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PubMed2004

Vitamin D receptor gene polymorphism as an important modifier of positive family history related breast cancer risk.

The association between vitamin D receptor (VDR) gene polymorphisms and diseases such as breast cancer, prostate cancer and osteoporosis has been extensively investigated during recent years. To date, several polymorphisms have been found in the VDR gene. In this Finnish case-control study, comprising 483 breast cancer patients and 482 healthy population controls, we investigated the association between altered breast cancer risk and two polymorphisms in the 3' end of the gene detectable with ApaI and TaqI restriction enzymes. A statistically significant difference was observed in the ApaI genotype distribution between cases and controls. Women with the VDR variant a allele containing genotypes showed a decreased risk for breast cancer [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.54-0.98] compared to women with the AA genotype. This association was especially strong among women with a positive family history of breast cancer (OR 0.14, 95% CI 0.03-0.76). Moreover, there was a trend (P for trend = 0.0007) for decreased risk with increasing number of variant alleles. The lowest risk of breast cancer was seen for the women with the aa genotype (OR 0.03, 95% CI 0.003-0.31) compared to women with the AA genotype. A tendency of decreased risk of breast cancer was also observed for the TaqI T allele containing genotypes (Tt and TT) (OR 0.68, 95% CI 0.41-1.12), but because the distribution of Taql alleles in the controls missed the Hardy-Weinberg equilibrium (P = 0.01), we were unable to properly assess the potential impact of the TaqI polymorphism in breast cancer susceptibility. In conclusion, our results suggest that the VDR ApaI genotype may be an important modifier of individual breast cancer risk among Finnish women, especially if they have a positive family history of breast cancer.

Breast Neoplasms↗
PubMed1992

Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus.

Adenomatous polyps are an intermediate in the pathway to colon carcinoma. An inherited disorder, familial adenomatous polyposis coli (APC), is characterized by hundreds to thousands of adenomatous polyps. A previously reported family had colon cancer associated with a low average but highly heterogenous number of colonic polyps, this phenotype mapped to the APC locus on 5q. Four new families have been ascertained in which the phenotypic pattern was different from classical polyposis but similar to that of the "prototype" kindred reported earlier. By multilocus linkage analysis, the gene responsible for the disease phenotype was mapped, with a high level of confidence, to the APC locus in two of the four families with the attenuated or variant form of polyposis (AAPC); the results for the two remaining kindreds were inconclusive. A combined maximum LOD score of approximately 7.6 at a recombination fraction of 0 was obtained when the results were summed over the four pedigrees with markers closest to the APC locus. The establishment of genetic linkage in such families may point to the APC locus as having a more significant role in inherited predispositions to colorectal cancer than was previously thought.

Adenomatous Polyposis Coli↗
PubMed2025

Sex Distributions in the Most Frequent Autosomal Genetic Causes of Retinitis Pigmentosa.

PURPOSE: The purpose of this study was to explore whether sex imbalances are detectable in the most frequent genetic causes of retinitis pigmentosa (RP). METHODS: Databases from centers in three countries (Moorfields Eye Hospital, London; Hospital for Sick Children, Toronto; and Australian Inherited Retinal Disease Registry, Perth, Australia) were searched, quantifying numbers of male and female patients with disease attributed to variants in the six most frequently involved autosomal RP genes. Proportions of female patients (with 95% confidence intervals [CIs]) were calculated for each gene. Two-tailed binomial testing was performed (Bonferroni corrected threshold, P = 0.008) to investigate whether proportions differed significantly from an underlying male:female ratio of 1:1. For genes where the 95% CI did not include 50%, sex distributions were also explored in previously published cohorts. RESULTS: Our search yielded 1454 patients with disease attributable to variants in USH2A (n = 550), RP1 (n = 277), RHO (n = 246), PRPF31 (n = 158), EYS (n = 124), and MYO7A (n = 99). Proportions of female patients (95% CI) for each gene were 46.2% (42.0-50.5%), 49.5% (43.4-55.5%), 55.3% (48.8-61.6%), 63.9% (55.9-71.3%), 39.5% (31.0-48.7%), and 42.4% (32.7-52.8%), respectively. The 95% CI did not include 50% for PRPF31 and EYS; binomial testing revealed P values of 6.24 × 10-4 and 0.025, respectively. Combining with data extracted from previously published cohorts yielded P values of 1.62 × 10-6 and 0.0084, respectively. CONCLUSIONS: We observed a significant preponderance of female patients for PRPF31-associated RP and a preponderance of male patients in those with EYS-associated RP. Our findings suggest that sex is likely to be a modifier affecting penetrance in PRPF31-associated disease and might act in the opposite direction in disease associated with EYS.

Humans↗
PubMed2003

CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer.

Previous case-only studies have shown that men with the CYP3A4*1B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A4*1B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (*1/*3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A4*1B and CYP3A5*1 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A4*1B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02-3.57; P=0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01-0.49; P=0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26-1.00; P=0.05). The CYP3A5*1 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22-0.78; P=0.006). As expected based on these genotype-level results, the CYP3A4*1B/CYP3A5*3 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36-6.23; P=0.006), and the CYP3A4*1B/CYP3A5*1 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01-0.51; P=0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness.

Age Factors↗
PubMed2003

Thiopurine methyltransferase genotype distribution in patients with Crohn's disease.

BACKGROUND: Inter-individual response to azathioprine is partly due to inter-individual variation in the thiopurine methyltransferase (TPMT) activity. The TPMT genotype, which reflects the TPMT activity, has previously been studied in healthy Caucasians, with the most common variant allele being TPMT*3A. TPMT genotyping in adult patients with Crohn's disease has never been performed systematically. AIM: To determine the TPMT genotype distribution in adult patients with Crohn's disease. METHODS: One hundred and twenty randomly selected Danish patients (64 females and 56 males) with azathioprine-dependent Crohn's disease were included, and a polymerase chain reaction assay was used for TPMT genotyping. The patients were genotyped for the low-level genotype G460-->A and A719-->G transitions. RESULTS: One hundred and nine patients (90.3%; 95% confidence interval, 84.1-95.3) had a wild-type/ wild-type genotype, whereas 10 patients (8.3%; 95% confidence interval, 4.1-14.8) had one non-functional mutant allele and one patient (0.8%; 95% confidence interval, 0.02-4.6) had two non-functional mutant alleles. Only the TPMT*3A variant allele was found. CONCLUSIONS: The study showed a TPMT genotype distribution amongst adult Danish patients with Crohn's disease which was similar to the distribution of TPMT variant alleles normally found in healthy Caucasians.

Adolescent↗
PubMed2003

The prohibitin 3' untranslated region polymorphism is not associated with risk of ovarian cancer.

OBJECTIVE: The 3' untranslated region of the prohibitin gene encodes an RNA molecule that arrests cell proliferation between the G(1) and S phases of the cell cycle, and a C-to-T transition within this region creates a variant lacking antiproliferative activity. The T allele was reported to be associated with an increased risk of breast cancer in North American women, specifically in those under age 50 years reporting a first-degree family history of breast cancer. We assessed the association of the prohibitin 3' untranslated region polymorphism with risk of ovarian cancer in the Australian population by case-control comparison. METHODS: We examined 553 cases of epithelial ovarian cancer and 300 unaffected controls to assess whether this polymorphism was associated with risk of ovarian cancer in Australian women. Genotyping was carried out using the Perkin-Elmer ABI Prism 7700 Sequence Detection System for fluorogenic polymerase chain reaction allelic discrimination. Genotype distributions were compared by logistic regression. RESULTS: Stratification of the ovarian cancer cases according to tumour behavior (low malignant potential or invasive), histology, grade, stage, or p53 immunohistochemical status failed to reveal any heterogeneity with respect to prohibitin genotype. There was no difference in genotype distribution between cases and controls, with an odds ratio (95% confidence interval) of 0.99 (0.72-1.35) for the CT/TT genotype. CONCLUSION: The prohibitin T variant does not appear to be associated with risk of ovarian cancer in Australian women.

3' Untranslated Regions↗
PubMed1999

Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis--evidence of an age-dependent thrombotic onset in carriers of factor V G1691A and prothrombin G20210A mutation.

UNLABELLED: Risk factors for venous thrombosis in adults are the prothrombin (PT) G20210A, the factor (F) V G1691A mutations and hereditary deficiencies of protein C, protein S and antithrombin. However, data are limited on the relevance of these risk factors for thrombosis in children and adolescents. We therefore investigated 119 patients aged 0-18 with spontaneous venous thrombosis and controls (n = 100) for the presence of the factor V G1691A mutation and the prothrombin G20210A variant with respect to thrombotic onset and thrombosis location. The following frequencies (patients vs. controls), odds ratios (OR), 95%-confidence intervals (CI) and p-values were found: FV G1691A, 19.3% vs. 5%, OR/CI 4.55/1.66-12.5, p = 0.0038 and prothrombin G20210A, 8.4% vs. 3%, OR/CI 2.96/0.8-11, p = 0.17. A combination of the FV G1691A mutation with the PT G20210A variant was found in 3 children (2.5% of cases) but only once in the controls. With a median (range) age of 2 years (0-17), carriers of the FV mutation were significantly younger compared with patients carrying the PT variant (16 years: 0-18, p < 0.001). Vascular accidents in carriers of the FV mutation occurred in deep veins of the leg (n = 11), cerebral veins (n = 4), renal veins (n = 3) and portal veins (n = 2). Patients with the PT mutation showed spontaneous thrombosis in the majority of cases in the deep veins of the leg (n = 5) and in the central nervous system (n = 2). Combined defects were found in a neonate with renal venous thrombosis and in two adolescents with deep vein thrombosis. CONCLUSION: Data presented here suggest that the heterozygous FV mutation is the most commonly found prothrombotic risk factor responsible for spontaneous thrombosis during infancy and early childhood. In contrast, the PT G20210A variant is likely to be more important during puberty and adolescence.

Adolescent↗
PubMed2003

Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK.

Cytochrome P450 2A13 (CYP2A13), an enzyme expressed predominantly in the human respiratory tract, exhibits high efficiency in the metabolic activation of tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A C-->T transition in the CYP2A13 gene causes Arg257Cys amino acid substitution and, thus, results in a significantly reduced activity toward NNK and other substrates. In this case-control study, we genotyped 724 patients with lung cancer and 791 controls for this polymorphism to examine the hypothesis that the variant CYP2A13 may have impact on risk of lung cancer in relation to tobacco smoking. A gene deletion polymorphism (CYP2A6*4) in CYP2A6, another enzyme involved in the metabolic activation of tobacco nitrosamines, was also analyzed as a comparison. We found that, compared with the CC genotype, the variant CYP2A13 genotype (CT + TT) was associated with substantially reduced risk for lung adenocarcinoma [odds ratio (OR), 0.41; 95% confidence interval (CI), 0.23-0.71], but not squamous cell carcinoma (OR, 0.86; 95% CI, 0.57-1.29) or other types of lung cancer (OR, 0.58; 95% CI, 0.32-1.09). Stratification analysis shows that the reduced risk of lung adenocarcinoma related to the variant CYP2A13 genotype was limited to smokers, especially light smokers (OR, 0.23; 95% CI, 0.08-0.68) but not nonsmokers or heavy smokers. No association was observed between CYP2A6 genotype and risk of lung cancer. Our results demonstrate for the first time that the variant CYP2A13 allele is associated with reduced risk of lung adenocarcinoma, suggesting the role of NNK-CYP2A13 interaction as a causative factor for the cancer.

Adenocarcinoma↗
PubMed2002

Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis.

OBJECTIVE: To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA). METHODS: Denaturing high-performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety-two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single-nucleotide polymorphism (SNP) identified in the 5'-flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. RESULTS: A tetranucleotide repeat CATT((5-7)) beginning at nucleotide position -794 and 3 SNPs at positions -173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA-specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the JIA patients for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele had an increased risk of JIA (34.8% versus 21.6%) (odds ratio 1.9, 95% confidence interval 1.4-2.7; P = 0.0002). Furthermore, the MIF-173* G and C variants resulted in altered expression of MIF in a cell type-specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF-173*C allele (P = 0.04). CONCLUSION: The -173-MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type-specific regulation of MIF, which may be central to understanding its role in inflammation.

Alleles↗
PubMed2006

IGHMBP2 Thr671Ala polymorphism might be a modifier for the effects of cigarette smoking and PAH-DNA adducts to breast cancer risk.

Laboratory and bioinformatics studies have suggested that immunoglobulin mu-binding protein 2 (IGHMBP2) is involved in DNA repair, replication and recombination. Using 1067 cases and 1110 controls from a population-based case-control study, we sought to clarify the potential role of the IGHMBP2 Thr671Ala polymorphism (A to G substitution) alone and as a modifier of the effects for cigarette smoking and PAH-DNA adducts on breast cancer risk. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Overall, there was no significant association between the IGHMBP2 variant-G allele and breast cancer risk (OR = 1.1, 95% CI = 0.9-1.3). Increased risk was found among women who had detectable PAH-DNA adducts and carried at least one variant-G allele (OR = 1.4, 95% CI = 1.0-1.8, p for trend = 0.01) compared to women carrying the wild-type AA genotype and with non-detectable adducts. Smokers carrying the IGHMBP2 variant-G allele had no significant increased breast cancer risk compared with non-smoking women with the AA genotype. Heavy smokers (>31 pack years) had a statistically significant association with breast cancer risk (OR=2.0, 95% CI=1.2-3.3) relative to nonsmokers with the AA genotype though the magnitude of association was not different than heavy smokers (> 31 pack years) with the AA genotype (OR=1.6, 95% CI=0.9-2.6). Overall our study observes only modestly higher effect estimates for PAH-DNA adduct exposure and cigarette smoking among those with the high-risk genotype, but these differences are not statistically significant. Additional studies focused on the biological function of the variant-G allele and interactions with other genetic polymorphisms are necessary to confirm our findings.

Aged↗
PubMed1976

Radiation-induced mutations at mouse hemoglobin loci.

In experiments designed to detect new mutations affecting hemoglobin, we irradiated the male or female parent in reciprocal crosses of two mouse strains that differ in alleles at the hemoglobin (Hba, Hbb) loci as well as at five other specific loci. Offspring were analyzed for hemoglobin properties (electrophoretic pattern, solubility, crystal pattern), serum albumin differences, erythrocyte lysis, reticulocyte count, and external appearance. Five hemoglobin variants were found among the mutants. In three, the genetic contribution from the irradiated father was not expressed with regard to the alpha-chain; one carried a tandem deuplication (the first known case in the mouse) involving Hbb; and one probably resulted from double nondisjunction of chromosome 7. The finding that major chromosome aberrations can mimic hemoglobin mutations indicates the need, in similar experiments, to follow F1 screening with thorough cytogenetic analysis. The variants in which there is nonexpression of the alpha chain may be the result of small deficiencies or of faults in transcription or translation. Mutation rates based on these three variants are not out of line with earlier specific-locus results, although confidence limits are still wide.

Anemia↗
PubMed2005

Trp64Arg polymorphism of the beta3-adrenergic receptor gene, pre-pregnancy obesity and risk of pre-eclampsia.

OBJECTIVE: Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) gene was reported to be associated with increased risk of obesity and insulin resistance. Both traits have been implicated in the epidemiology and pathogenesis of pre-eclampsia. We investigated the relation of the beta3-AR gene to pre-pregnancy obesity and risk of pre-eclampsia. The present study is a case-control study of 87 Caucasian pre-eclampsia cases and 214 controls. METHODS: Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for maternal age and parity. Normotensive carriers of the variant allele (i.e. Arg64 allele) were 3.6 times more likely to be obese (body mass index (BMI) > or = 30 kg/m2) as compared with women not carrying the variant allele (OR = 3.6, 95% CI 0.8-15.0). RESULTS: Arg64 allele was more frequent in controls as compared with pre-eclampsia cases (11.7 vs. 5.3%, p < 0.01). After adjusting for age and parity, carriers experienced a 60% reduction in risk of pre-eclampsia (OR = 0.4, 95% CI 0.2, 0.9) as compared with women not carrying this allele. The association between carriage of the variant allele and risk of pre-eclampsia appeared to be modified by maternal BMI. Compared with lean carriers, lean women without the variant allele experienced only a small increase in the risk of pre-eclampsia (OR = 1.5; 95% CI: 0.6, 3.9). The OR for overweight women without the variant allele was 7.3 (95% CI 2.7-19.2). CONCLUSIONS: Our results suggest a puzzling relationship between the polymorphism and the risk of pre-eclampsia. Future studies are needed to confirm these findings.

Adult↗
PubMed2004

Does the addition of information on genotype improve prediction of the risk of melanoma and nonmelanoma skin cancer beyond that obtained from skin phenotype?

The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA samples were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39; odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35; odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42; odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.

Adult↗
PubMed2004

Genome wide identification and classification of alternative splicing based on EST data.

MOTIVATION: Alternative splicing is currently seen to explain the vast disparity between the number of predicted genes in the human genome and the highly diverse proteome. The mapping of expressed sequences tag (EST) consensus sequences derived from the GeneNest database onto the genome provides an efficient way of predicting exon-intron boundaries, gene structure and alternative splicing events. However, the alternative splicing events are obscured by a large number of putatively artificial exon boundaries arising due to genomic contamination or alignment errors. The current work describes a methodology to associate quality values to the predicted exon-intron boundaries. High quality exon-intron boundaries are used to predict constitutive and alternative splicing ranked by confidence values, aiming to facilitate large-scale analysis of alternative splicing and splicing in general. RESULTS: Applying the current methodology, constitutive splicing is observed in 33,270 EST clusters, out of which 45% are alternatively spliced. The classification derived from the computed confidence values for 17 of these splice events frequently correlate (15/17) with RT-PCR experiments performed for 40 different tissue samples. As an application of the confidence measure, an evaluation of distribution of alternative splicing revealed that majority of variants correspond to the coding regions of the genes. However, still a significant fraction maps to non-coding regions, thereby indicating a functional relevance of alternative splicing in untranslated regions. AVAILABILITY: The predicted alternative splice variants are visualized in the SpliceNest database at http://splicenest.molgen.mpg.de

Algorithms↗
PubMed1999

[Bovine spongiform encephalopathy in ruminants and the new variant of Creutzfeldt-Jakob disease in humans].

The feeding of meat and bone meal which was contaminated with bovine spongiform encephalopathy (BSE) infectivity led to a huge epidemic in the British cattle population. After the emergence of a new variant form of Creutzfeldt-Jakob diseases (nvCJD) in 1996, European consumers lost confidence in beef meat. Given the coincidence by time and place and disease and agent specific characteristics, it must be assumed that nvCJD is caused by the transmission of BSE agent to man. This article gives an overview over the characteristics and diagnosis of transmissible spongiform encephalopathies, namely BSE and nvCJD, in animals and man.

Animals↗
PubMed1998

[Endothelial nitric oxide synthase gene polymorphism and hypertension].

Nitric oxide (NO) is produced by endothelial cells and serves as a potent vasodilator. Several lines of evidence have shown that NO plays an important role in the regulation of blood pressure and regional blood flow. Endothelial NO synthase (eNOS) gene polymorphisms exhibit a positive association in myocardial infarction and smoking-dependent risk of coronary artery disease. However, the relationship between eNOS gene polymorphisms and hypertension is controversial. To examine the possible involvement of the eNOS gene in the genetic basis for hypertension, we identified genotypes for 2 eNOS gene polymorphisms in 166 hypertensive and 174 normotensive populations in Aomori prefecture, in northern Japan. The specific genotypes for Glu298Asp missense variant and variable numbers of tandem repeats in intron 4 (eNOS 4b/4a) were isolated using allele specific gene amplification and restriction fragment length polymorphism. The 298Asp variant was significantly correlated to hypertension in these groups (odds ratio, 1.8; 95% confidence interval, 1.1-3.2). The allelic frequencies of 298Asp for Glu298 in hypertensive patients were significantly higher than those in normotensive subjects (0.136 vs 0.083, p < 0.05). However, disequilibrium of eNOS4b/4a was absent between these 2 groups. These results suggest that Glu298Asp is a genetic susceptibility factor for hypertension.

Aged↗
PubMed2007

Variant alleles of TGFB1 and TGFBR2 are associated with a decreased risk of gastric cancer in a Chinese population.

Growing evidence suggests that the transforming growth factor beta (TGF-beta) signaling pathway occupies a central position in the signaling networks that control cell growth and differentiation. TGF-beta1 and its receptor TGF-betaRII have been correlated with the development of certain forms of cancer, including gastric cancer. We hypothesized that functional genetic variants in TGFB1 and TGFBR2 are associated with gastric cancer risk. To test this hypothesis, we genotyped C-509T and Leu10Pro polymorphisms in TGFB1 and G-875A variant in TGFBR2, using the primer-introduced restriction analysis (PIRA)-PCR assay, in a case-control study of 675 gastric cancer cases and 704 healthy controls in a Chinese population. We found that the variant alleles of the promoter polymorphisms, TGFB1 C-509T and TGFBR2 G-875A, were associated with a significantly decreased risk of gastriccancer [adjusted odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.52-0.82 for -509CT/TT and adjusted OR = 0.67, 95% CI = 0.53-0.85 for -875GA/AA]. Furthermore, subjects with both variant genotypes of the TGFB1 C-509T and TGFBR2 G-875A were associated with a significantly (56%) decreased risk of gastric cancer (adjusted OR = 0.44, 95% CI = 0.32-0.62). These findings indicate, for the first-time, that the functional variants in the promoter of TGFB1 and TGFBR2 might contribute to gastric cancer susceptibility.

Alleles↗
PubMed2004

A prospective study of genetic polymorphisms in the cytochrome P-450 2C9 enzyme and the risk for distal colorectal adenoma.

BACKGROUND & AIMS: Regular aspirin use is associated with a reduced risk for colorectal adenoma, whereas smoking increases risk. The cytochrome P-450 (CYP) 2C9 (CYP2C9) enzyme is involved in the metabolism of several drugs, including possibly aspirin, and such carcinogens as smoking-related polycyclic aromatic hydrocarbons. Genetic variation in this enzyme may modulate the influence of aspirin and smoking on adenoma risk. METHODS: We examined the risk for incident distal colorectal adenoma according to CYP2C9 genotype, aspirin use, and smoking in a prospective nested case-control study of women. RESULTS: Among 394 cases and 396 controls, women with at least 1 variant CYP2C9 allele had a significantly greater risk for adenoma (multivariate odds ratio [OR], 1.56; 95% confidence interval [CI], 1.13-2.15; P = 0.007). Although women who used aspirin regularly (>/=2 standard tablets/wk) experienced a lower risk for adenoma compared with non-regular users, the effect was similar irrespective of genotype. Women who smoked >20 pack-years had an OR of adenoma of 1.50 (95% CI, 1.07-2.12; P = 0.02) compared with those who smoked </=20 pack-years. Among women with at least 1 variant allele who smoked >20 pack-years, the OR of adenoma was 2.50 (95% CI, 1.44-4.38; P = 0.001) compared with women with no variant alleles who smoked </=20 pack-years. CONCLUSIONS: Polymorphisms in the CYP2C9 enzyme are associated with elevated risk for colorectal adenoma. This observation does not appear to be related to modification of the effect of aspirin on adenoma risk, but may be associated with differential metabolism of environmental carcinogens.

Adenoma↗