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PubMed2003

BRCA1 wild-type allele modifies risk of ovarian cancer in carriers of BRCA1 germ-line mutations.

Strong inter- and intrafamilial variation of penetrance of breast and ovarian cancer is observed in BRCA1 mutation carriers. The wild-type copy of the BRCA1 gene is a plausible candidate as a cancer risk modifier given that the residual function corresponding to the intact BRCA1 allele may influence the process of tumor formation in BRCA1 carriers. Indeed, growing evidence is now becoming available on impaired reparation of double-strand DNA breaks in cells heterozygous for BRCA1 mutations, implying an enhanced mutability of BRCA1(+/-) cells. To determine whether certain variant forms of the wild-type BRCA1 allele are implicated in variation of the BRCA1-related cancer risk, their effect was studied in a panel of 591 women with BRCA1 germ-line mutations. We found that BRCA1 carriers with the wild-type BRCA1 copy bearing a common Gly1038 variant were at increased risk of ovarian cancer (hazards ratio, 1.50; 95% confidence interval, 1.03-2.19). The results of our study imply that a quite significant proportion of the interindividual variability in ovarian cancer penetrance in BRCA1 carriers may be explained by a common BRCA1 Gly1038 wild-type allele, given its high frequency (0.27).

Adult↗
PubMed2003

A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer.

XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA base damage and strand breaks. A common polymorphism (Arg-->Gln) at codon 399 of the XRCC1 gene has been previously linked to functional changes of the gene product and risk of cancers. We evaluated the association between XRCC1 Arg399Gln polymorphism and breast cancer risk in the population-based Shanghai Breast Cancer Study involving 1088 cancer patients and 1182 community controls. Genomic DNA from peripheral blood was used in genotyping assays, and exposure information and anthropometrics were collected through in-person interview. Plasma estrogen and sex hormone-binding globulin (SHBG) levels were measured for 190 postmenopausal breast cancer patients who had donated a pretreatment blood sample and 407 postmenopausal controls. Conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting potential confounders. Approximately 27% of controls carried the variant allele (Gln), and cases and controls had a similar distribution for both allele type and genotype of this polymorphism. We found that 7.8% of cases and 6.3% of controls were homozygous for the variant allele, resulting in an OR of 1.20 (95% CI, 0.85-1.69). The OR was slightly higher among younger women [<45 years of age (OR, 1.39; 95% CI, 0.82-2.36)] than older women [> or = 45 years of age (OR, 1.07; 95% CI, 0.68-1.67)], but neither OR was statistically significant. No modifying effect of major breast cancer risk factors, including years of menstruation, body mass index, waist:hip ratio, and blood estrogen levels, was noted. Homozygosity for the variant Gln allele was associated with an elevated risk of postmenopausal breast cancer among subjects with a higher blood level of SHBG (OR, 3.27; 95% CI, 1.16-9.20) and a reduced risk among those with a lower level of SHBG (OR, 0.60; 95% CI, 0.18-1.97). The overall results of the study suggest that Arg399Gln polymorphism of the XRCC1 gene alone may not play a substantial role in the risk of breast cancer among Chinese women.

Adult↗
PubMed1994

Angina-linked syncope and lack of calcium antagonist therapy predict cardiac arrest before definitive diagnosis of vasospastic angina.

BACKGROUND: Several prognostic factors have been identified in patients with vasospastic angina; however, factors that would predict potentially fatal cardiac arrest during the period between the onset of angina and its definitive diagnosis remain unknown. We investigated the predictive value of the clinical findings that are available when a patient is hospitalized after a cardiac arrest but before a definitive diagnosis of vasospastic angina is made. METHODS: We compared the clinical findings in 11 patients who experienced cardiac arrest before vasospastic angina was definitively diagnosed (group I) with 81 patients with vasospastic angina without cardiac arrest (group II). The definitive diagnosis of vasospastic angina was made on the basis of results of coronary spasm provocation test or ECGs during spontaneous attacks, or both. RESULTS: The incidence of angina-linked syncope was significantly higher in group I than in group II (six out of 11 versus nine out of 81, P < 0.005). Significantly fewer group I patients were receiving calcium antagonists than group II patients (three out of 11 versus 63 out of 81, P < 0.005). Serious arrhythmias were significantly more common in group 1 than in group II (seven out of 11 versus 12 out of 81, P < 0.005). Logistic regression analysis of the eight clinical variables available when first seen in the hospital indicated that angina-linked syncope and the lack of calcium antagonist therapy were independently related to risk of cardiac arrest. CONCLUSIONS: From the clinical findings available, a history of angina-linked syncope and lack of calcium antagonist therapy were found to be independent predictors of cardiac arrest before a definitive diagnosis had been made. Patients who have suspected vasospastic angina may benefit from early treatment with calcium antagonists if they have a history of angina-linked syncope.

Aged↗
PubMedDate not supplied

Gene-environment interactions between the codon 194 polymorphism of XRCC1 and antioxidants influence lung cancer risk.

X-ray repair cross complementing group 1 (XRCC1) is a DNA repair gene whose polymorphisms appear to influence the risk of lung cancer. We explored the influence of antioxidants on the association between the codon 194 arganine to tryptophan substitution polymorphism of XRCC1 and lung cancer risk. In a case-control study nested within a cohort of tin miners the cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Individuals with the variant Arg194Trp allele seemed to be at lower risk for lung cancer (odds ratio (OR): 0.7, 95% confidence interval (95%CL): 0.4-1.2). Furthermore, high serum alpha-tocopherol (OR: 0.4, 95%CL: 0.2-0.9) and retinol (OR: 0.4, 95%CL: 0.2-0.9) levels were associated with significantly reduced risk of lung cancer among individuals with the Arg194Trp variant allele, but not among individuals with the wild-type genotype. In addition, the Arg194Trp variant reduced the risk of lung cancer associated with increased serum carotenoids compared to those with the homozygous wild-type allele. Our results show that Arg194Trp XRCC1 variant modifies the association between serum antioxidants and lung cancer risk.

Adult↗
PubMed2002

Microsomal epoxide hydrolase polymorphisms and lung cancer risk in non-Hispanic whites.

Microsomal epoxide hydrolase (mEPHX) is a critical metabolic enzyme involved in the activation and subsequent detoxification of specific tobacco carcinogens. mEPHX harbors polymorphisms in exon 3 and exon 4 that modulate enzymatic activity. The exon 3 polymorphism decreases mEPHX metabolic activity, whereas the exon 4 polymorphism increases activity. We hypothesized that the mEPHX polymorphisms modulate lung cancer risk. Using a case-control study design and restriction fragment length polymorphism polymerase chain reaction assay, we determined the mEPHX polymorphic genotypes of 181 lung cancer cases among non-Hispanic whites and 163 controls (matched for age, sex, ethnicity, and smoking history). Our results showed that the variant allele of mEPHX exon 4 increased the overall lung cancer risk by 56% (odds ratio [OR]=1.56, 95% confidence interval [CI]=0.99-2.46). Additionally, the risk estimates were elevated significantly for younger people (<64 yr) (OR=2.27, 95% CI=1.15-4.50) and current smokers (OR=2.22, 95% CI=1.06-4.65). The variant allele of mEPHX exon 3 had no effect overall (OR=0.88, 95% CI=0.56-1.38), but there was a 53% protective effect (OR=0.47, 95% CI=0.22-0.99) in younger people. When we analyzed the exon 3 and exon 4 polymorphisms together, those people with the high enzymatic activity genotype had an elevated lung cancer risk of 1.72 (95% CI=0.90-3.29). This elevated risk was also evident only in younger people. These findings suggest that these variant alleles of exon 3 and exon 4 of mEPHX modulates lung cancer risk.

Base Sequence↗
PubMed2006

Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men.

Recently, we described the association of genetic variation in the discs large homolog 5 (DLG5) gene with inflammatory bowel disease (IBD) in a large European study sample (Stoll et al. in Nat Genet 36:476-480, 2004). Here, we report that the R30Q variant constitutes a susceptibility factor for Crohn disease (CD) in men [odds ratio (OR)=2.49, 95% confidence interval (CI) 1.53-4.06, P<0.001] but not women (OR=1.01, 95% CI=0.70-1.45, P=0.979) using multivariate logistic regression analyses in a unified study sample from Germany, Italy and Quebec. R30Q is a significant predictor for CD in men even when accounting for CARD15 and IBD5 risk variants (adjusted OR=2.41, 95% CI=1.41-4.12, P=0.001). The observed association is driven by a gender-dependent transmission ratio distortion (TRD) among healthy controls (frequency of Q allele: men 5.2%, women 11.3%), an effect that is offset in CD patients (frequency of Q allele: men 10.1%, women 10.9%). This finding is further substantiated by two non-IBD study samples, one of which consists of a newborn screening sample (newborn males 7.1%; newborn females 11%, P=0.036). Further investigation of the observed TRD may contribute towards enlightening the role of DLG5 in physiological processes influencing transmission of chromosomes to the surviving offspring, which, in turn, may help in understanding its implication in the development of CD among men.

Adult↗
PubMed2001

CYP1A1, GSTM1, and GSTT1 polymorphisms and the risk of cervical squamous intraepithelial lesions in a multiethnic population.

OBJECTIVE: In this investigation, we explored the hypothesis that genetic polymorphisms in the cytochrome P4501A1 (T3801C) and glutathione S-transferase classes mu and theta (GSTM1 and GSTT1) gene deletions promote the development of cervical dysplasia by moderating the activation and detoxification of polycyclic hydrocarbons and other compounds that influence oxidative stress and DNA adduct formation. METHODS: A multiethnic, case-control study of 131 women with biopsy-confirmed cervical squamous intraepithelial lesions (SIL) and 180 controls with cytologically normal cervical (Pap) smears was conducted between 1992 and 1996 in Honolulu, Hawaii. We collected in-person interviews, a blood sample to extract genomic DNA, and an exfoliated cervical cell sample to determine the presence and type of human papillomavirus (HPV) using PCR dot-blot hybridization. Genotyping for the CYP1A1 MspI allelic variant and deletion of the GSTM1 and GSTT1 gene loci followed a PCR method. RESULTS: Women who were homozygous, but not heterozygous, for the CYP1A1 MspI variant allele were at significantly increased risk of cervical SIL (odds ratio (OR) = 3.4; 95% confidence interval (CI) = 1.1-10.7) compared to women who were homozygous for the wild-type allele. Subjects with the GSTM1 null genotype had a nonsignificant elevated risk of cervical SIL (OR = 1.6; 95% CI = 0.8-3.0) compared to women with the gene present. No difference in the risk of cervical disease was associated with the GSTT1 null genotype. The combination of the CYP1A1 homozygous variant and the GSTM1 null genotypes increased the odds ratio for cervical SIL to 5.1 (95% CI = 1.3-20.7). There was no evidence for an interaction between genotype and exposure to tobacco smoke, alcohol drinking, or HPV DNA positivity. CONCLUSIONS: These findings, although based on a small number of subjects, suggest that the CYP1A1 MspI polymorphism may be a susceptibility factor for early, premalignant changes in the cervical epithelium.

Adult↗
PubMed2005

Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma.

Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case-control study, four polymorphisms in the Cox-2 gene (two in the promoter, -663 insertion/deletion, GT/(GT) and -798 A/G; one in intron 5-5229, T/G; one in 3'untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at -663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34-1.02 and OR=0.48, CI: 0.24-0.99, respectively), whereas the heterozygous genotype T/C at 3'UTR-8494 had a positive association (OR=1.31, CI: 1.01-1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3'UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07-1.70), but the one with a risk allele at 3'UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66-1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.

Adenoma↗
PubMed2003

TAP1 and TAP2 polymorphisms analysis in northwestern Colombian patients with systemic lupus erythematosus.

OBJECTIVE: To determine the influence of TAP1 and TAP2 alleles in northwestern Colombian patients with systemic lupus erythematosus (SLE). METHODS: Unselected patients with SLE (n=140) and controls (n=120) matched for sex, age, and ethnicity were analysed. Clinical manifestations, clinical activity, and severity of disease were recorded. Autoantibodies were detected by enzyme linked immunosorbent assay (ELISA). TAP1 and TAP2 polymorphisms were determined by amplification refractory mutation system-polymerase chain reaction. A Hardy-Weinberg equilibrium test, microdifferentiation analysis, linkage disequilibrium analysis, and haplotype and allele frequency comparisons were performed. RESULTS: The TAP2 variant Val379/Ala565/Ala665 (allele TAP2*0201) was associated with SLE (56% v 39%; odds ratio=2, 95% confidence interval 1.22 to 3.30, p(c)=0.03). There was no stratification between patient and control samples. Linkage disequilibrium between TAP1 and TAP2 loci was found in controls but not in patients. An excess in the number of heterozygotes in the TAP2 locus was found in patients. No association between TAP1 and TAP2 variants and the presence of autoantibodies, clinical expression, or severity of disease was found. CONCLUSIONS: The TAP2 locus influences susceptibility to SLE in our patient group; however, it has no significant effect on the immune response or on the clinical course of the disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Association between the V109G polymorphism of the p27 gene and the risk and progression of oral squamous cell carcinoma.

PURPOSE: Abnormalities in p27 may alter cell cycle delay required for DNA repair after exposure to carcinogens. A coding exon 1 polymorphism at codon 109 (T-->G) in p27 was identified and thought to have an effect on the functions of its protein. We hypothesized that this p27 T109G polymorphism is associated with squamous cell carcinoma of the head and neck (SCCHN) risk. EXPERIMENTAL DESIGN: We tested this hypothesis in a hospital-based case-control study of 713 patients newly diagnosed with SCCHN and 1224 cancer-free controls frequency matched to the cases by age (+/-5 years), sex, and smoking status. All subjects were non-Hispanic whites. We genotyped for this p27 variant using genomic DNA from each subject. RESULTS: Compared with the p27 109VV variant, the p27 109GG variant was associated with a nonsignificantly increased risk of SCCHN [crude odds ratio (OR) = 1.29; 95% confidence interval (CI) = 0.88-1.90; adjusted OR = 1.20; 95% CI = 0.81-1.77], but the risk was statistically significant among men (adjusted OR = 1.55, 95% CI = 1.00-2.42), current alcohol users (adjusted OR = 1.68, 95% CI = 1.01-2.82), and patients with oral cavity cancer (adjusted OR = 1.77, 95% CI = 1.03-3.04). The p27 109GG variant was also associated with oral tumor overall stage, suggesting that it may play a role in tumor progression. CONCLUSIONS: Our findings suggest that the p27 109GG variant genotype may not play a major role in the etiology of SCCHN but may be associated with an increased risk in at-risk subgroups or subsets of SCCHN, particularly oral cavity cancer and possibly tumor progression. Larger studies with oral squamous cell carcinoma are needed to verify these findings.

Adolescent↗
PubMed2004

Insulin resistance in healthy prepubertal twins.

OBJECTIVES: To evaluate insulin sensitivity (S(I)) in prepubertal twins and to examine the relation to reduced birth weight, prematurity, and peroxisome proliferator-activated receptor-gamma (PPAR gamma) polymorphism. STUDY DESIGN: Fifty twins (birth weight SDS, -0.7 +/- 0.2; gestation, 33.5 +/- 0.5 weeks; and body mass index SDS, -0.04 +/- 0.2) were studied at 8.2 +/- 0.3 years. S(I) was measured by Bergman's minimal model from a 90 minutes frequently sampled intravenous glucose test. Twenty control children (height SDS, -1.7 +/- 0.3; birth weight SDS, -0.3 +/- 0.2; and gestation of 39.2 +/- 0.7 weeks) were also evaluated at 7.0 +/- 0.4 years. The PPAR gamma T-variant polymorphism was evaluated in 41 twins. Values are expressed as mean +/- SEM, or 95% confidence intervals. RESULTS: S(I) was reduced in twins compared with control subjects, (12.7 [11-15] versus 23.0 [16.8-31.4] 10(-4) min(-1) microU/mL, respectively, P=.005). The reduction in S(I) was independent of prematurity and birth weight and zygosity (P<.0001). There was no difference in S(I), even in twin pairs with >20% difference in birth weight (P=.9). The PPAR gamma heterozygote T-variant polymorphism was present in 7 of 41, with a further reduction in S(I) (P=.03) and a later gestation (P=.03). These twins also had increased fat mass (P=.02) but with similar fat free mass (P=.14). CONCLUSIONS: Twin children, independent of prematurity or birth weight, had a marked reduction in S(I). To use twins as a model to study the fetal origins of adult diseases for glucose homeostasis is not valid.

Case-Control Studies↗
PubMed2003

Standardization of two immunoassays for human glandular kallikrein 2.

BACKGROUND: Measurement of human kallikrein 2 (hK2) has improved early detection and staging of prostate cancer. However, reported concentrations of hK2 among currently used assays have not been standardized in any way. We compared two hK2 assays and five different recombinant hK2 variants (rhK2) and suggest a common calibrator as an important step and putative reference substance in hK2 assay standardization. METHODS: We measured 146 sera by two hK2 assays, using assay-specific calibrators to assess the difference between the two assays. Serial dilutions of five rhK2 preparations were measured repeatedly, with one preparation assigned as calibrator and the others as unknowns to define which variant provided the closest match between the two assays. This rhK2 variant was used to recalibrate both assays. We measured hK2 concentrations in the same 146 patients to evaluate the change in the difference. RESULTS: Use of assay-specific calibrators for comparison of the two assays yielded a Deming regression equation of: y = 0.789 (95% confidence interval, 0.674-0.922)x + 0.014 (0.004-0.025) micro g/L; R(2) = 0.667. Analysis of five rhK2 variants revealed that the enterokinase (ek)-rhK2 form provided the best match between both assays. Using the ek-rhK2 as a common calibrator, we observed a change in the slope of the regression curve to: y = 1.106 (0.872-1.340)x + 0.006 (-0.002 to 0.016) micro g/L; R(2) = 0.648, suggesting an increase in the mean estimate of agreement between the two assays. CONCLUSION: Calibration with a common calibrator substantially increased agreement between the assays. The ek-rhK2 variant provided the best performance of all tested rhK2 variants and should undergo mass spectrometry and amino acid analysis for exact mass determination and value assignment to evaluate its potential as a reference material for immunoassays for hK2.

Biomarkers, Tumor↗
PubMed2026

Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.

BACKGROUND: Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored. METHODS: We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting. RESULTS: We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (ADH1A, ADH1B, ADH4, ADH6) and ZNF827, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of ZNF827 in TAA and ADH6 in AAA at both mRNA and protein levels, corroborating the genetic predictions. CONCLUSION: This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.

MAGMA↗
PubMed2004

Quinone oxidoreductase (NQO1) gene polymorphism (609C/T) may be associated with tardive dyskinesia, but not with the development of schizophrenia.

The association between the quinone oxidoreductase gene (NQO1) polymorphism (609C/T) and schizophrenia was examined to replicate and extend the findings of a previous study (Hori et al., 2003). The study sample was 107 schizophrenia in-patients and 106 healthy controls. The distributions of the NQO1 genotypes and alleles were not different between the schizophrenia patients and the controls. However, the frequency of the variant genotype was significantly higher in the subgroup with tardive dyskinesia (TD) than in the subgroup without (p=0.019). The subjects with allele T were significantly more frequent in the TD patients than in those without (odds ratio 2.256, 95% confidence interval 1.235-4.133). In addition, the Abnormal Involuntary Movement Scale (AIMS) score was significantly higher in the variant genotype group (T/T) than in other genotypic groups (C/C and C/T) (p=0.004). This study suggests that the NQO1 gene polymorphism (609C/T) may confer susceptibility to the development of TD in schizophrenia, at least in the Korean population.

Adult↗
PubMed2002

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity.

Mutagen sensitivity, measuring the extent of chromosome damage induced by an in vitro treatment of peripheral lymphocytes with bleomycin, has been associated with an increased risk of various human cancers. Sensitivity to bleomycin appears to have high heritability and is usually considered to reflect individual capacity to repair DNA lesions. Another potential contributor to variation in bleomycin sensitivity could be inherited differences in the metabolism of bleomycin. We assessed whether genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes (XMEs) could explain bleomycin sensitivity. Frequencies of bleomycin-induced chromatid breaks per cell (b/c) were determined for 80 healthy Caucasians. Genotypes of DNA repair genes XRCC (X-ray repair cross-complementing) 1 and 3 and XME genes bleomycin hydrolase (BLHX), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) were analyzed from leukocyte DNA using methods based on polymerase chain reaction. The mean number of chromatid b/c was increased in individuals with XRCC1 codon 280 variant allele (P = 0.002; two-sided Mann-Whitney test). Smokers carrying BLHX codon 1450 variant allele showed a decrease in the mean number of chromatid b/c (P = 0.036). In multiple linear regression models including adjustment for age, sex, smoking and genotype, the adjusted relative risks (and 95% confidence intervals) were 1.18 (0.98-1.41) and 0.84 (0.69-1.00) for carriers of XRCC1 codon 280 and BLHX codon 1450 variant alleles, respectively. XRCC1 codon 280 polymorphism had a significant effect (P = 0.012) in predetermining whether the individual was classified as non-sensitive, sensitive or hypersensitive to bleomycin. Although based on relatively few individuals, our results suggest that bleomycin sensitivity is partially explained by genetic polymorphisms affecting DNA repair (XRCC1) and in vitro metabolism of bleomycin (BLHX).

Arylamine N-Acetyltransferase↗
PubMed2005

Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer.

PURPOSE: Interindividual differences in DNA repair capacity not only modify individual susceptibility to carcinogenesis, but also affect individual response to cancer treatment. Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells involved in the removal of a wide variety of DNA lesions. Polymorphisms in NER genes may influence DNA repair capacity and affect clinical outcome of bladder cancer treatment. EXPERIMENTAL DESIGN: To test the influence of NER gene polymorphisms on superficial bladder cancer outcome (recurrence and progression), we conducted a follow-up study of 288 patients with superficial bladder cancer. Median follow-up among patients who were recurrence-free at the end of observation was 21.7 months from diagnosis. The specific polymorphic loci examined include XPA [A/G at 5' untranslated region (UTR)], XPC (poly AT, Ala(499)Val, Lys(939)Gln), XPD (Asp(312)Asn, Lys(751)Gln), XPG (His(1104)Asp), ERCC 1 (G/T at 3' UTR), and ERCC6 (Met(1097)Val, Arg(1230)Pro). RESULTS: The ERCC6 (Met(1097)Val) polymorphism had a significant impact on recurrence: carriers of at least one variant allele (Val) had a significantly higher recurrence risk than carriers of the wild-type allele (Met/Met; hazard ratio, 1.54; 95% confidence interval, 1.02-2.33). There were no overall statistically significant differences in the distributions of the other polymorphisms between patients with and without recurrence. However, when we combined these variant genotypes, there was a significant trend for an increased recurrence risk with an increasing number of putative high-risk alleles. Using individuals with five or fewer putative high-risk alleles as the reference group, individuals with six to seven risk alleles and individuals with eight or more risk alleles had higher recurrence risks, with hazard ratios of 0.92 (0.54-1.57) and 2.53 (1.48-4.30), respectively (P for trend < 0.001). There was also a significant trend for shorter recurrence-free survival time with increasing number of variant alleles (log rank test, P = 0.0007). When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively). There were no significant individual or joint associations between these polymorphisms and progression. CONCLUSIONS: These data suggest that interindividual differences in DNA repair capacity may have an important impact on superficial bladder cancer recurrence. A pathway-based approach is preferred to study the effects of individual polymorphism on clinical outcomes.

Aged↗
PubMed2003

Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes.

The matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) have been shown to play important roles in multiple ways in all stages of cancer initiation and development. Single nucleotide polymorphisms identified in the promoters of MMP2 (-1306C-->T) and TIMP2 (-418G-->C) abolish the Sp1-binding site and thus may down-regulate expression of the genes. This case-control study examined the contribution of these functional polymorphisms to susceptibility to development and metastasis of breast cancer. MMP2 genotypes were determined by PCR-based denaturing high performance liquid chromatography analysis and TIMP2 genotypes identified by a PCR-RFLP method in 462 breast cancer patients and 509 frequency matched control women. We found that the variant MMP2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.46; 95% confidence interval (95% CI), 0.34-0.63], compared with the CC genotype. For TIMP2, a moderately reduced risk of the cancer (OR, 0.76; 95% CI, 0.58-0.99) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, it seemed that the polymorphisms in the two genes had some additive effect and the reduced risk related to the polymorphisms appeared to be more pronounced in younger subjects. However, no significant associations were observed between the polymorphisms in the two genes and tumor stage and metastasis of the cancer at the time of diagnosis. These findings suggest that the presence of the variant allele in the promoter of MMP2 or TIMP2 may be a protective factor for the development of breast cancer.

Adult↗
PubMed2002

Suppressive effect of the Gly389 allele of the beta1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy.

Beta-1-adrenergic receptor (beta1-AR) blockers reduce both the incidence of sudden death and the ventricular volume in heart failure. In vitro, the Gly389 variant of beta1-AR mediates less adenylyl cyclase activities than the Arg389 variant, so Arg389Gly polymorphism was investigated with regard to the genesis, progression, or arrhythmogenesis of dilated cardiomyopathy (DCM). Allele and genotype frequencies of the Arg389Gly polymorphism were determined in 163 DCM patients and 157 age- and sex-matched controls. There were no differences in genotype and allele frequencies between patients and controls. Echocardiograms, left ventriculograms and 24h-Holter electrocardiograms were evaluated in the DCM patients and none of the clinical indices, other than ventricular tachycardia (VT), differed among the 3 genotypes. The Gly389 allele was more frequent in the VT(-) group than in the VT(+) group (0.46 vs 0.24, p=0.001). In univariate analysis, the odds ratio for VT in patients carrying 1 or 2 copies of the Gly389 allele was 0.29 ([95% confidence interval, 0.13-0.64], p=0.002), when compared with the Arg389 homozygotes. The Gly389 variant supressed the occurrence of VT in DCM, suggesting that this allele confers a decreased risk of sudden death.

Alleles↗