A1 and Overall Cancer Risk: A Meta-Analysis

Background

Cytochrome P450 1A1 (CYP1A1) is a member of the CYP1 family, which is a key enzyme in the metabolism of many endogenous substrates and exogenous carcinogens. To date, many studies have examined the association between CYP1A1 MspI and Ile462Val polymorphisms and cancer risk in various populations, but their results have been conflicting rather than consistent.

Methods

To assess this relationship more precisely, a meta-analysis based on 198 publications was performed. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with a chi-square-based Q-test.

Results

Overall, a significant elevated risk of cancer was associated with CYP1A1 MspI and Ile462Val polymorphisms for all genetic models studied. Further stratified analysis by cancer types revealed that the MspI polymorphism may increase the risk of lung cancer and cervical cancer whereas the Ile462Val polymorphism may contribute to a higher risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer. In the subgroup analysis by ethnicity, obvious associations were found in the Asian population for the MspI polymorphism while an increased risk of cancer was observed in Asians and Caucasians for the Ile462Val polymorphism.

Conclusions

The results of this meta-analysis suggest that CYP1A1 MspI and Ile462Val polymorphisms contribute to increased cancer susceptibility among Asians. Additional comprehensive system analyses are required to validate this association and other related polymorphisms.     

Association of functionally important polymorphisms in cytochrome P4501B1 with lung cancer

In the present study, genotype and haplotype frequencies of four polymorphisms of cytochrome P450 1B1 (CYP1B1) that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at 432 and Asn-Ser at codon 453) were studied in 200 patients suffering from lung cancer and equal number of controls. A significant difference was observed for the distribution of variant genotypes of CYP1B1Arg48Gly and Ala119Ser polymorphisms (CYP1B1*2) in cases when compared to the controls. No significant difference was observed for the distribution of variant genotypes of CYP1B1Leu432Val (CYP1B1*3) and CYP1B1Asn453Ser (CYP1B1*4) polymorphism. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the three haplotypes (G-T-C-A, G-T-G-A and G-T-C-G) were observed in the cases when compared to controls. Tobacco use in the form of smoking as well as chewing was found to significantly increase the risk of lung cancer in patients by interacting with CYP1B1Ala119Ser genotypes demonstrating the role of gene-environment interaction in lung cancer. Further, the risk of lung cancer increased several fold in the patients carrying the genotype combinations of CYP1B1Ala119Ser and CYP1B1Leu432Val with GSTM1, a phase II enzyme suggesting the importance of gene-gene interactions in enhancing the susceptibility to lung cancer.     

Human CYP1A1 variants lead to differential eicosapentaenoic acid metabolite patterns

To answer the question whether the most common allelic variants of human CYP1A1, namely CYP1A1.1 (wild type), CYP1A1.2 (Ile462Val), and CYP1A1.4 (Thr461Asn), differ in their catalytic activity towards eicosapentaenoic acid (EPA), in vitro enzymatic assays were performed in reconstituted CYP1A1 systems. All CYP1A1 variants catalyzed EPA epoxygenation and hydroxylation to 17(R),18(S)-epoxyeicosatetraenoic acid (17(R),18(S)-EETeTr) and 19-OH-EPA, yet with varying catalytic efficiency and distinct regiospecificity. CYP1A1.1 and CYP1A1.4 formed 17(R),18(S)-EETeTr as main product (K(m)=53 and 50 microM; V(max)=0.60 and 0.50 pmol/min/pmol; V(max)/K(m)=0.11 and 0.10 microM(-1)min(-1), respectively), followed by 19-OH-EPA (K(m)=76 and 93 microM; V(max)=0.37 and 0.37 pmol/min/pmol; V(max)/K(m)=0.005 and 0.004 microM(-1)min(-1), respectively). The variant CYP1A1.2 produced almost equal amounts of both metabolites, but its catalytic efficiency for hydroxylation was five times higher (K(m)=66 microM; V(max)=1.7 pmol/min/pmol; V(max)/K(m)=0.026 microM(-1)min(-1)) and that for epoxygenation was twice higher (K(m)=66 microM; V(max)=1.5 pmol/min/pmol; V(max)/K(m)=0.023 microM(-1)min(-1)) than those of the wild-type enzyme. Thus, the Ile462Val polymorphism in human CYP1A1 affects EPA metabolism and may contribute to interindividual variance in the local production of physiologically active fatty acid metabolites in the cardiovascular system and other extrahepatic tissues, where CYP1A1 is expressed or induced by polycyclic aromatic hydrocarbons and other xenobiotics.     

CYP1A1 Ile462Val is a risk factor for ovarian cancer development

Published data on the association between CYP1A1 gene polymorphism and ovarian cancer risk are conflicting and heterogeneous. To derive a more precise estimation of the relationship, a meta-analysis was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed for heterozygous, homozygous, dominant model, recessive model and allele, respectively. A total of 15 case-control studies were identified, among which, 13 studies (1815 cases and 3501 controls) were eligible for CYP1A1 Ile(462)Val and nine studies (2495 cases and 3553 controls) were eligible for CYP1A1 Msp1. Overall, Ile(462)Val was significantly associated with ovarian cancer, with homozygous carriers (Val/Val vs. Ile/Ile: OR=2.64; 95% CI: 1.63-4.28) and recessive model (Val/Val vs. Ile/Ile and Ile/Val: OR=2.30; 95% CI: 1.45-3.65) being risk factors for ovarian cancer development. In the subgroup analysis by ethnicity, significantly increased risks were found for Caucasians (homozygous carriers: OR=4.91; 95% CI: 2.07-11.66; recessive model: OR=3.26; 95% CI: 1.41-7.50) and Asians (homozygous carriers: OR=3.06; 95% CI: 1.48-6.33; recessive model: OR=2.75; 95% CI: 1.40-5.41; Val allele: OR=1.67; 95% CI: 1.19-2.35). However, no significant associations were found between Msp1 and ovarian cancer in the overall analyses or the subgroup analyses by ethnicity. This meta-analysis denotes the importance for in-depth research regarding of gene-gene, gene-environment interactions, race-specific and histological subtypes specific to obtain a more conclusive response about the function of CYP1A1 in ovarian cancer.     

Is CD36 gene polymorphism in region encoding lipid-binding domain associated with early onset CAD?

CD36 is a fatty acid translocase in striated muscle cells and cardiomyocytes. Some study suggested that alterations in CD36 gene may be associated with coronary artery disease (CAD) risk. The aim of the current study was to compare the frequency of CD36 variants in region encoding lipid-binding domain in Caucasian patients with early-onset CAD, no-CAD adult controls and neonates. The study group comprised 100 patients with early onset CAD. The genetic control groups were 306 infants and 40 no-CAD adults aged over 70 years. Exons 4, 5 and 6 including fragments of flanking introns were studied using the denaturing high-performance liquid chromatography technique and direct sequencing. Changes detected in analyzed fragment of CD36: IVS3-6 T/C (rs3173798), IVS4-10 G/A (rs3211892), C311T (Thr104Ile, not described so far) in exon 5, G550A (Asp184Asn, rs138897347), C572T (Pro191Leu, rs143150225), G573A (Pro191Pro, rs5956) and A591T (Thr197Thr, rs141680676) in exon 6. No significant differences in the CD36 genotype, allele and haplotype frequencies were found between the three groups. Only borderline differences (p = 0.066) were found between early onset CAD patients and newborns in the frequencies of 591T allele (2.00% vs 0.50%) and CGCGCGT haplotype (2.00% vs 0.50%) with both IVS3-6C and 591T variant alleles. In conclusion, CD36 variants: rs3173798, rs3211892, rs138897347, rs5956, rs143150225 rs141680676 and C311T do not seem to be involved in the risk of early-onset CAD in Caucasian population.     

Association between CYP1A1 Ile462Val Variation and Acute Leukemia Risk: Meta-Analyses Including 2164 Cases and 4160 Controls

Background

Previously, CYP1A1 Ile462Val polymorphism has been indicated to be a risk factor for several malignancies. Increasing reports have focused on the association of CYP1A1 Ile462Val polymorphisms with susceptibility to acute leukemia and have generated controversial results. The goal of the present study was to derive a more precise estimation of the relationship.

Methods

Relevant literature has been rigorously searched and screened. Eligible studies were identified for the period up to Apr 2012. Meta-analyses evaluating the association of CYP1A1 Ile462Val variation with acute leukemia were carried out. Subgroup analyses on ethnicity, clinical types and source of controls were further performed.

Results

A total of thirteen publications including fourteen case-control studies with 2164 cases and 4160 controls were selected for analysis. The overall data indicated a significant association of CYP1A1 Ile462Val polymorphism with acute leukemia risk (Val/Val vs Ile/Ile OR = 1.49; 95% CI = 1.11–1.98; dominant model: OR = 1.26; 95% CI = 1.05–1.51; recessive model: OR = 1.38; 95% CI = 1.04–1.83). In subgroup analysis on ethnicity, increased risk was shown among mixed ethnicities (Val/Val vs Ile/Ile: OR = 2.36; 95% CI = 1.46–3.82; dominant model: OR = 1.37; 95% CI = 1.01–1.86; recessive model: OR = 2.20; 95% CI = 1.37–3.53) but not Asians or Caucasians. In subgroup analysis on clinical types, increased risk was observed in the acute lymphocytic leukemia (ALL) subgroup (Val/Val vs Ile/Ile: OR = 2.06; 95% CI = 1.42–3.01; recessive model: OR = 1.91; 95% CI = 1.32–2.76) but not in the acute myeloid leukemia (AML) subgroup.

Conclusion

The results of the present study suggest that CYP1A1 Ile462Val polymorphism might be a low-penetrant risk factor for acute leukemia. Subgroup analyses suggest that homozygous Val/Val alleles might modify the susceptibility to ALL.     

Association between CYP1A2 and CYP1B1 Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis

Background

The previous published data on the association between CYP1A2*F (rs762551), CYP1B1 Leu432Val (rs1056836), Asn453Ser (rs180040), and Arg48Gly (rs10012) polymorphisms and colorectal cancer risk remained controversial.

Methodology/Principal Findings

The purpose of this study is to evaluate the role of CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly genotypes in colorectal cancer susceptibility. We performed a meta-analysis on all the eligible studies that provided 5,817 cases and 6,544 controls for CYP1A2*F (from 13 studies), 9219 cases and 10406 controls for CYP1B1 Leu432Val (from 12 studies), 6840 cases and 7761 controls for CYP1B1 Asn453Ser (from 8 studies), and 4302 cases and 4791 controls for CYP1B1Arg48Gly (from 6 studies). Overall, no significant association was found between CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly and colorectal cancer risk when all the eligible studies were pooled into the meta-analysis. And in the subgroup by ethnicity and source of controls, no evidence of significant association was observed in any subgroup analysis.

Conclusions/Significance

In summary, this meta-analysis indicates that CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly polymorphisms do not support an association with colorectal cancer, and further studies are needed to investigate the association. In addition, our work also points out the importance of new studies for CYP1A2*F polymorphism in Asians, because high heterogeneity was found (dominant model: I ² = 81.3%; heterozygote model: I ² = 79.0).     

Polymorphisms of glutathione S-transferases M1, T1, P1 and A1 genes in the Tunisian population: an intra and interethnic comparative approach

Genetic polymorphisms in glutathione S-transferases (GSTs) genes might influence the detoxification activities of the enzymes predisposing individuals to cancer risk. Owing to the presence of these genetic variants, inter-individual and ethnic differences in GSTs detoxification capacity have been observed in various populations. Therefore, the present study was performed to determine the prevalence GSTM1 0/0, GSTT1 0/0, GSTP1 Ile(105)Val, and GSTA1 A/B polymorphisms in 154 healthy individuals from South Tunisia, and to compare them with those observed in North and Centre Tunisian populations and other ethnic groups. GSTM1 and GSTT1 polymorphisms were analyzed by a Multiplex-PCR approach, whereas GSTP1 and GSTA1 polymorphisms were examined by PCR-RFLP. The frequencies of GSTM10/0 and GSTT1 0/0 genotypes were 53.9% and 27.9%, respectively. The genotype distribution of GSTP1 was 47.4% (Ile/Ile), 40.9% (Ile/Val), and 11.7% (Val/Val). For GSTA1, the genotype distribution was 24.7% (A/A), 53.9% (A/B), and 21.4% (B/B). The combined genotypes distribution of GSTM1, GSTT1, GSTP1 and GSTA1 polymorphisms showed that thirty one of the 36 possible genotypes were present in our population; eight of them have a frequency greater than 5%. To the best of our knowledge, this is the first report of GSTs polymorphisms in South Tunisian population. Our findings demonstrate the impact of ethnicity and reveal a characteristic pattern for Tunisian population. The molecular studies in these enzymes provide basis for further epidemiological investigations in the population where these functional polymorphisms alter therapeutic response and act as susceptibility markers for various clinical conditions.     

Soy isoflavones, CYP1A1, CYP1B1, and COMT polymorphisms, and breast cancer: a case-control study in southwestern China

CYP1A1, CYP1B1, and COMT are key enzymes involved in estrogen metabolism. Soy isoflavones, phytoestrogens found in soy foods, may modify the activity of these enzymes. A case-control study was conducted to assess the associations between soy isoflavone intake and the CYP1A1 Ile462Val, CYP1B1 Val432Leu, and COMT Val158Met polymorphisms and breast cancer, as well as their combined effects on breast cancer. A total of 400 newly diagnosed breast cancer cases and 400 healthy controls were recruited. Participants' daily intake of soy isoflavones (DISI [mg/day]) was calculated and transformed to energy-adjusted DISI by the residual method. Gene sequencing was used to analyze CYP1A1, CYP1B1, and COMT polymorphisms. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated by conditional logistic regression. A strong protective dose-dependent effect of energy-adjusted DISI on breast cancer was found in both pre- and postmenopausal women (P(trend)??1, OR 95% CIs exclude 1). In premenopausal women, only carrying CYP1B1 Leu/Leu was associated with breast cancer risk (aOR?=?2.05, 95% CI: 1.11-3.79). Carrying CYP1A1 Val/Val was related to breast cancer risk only among all women. A stratified analysis was performed at two levels of energy-adjusted DISI, with wildtype homozygous genotypes and low energy-adjusted DISI as the reference. In the high energy-adjusted DISI subgroup, carrying the CYP1B1 Leu/Leu genotype did not affect breast cancer risk in either all women or in the menopausal subgroups, compared with the reference. Overall, in Han Chinese women, carrying CYP1A1 Val/Val and COMT Met/Met appears to be associated with breast cancer risk, especially in postmenopausal women. CYP1B1 susceptible genotypes (Val/Leu or Leu/Leu) also contribute to increased breast cancer risk, regardless of menopausal status, but high soy isoflavone intake may reduce this risk.     

PPARGC1A基因Thr394Thr/Gly482Ser多态性与2型糖尿病的关联研究

对344例2型糖尿病患者和307名正常人的PPARGC1A基因单核苷酸多态性rs2970847(Thr394Thr)和rs8192678(Gly482Ser)与2型糖尿病的关系进行了单标记和单体型关联分析以及Logistic回归分析。在单标记分析中,对照组与病例组Thr394Thr的基因型和等位基因频率有显著差异(基因型, P =0.006; 等位基因, P < 0.001); Logistic回归和单体型分析表明, Thr394Thr的AA基因型及Thr394(ACA)-Ser482单体型增加患2型糖尿病的风险。Gly482Ser的基因型和等位基因频率在对照组与病例组间无显著差异。PPARGC1A基因是湖北汉人的一个2型糖尿病易感基因。     

Exploring the effect of D61G mutation on SHP2 cause gain of function activity by a molecular dynamics study

Noonan syndrome (NS) is a common autosomal dominant congenital disorder which could cause the congenital cardiopathy and cancer predisposition. Previous studies reported that the knock-in mouse models of the mutant D61G of SHP2 exhibited the major features of NS, which demonstrated that the mutation D61G of SHP2 could cause NS. To explore the effect of D61G mutation on SHP2 and explain the high activity of the mutant, molecular dynamic simulations were performed on wild type (WT) of SHP2 and the mutated SHP2-D61G, respectively. The principal component analysis and dynamic cross-correlation mapping, associated with secondary structure, showed that the D61G mutation affected the motions of two regions (residues Asn 58-Thr 59 and Val 460-His 462) in SHP2 from β to turn. Moreover, the residue interaction networks analysis, the hydrogen bond occupancy analysis and the binding free energies were calculated to gain detailed insight into the influence of the mutant D61G on the two regions, revealing that the major differences between SHP2-WT and SHP2-D61G were the different interactions between Gly 61 and Gly 462, Gly 61 and Ala 461, Gln 506 and Ile 463, Gly 61 and Asn 58, Ile 463 and Thr 466, Gly 462 and Cys 459. Consequently, our findings here may provide knowledge to understand the increased activity of SHP2 caused by the mutant D61G.     

HER2 Ile655Val and PTEN IVS4 polymorphisms in patients with breast cancer

Although HER2/PTEN pathway is commonly disrupted in cancer, association of HER2 and PTEN polymorphisms with breast cancer (BC) remains controversial. We investigated the HER2 Ile655 Val and PTEN IVS4 polymorphisms in patients with BC in Turkish population. HER2 Ile655Val (rs 1136201) and PTEN IVS4 (rs 3830675) polymorphisms were determined using polymerase chain reaction-based restriction fragment length polymorphism (PCR–RFLP) in blood samples of 118 BC patients and 118 age-matched healthy controls. We found that the frequency of the Ile/Val genotype of HER2 Ile655Val gene was significantly higher in BC patients (p < 0.009; OR: 1,983 95 % CI: 1.181—3.328). The presence of ATCTT insertion (+/+) genotype at downstream of exon 4 in intron 4 of PTEN IVS4 gene was also associated with 1.83 fold decreased risk of BC development (p < 0.033; OR: 1.83, 95 % CI: 1.11—3.03). Analysis on clinico-pathological parameters showed neither HER2 Ile655Val nor PTEN IVS4 genotypes were not associated with any of the variables (p > 0.05).In conclusion, our findings suggest that the Ile/Val genotype of HER2 and ATCTT insertion (+/+) genotype of PTEN IVS4 gene may play an important role as genetic markers for breast cancer risk, but both genes genotypes may not be useful for predicting tumor prognosis in Turkish population.     

Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population.

Cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) metabolize tobacco-related carcinogens. To investigate the prevalence of CYP1A1 and GSTM1, and their association with increased risk of lung carcinoma in Chinese, allele-specific PCR and multiplex PCR technique were employed to identify the genotypes of CYP1A1 and GSTM1 in a case-control study of 106 lung carcinoma patients with histopathological diagnosis and 106 matched controls free of malignancy in Jiangsu Province, China. Logistic regression analysis was performed to calculate the odds ratio (OR) and 95% confidence intervals (CI). The results showed that individuals with GSTM1 null, and the combined GSTM1 null/CYP1A1 Ile/Val or GSTM1 null/CYP1A1 Val/Val had an elevated risk of lung carcinoma, with the OR, 1.92 (P=0.02; CI, 1.07-3.46), 3.27 (P=0.01; CI, 1.23-8.84) and 9.33 (P=0.04; CI, 1.01-217.42), respectively. Light smokers (<30 pack-years) carrying GSTM1 null genotype were shown to have the increased risk to lung carcinoma (OR=3.47; CI, 1.13-7.57). Our study suggested that the null GSTM1 genotype, independently or in combined with at least one Val allele of CYP1A1, might affect the genetic susceptibility for lung carcinoma in Chinese population.     

Lung cancer risk in north Indian population: role of genetic polymorphisms and smoking

Lung cancer (LC) is the leading cause of cancer-related mortality in developing as well as developed countries. Life style choices, particularly tobacco smoking, have been implicated as the main cause in the development of the LC. Despite the fact that majority cases of the LC occur among smokers, only 1–15% of smokers develop LC. In the present study, we have explored the role of genetic polymorphism, smoking habit and their association to LC in a cohort of north Indian population. The polymorphic genes explored were CYP1A1, GSTM1, GSTP1 and GSTT1 using techniques of Polymerase chain reaction (PCR), Restriction Fragment Length Polymorphism (RFLP), Real Time PCR (RT PCR), and gene sequencing. Genetic polymorphism was analysed in 253 normal participants (control) and 93 LC patients originating from Lucknow, India. Data were compared using odds ratio and Fisher Exact Test. We found that smoking increases the susceptibility to LC threefold (OR = 2.9; 95% CI: 0.9–2.8). The most significant risk for LC (OR = 3.2; 95% CI: 0.7–3.8) was found in the association of the homozygous variant of CYP1A1 gene at A2455G base change at Exon 7 (Val/Val) genotype. There was a marginally significant association between LC and GSTT1 null genotype (OR = 1.3; 95% CI: 1.0–1.7) while no significant risk association was found between GSTP1 polymorphism and LC. The present study demonstrates that the presence of null genotype of GSTM1/GSTT1 taken together with CYP1A1 (Val/Val) genotype increases the susceptibility to LC eightfold in comparison to CYP1A1 (Ile/Ile) and GSTM1/ GSTT1 genotype.