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PubMed2003

Association of resistin gene 3'-untranslated region +62G-->A polymorphism with type 2 diabetes and hypertension in a Chinese population.

Resistin, a recently discovered polypeptide, antagonizes insulin action and may play a part in the pathogenesis of insulin resistance. This study investigates whether resistin gene polymorphism can be associated with type 2 diabetes. We studied 1102 Chinese type 2 diabetes patients and 743 subjects without diabetes. The resistin 3'-untranslated region (UTR) +62G-->A polymorphism was determined by PCR. Type 2 diabetes subjects had a lower frequency of resistin gene 3'UTR +62A allele (GG:GA/AA, 83.5%:16.5%) than the controls (GG:GA/AA, 75.1%:24.9%; odds ratio, 1.524; 95% confidence interval, 1.268-1.831; P < 0.001). Unexpectedly, diabetic patients with the GG genotype had a higher prevalence of hypertension (GG:GA/AA, 49.8%:36.2%; odds ratio, 1.375; 95% confidence interval, 1.116-1.693; P = 0.001). Logistic regression analysis confirmed that the resistin gene 3'UTR +62G-->A polymorphism acts as an independent contributing factor to type 2 diabetes and hypertension. The mean systolic and diastolic blood pressure levels in diabetic subjects with the GG genotype (144 +/- 21/87 +/- 13 mm Hg) were significantly higher than those in subjects with GA/AA variants (139 +/- 21/84 +/- 14 mm Hg; P = 0.004 and P = 0.002, respectively). Multiple linear regression analysis showed resistin gene polymorphism to be an independent factor associated with systolic and diastolic blood pressures in type 2 diabetes patients. These findings suggest that resistin may play a role in the pathogenesis of type 2 diabetes and insulin resistance-related hypertension.

3' Untranslated Regions↗
PubMed2005

Clinical restenosis after coronary stent implantation is associated with the heme oxygenase-1 gene promoter polymorphism and the heme oxygenase-1 +99G/C variant.

BACKGROUND: Vascular remodeling after percutaneous coronary stent implantation frequently leads to restenosis. Heme oxygenase 1 (HO-1) is involved in the generation of the endogenous antioxidant bilirubin and carbon monoxide, both of which exert antiinflammatory and antiproliferative effects. The aim of the present study was to evaluate the influence of genetic risk factors combined with the conventional risk factors on the development of coronary restenosis after percutaneous coronary intervention (PCI) with stent implantation. METHODS: The HO-1 gene GT dinucleotide repeat promoter polymorphism and HO-1 +99G/C variant were evaluated in 199 patients with coronary artery disease after coronary stent implantation and control angiography at 6 months after the intervention. Coronary restenosis was confirmed by quantitative angiography. RESULTS: Carriers of the long allele of the HO-1 gene promoter (>29 repeats) had a significantly higher risk of developing restenosis after PCI than noncarriers [odds ratio (OR)=1.9; 95% confidence interval (95% CI), 1.0-3.4; P=0.04]. Interestingly, the allele longer than 29 repeats conferred a significantly higher risk of developing restenosis (OR=3.4; 95% CI, 1.2-9.1; P=0.017) in nonsmokers than in smokers (OR=2.0; 95% CI, 0.7-5.2; P=0.18). CONCLUSIONS: The long allele of the HO-1 gene promoter (>29 repeats) polymorphism, which leads to low HO-1 inducibility, may represent an independent prognostic marker for restenosis after PCI and stent implantation. The effect of the >29 repeat allele is attenuated in smokers, who have chronic exogenous CO exposure.

Aged↗
PubMed2003

Protective efficacy of the RTS,S/AS02 Plasmodium falciparum malaria vaccine is not strain specific.

RTS,S/AS02 is a recombinant protein malaria vaccine that contains a large portion of the C-terminal of the circumsporozoite protein (CSP) sequence of the NF54 isolate of Plasmodium falciparum fused to the hepatitis B virus surface antigen. It has been shown to induce significant protection to challenge infection with a homologous parasite strain in American volunteers. In a recently completed trial in semi-immune Gambian adults, vaccine efficacy against natural infection was 34% (95% confidence interval = 8-53%, P = 0.014) during the malaria season following vaccination. Breakthrough P. falciparum parasites sampled from vaccinated subjects and from controls were genotyped at two polymorphic regions of the csp gene encoding T cell epitopes (csp-th2r and csp-th3r) to determine if the vaccine conferred a strain-specific effect. The overall distribution of csp allelic variants was similar in infections occurring in vaccine and control groups. Also, the mean number of genotypes per infection in the RTS,S/AS02 group was not reduced compared with the controls.

Adolescent↗
PubMed2003

Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk.

XRCC1 (X-ray cross-complementing group 1) and ERCC2 (excision repair cross-complementing group 2) are two major DNA repair proteins. Polymorphisms of these two genes have been associated with altered DNA repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms (Asp312Asn and Lys751Gln) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was 1.3 [95% confidence interval (CI), 1.0-1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2-5.0), whereas for heavy smokers (>/=55 pack-years), the OR decreased to 0.5 (95% CI, 0.3-1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7-16.6) for nonsmokers and 0.3 (95% CI, 0.1-0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk.

Adult↗
PubMed2006

Association of cathepsin B gene polymorphisms with tropical calcific pancreatitis.

BACKGROUND AND AIMS: Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to countries in the tropics. Mutations in pancreatic secretory trypsin inhibitor (SPINK1) rather than cationic trypsinogen (PRSS1) explain the disease in only 50% of TCP patients. As cathepsin B (CTSB) is known to activate cationic trypsinogen, we attempted to understand the role of CTSB mutations in TCP. Evidence of epistatic interaction was investigated with the previously associated N34S SPINK1 allele, a variant considered to be a modifier rather than a true susceptibility allele. SUBJECTS AND METHODS: We sequenced the coding region of CTSB gene in 51 TCP patients and 25 controls and further genotyped 89 patients and 130 controls from the same cohort for Leu26Val, C595T, T663C, and Ser53Gly polymorphisms. The positive findings observed in the earlier cohort were re-examined in an ethnically matched replication cohort comprising 166 patients and 175 controls. Appropriate statistical analyses were performed and Bonferroni correction for multiple testing was applied. RESULTS: We found a statistically significant association of the Val26 allele at Leu26Val polymorphism with an odds ratio (OR) of 2.15 (95% confidence interval (CI) 1.60-2.90 (p = 0.009)), after Bonferroni correction (corrected p value = 0.025). This significant association of Leu26Val with TCP was replicated in another cohort (OR 2.10 (95% CI 1.56-2.84); p = 0.013). Val26 allele also showed significantly higher frequency in N34S positive and N34S negative patients than in controls (p = 0.019 and 0.013, respectively). We also found significant differences in the mutant allele frequencies at Ser53Gly and C595T single nucleotide polymorphisms between N34S positive patients and controls (p = 0.008 and 0.001, respectively). Although haplotype analysis did not complement the results of allelic association, it did uncover a unique haplotype protective for TCP (p = 0.0035). CONCLUSION: Our study suggests for the first time that CTSB polymorphisms are associated with TCP. As PRSS1 mutations are absent in TCP and the N34S SPINK1 mutation is proposed to play a modifier role, these variants may be critical as a trigger for cationic trypsinogen activation.

Calcinosis↗
PubMed2006

Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis.

OBJECTIVE: Our objective was to investigate a role of the intracellular tyrosine phosphatase PTPN22*R620W variant in autoimmune myasthenia gravis (MG), considering disease heterogeneity. METHODS: We used a case-control design, comparing 470 patients and 296 controls, all French whites. Patients were categorized depending on the presence of a thymoma and serum anti-titin antibodies. RESULTS: The 620W risk allele was increased in 293 nonthymoma patients without anti-titin antibodies (odds ratio, 1.97; 95% confidence interval, 1.32-2.97, p = 0.00059) but not in nonthymoma patients with anti-titin antibodies or in thymoma patients. INTERPRETATION: Our genetic findings strengthen the concept that these groups of patients correspond to etiologically distinct disease entities.

Adult↗
PubMed1998

Genetic association of apolipoprotein E with age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common geriatric eye disorder leading to blindness and is characterized by degeneration of the neuroepithelium in the macular area of the eye. Apolipoprotein E (apoE), the major apolipoprotein of the CNS and an important regulator of cholesterol and lipid transport, appears to be associated with neurodegeneration. The apoE gene (APOE) polymorphism is a strong risk factor for various neurodegenerative diseases, and the apoE protein has been demonstrated in disease-associated lesions of these disorders. Hypothesizing that variants of APOE act as a potential risk factor for AMD, we performed a genetic-association study among 88 AMD cases and 901 controls derived from the population-based Rotterdam Study in the Netherlands. The APOE polymorphism showed a significant association with the risk for AMD; the APOE epsilon4 allele was associated with a decreased risk (odds ratio 0.43 [95% confidence interval 0.21-0. 88]), and the epsilon2 allele was associated with a slightly increased risk of AMD (odds ratio 1.5 [95% confidence interval 0.8-2. 82]). To investigate whether apoE is directly involved in the pathogenesis of AMD, we studied apoE immunoreactivity in 15 AMD and 10 control maculae and found that apoE staining was consistently present in the disease-associated deposits in AMD-maculae-that is, drusen and basal laminar deposit. Our results suggest that APOE is a susceptibility gene for AMD.

Aged↗
PubMed2005

Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype.

BACKGROUND: Polymorphisms in the interleukin 1beta gene (IL-1B-31T/C and IL-1B-511C/T single nucleotide changes) and in the interleukin 1 receptor anatagonist gene (IL-1RN2 variable number of tandem repeats) have been studied with respect to gastric cancer susceptibility. Available data support an aetiologic role of these genetic variants in the presence of concomitant Helicobacter pylori infection. Their contribution without H. pylori infection is still an open field of investigation. MATERIALS AND METHODS: IL-1B and IL-1RN polymorphisms were investigated in 138 H. pylori-negative Italian patients with sporadic gastric cancer and 100 H. pylori-negative controls. Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with disease. RESULTS: In all gastric cancer cases, carriers of the homozygous IL-1B-511T/T genotype showed a significant risk for the development of the disease (OR 3.2 with 95% CI 1.27-8.05). In cases with intestinal-type gastric cancer, however, both IL-1B-511T and IL-1RN2 alleles were associated with disease. In this subgroup, the odds ratio for carriers of both IL-1B-511T and IL-1RN2 was 6.49 (95% CI 2.07-20.4). Haplotype analysis supported the aetiologic contribution of these alleles in gastric cancer of the intestinal histotype. CONCLUSIONS: In conclusion, IL-1B-511T and IL-1RN2 may contribute to intestinal gastric cancer risk in the absence of concomitant H. pylori infection. In this setting, future epidemiologic studies should consider dietary habits and exposure to carcinogens interacting with pro-inflammatory host genotypes.

Adult↗
PubMed2003

The correlation of fecundability among twins: evidence of a genetic effect on fertility?

BACKGROUND: Numerous rare genetic conditions are known to influence fecundability in both males and females. It is less clear to what extent more subtle genetic differences influence fecundability on a population level. METHODS: In 1994 a population-based survey was conducted among Danish twins born 1953-1982. Fecundability was assessed as the waiting time to pregnancy at the first attempt to achieve a pregnancy. RESULTS: The reported time to pregnancy for males was slightly shorter than for females but there were no sex differences in intrapair similarity. We found an intrapair correlation in time to pregnancy for 645 monozygotic twin pairs (r = 0.22; 95% confidence interval = 0.12 to 0.32), but no intrapair correlation for 826 like-sex dizygotic twin pairs (r = 0.00; 95% confidence interval = -0.09 to 0.10). CONCLUSIONS: The correlation in time to pregnancy for monozygotic twins suggests genetic factors, although similarities in reporting behaviors could also be contributing to the correlation. The lack of correlation in time to pregnancy for dizygotic twins indicates that possible genetic factors of importance for fecundabililty are acting nonadditively. Hence, it may prove difficult to identify specific gene variants that influence fecundability on a population level if their effects depend on gene-gene interactions.

Age Factors↗
PubMed2005

Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis.

Although tobacco is the major lung cancer risk factor, folate deficiency has also been implicated as a risk. Methionine synthase (MS; gene symbol, MTR) and methionine synthase reductase (MSR; gene symbol, MTRR) play important roles in the folate metabolism pathway. It was hypothesized that polymorphisms of MTR and MTRR are associated with lung cancer risk and interact with dietary intake of folate-related nutrients in lung cancer etiology. In a hospital-based, case-control study of 1,035 lung cancer cases and 1,148 controls of non-Hispanic whites, frequency matched by age, sex, ethnicity and smoking status, the MTR 2756A>G and MTRR 66A>G polymorphisms were genotyped. It was found that the MTRRG allele was associated with a significantly increased lung cancer risk [adjusted odd ratio (OR)=1.34, 95% confidence interval (CI)=1.06-1.70 for the AG genotype and OR=1.39, 95% CI=1.08-1.78 for the GG genotype compared to the AA genotype]. Further analysis suggested some evidence of gene-diet interactions between the MTRR 66A>G polymorphism and dietary intake of total folate and vitamin B12. When the two polymorphisms were evaluated together by the number of the variant alleles (i.e. the MTR2756G and MTRR66A), lung cancer risk was significantly increased in a dose-dependent manner (Ptrend=0.045). The risk of lung cancer was 1.29 (0.98-1.69) for one variant allele, and 1.36 (1.04-1.77) for two or more variant alleles compared to the wild-type (0 variant allele) genotype. In conclusion, our data provide evidence supporting the association between the MTR 2756A>G and MTRR 66A>G polymorphisms and lung cancer risk, which may be modulated by dietary nutrient intake.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2025

Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race.

BACKGROUND: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race. METHODS: HRD features were identified using matched tumor-normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race. RESULTS: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43-1.09; White HR = 0.38; 95% CI, 0.14-1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%). CONCLUSIONS: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals. IMPACT: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.

Adult↗
PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗
PubMed2006

Association between osteopontin and human abdominal aortic aneurysm.

OBJECTIVES: In vitro and animal studies have implicated osteopontin (OPN) in the pathogenesis of aortic aneurysm. The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm (AAA) was investigated. METHODS AND RESULTS: OPN genotypes were examined in 4227 subjects in which aortic diameter and clinical risk factors were measured. Serum OPN was measured by ELISA in two cohorts of 665 subjects. The concentration of serum OPN was independently associated with the presence of AAA. Odds ratios (and 95% confidence intervals) for upper compared with lower OPN tertiles in predicting presence of AAA were 2.23 (1.29 to 3.85, P=0.004) for the population cohort and 4.08 (1.67 to 10.00, P=0.002) for the referral cohort after adjusting for other risk factors. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors (standardized coefficient 0.24, P=0.001). The concentration of OPN in the aortic wall was greater in patients with small AAAs (30 to 50 mm) than those with aortic occlusive disease alone. There was no association between five single nucleotide polymorphisms or haplotypes of the OPN gene and aortic diameter or AAA expansion. CONCLUSIONS: Serum and tissue concentrations of OPN are associated with human AAA. We found no relationship between variation of the OPN gene and AAA. OPN may be a useful biomarker for AAA presence and growth.

Adult↗
PubMed2006

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.

BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

Adult↗
PubMed1995

A common variant in the gene for lipoprotein lipase (Asp9-->Asn). Functional implications and prevalence in normal and hyperlipidemic subjects.

Subjects with combined hyperlipidemia (CHL) were screened for mutations in the lipoprotein lipase (LPL) gene by single-strand conformational polymorphism, and a previously reported G-->A DNA sequence change in exon 2, causing substitution of Asp by Asn at position 9, was identified in 2 individuals. Because this substitution destroys a recognition site for Taq I, pooling of DNA samples, amplification, and digest with Taq I allowed the rapid screening of 1563 healthy individuals and patients of Dutch, Swedish, English, and Scottish origin. In the general populations of all four countries, healthy carriers of the mutation were detected at a frequency of 1.6% to 4.4% (mean, 3.0%; 95% confidence interval, 2.0% to 4.0%). The frequency of carriers was roughly twice as high (range, 4.0% to 9.8%) in selected patients with CHL or type IV hyperlipoproteinemia or in subjects with angiographically assessed atherosclerosis; the frequency was consistently higher in each patient group compared with its matched control group. In 773 healthy men from two general practices in the United Kingdom, 25 carriers and 2 homozygotes for the mutation were identified. In these 27, plasma triglyceride but not plasma cholesterol levels were significantly higher than in noncarriers (2.25 versus 1.82 mmol/L, P < .02), and this difference was maintained in three subsequent annual measurements. Postheparin LPL activity data were available for some carriers and for 7 of 9 individuals from the patient groups, and 6 of 6 individuals from the control groups had LPL activity that was lower than the respective group mean. In vitro mutagenesis and transient expression in COS cells showed that compared with the LPL-Asp9 construct, LPL-Asn9 activity and mass were reduced by 20% to 30% in the culture media. Overall however, LPL-Asn9 had only slightly reduced specific activity (by 18%). Thus, although the precise mechanism of the effect is unclear, the data strongly suggest that the LPL-Asn9 variant is associated with and may play a direct role in predisposing carriers to develop hypertriglyceridemia.

Adult↗
PubMed2000

Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant--463A of the myeloperoxidase gene.

Myeloperoxidase (MPO), an enzyme that is highly expressed in neutrophil leukocytes, transforms precarcinogens such as benzo(a)pyrene and aromatic amines to highly reactive intermediates. A G/A polymorphism located 463 bp upstream of exon 1 in the promoter region strongly reduces MPO mRNA expression. In a matched case-control study, 196 lung cancer, 245 laryngeal cancer, and 255 pharyngeal cancer patients from the Berlin area were investigated for frequency of the G-463A polymorphism by PCR/RFLP, using AciI. They were matched by age and gender to hospital patients without known malignancies. Moreover, 270 healthy volunteers were genotyped, obtaining 61.1% of individuals with MPO genotype -463G/G, 34.8% of individuals with genotype G/A, and 4.1% of individuals with genotype A/A. In lung and laryngeal cancer patients, but not in pharyngeal cancer patients, mutant genotypes were significantly less frequent. Crude odds ratios for carriers of one or two A alleles, compared to wild-type G/G, were 0.58 [95% confidence interval (CI), 0.38-0.88; P = 0.011] for lung cancer patients, 0.63 (95% CI, 0.43-0.92; P = 0.017) for laryngeal cancer patients, and 0.82 (95% CI, 0.57-1.17; P = 0.27) for pharyngeal cancer patients. The relative risks, adjusted for age, gender, and extent of cigarette smoking were 0.47 (95% CI, 0.28-0.79; P = 0.004), 0.66 (95% CI, 0.44-1.01; P = 0.054), and 0.75 (95% CI, 0.51-1.12; P = 0.16) for lung, larynx, and pharyngeal cancer, respectively. Strikingly, relative risk for carriers of -463A among adenocarcinoma of the lung was 0.24 (95% CI, 0.10-0.58; P = 0.002). Two cases with larynx cancer, one case with lung cancer, and one reference subject displayed novel G/A mutations at -297 nucleotide and -296 nucleotide, destroying a constitutive AciI cleavage site. Our data finally suggest that the MPO -463A variant is a protective factor in the etiology of lung and larynx cancer, but possibly not of pharyngeal cancer.

Adult↗
PubMed2002

CYP1A1 gene polymorphism and risk of epithelial ovarian neoplasm.

OBJECTIVE: Gene-environment interactions have been the focus of a number of recent studies of the occurrence of human cancers, and an association between the risk and the CYP1A1*3 polymorphism has been noticed for several cancers. Previous studies suggest that estrogens are involved in the etiology of ovarian cancer. The cytochrome P450 1A1 (CYP1A1) gene polymorphism may play role in the development of epithelial ovarian neoplasm by detoxification of polycyclic hydrocarbons and other compounds and the concentration of estrogens and their metabolites. Therefore, we assessed the association of CYP1A1 gene polymorphism in patients with epithelial ovarian neoplasm in the Turkish populations through a case-control study. METHODS: Using an allele-specific polymerase chain reaction (PCR)-based method, CYP1A1*3 polymorphism, in exon 7 of the gene, was analyzed in 117 epithelial ovarian neoplasm patients and 202 control subjects. RESULTS: The CYP1A1 Ile/Val genotype significantly increased the risk for patients with epithelial ovarian neoplasm (OR 5.7, 95% CI 3.34-9.76). Furthermore, there were statistical differences in the distribution of CYP1A1 Val/Val genotype among all patients (OR 5.85, 95% CI 2.40-14.25). In other words, the presence of the Val allele significantly increased the risk of epithelial ovarian neoplasm. Among benign tumors, the frequency of Ile/Val and Val/Val genotypes was found to be statistically significant with an ORs of 6.01 and 4.38 (95% CI 2.61-13.84 and 1.04-18.38, respectively). In the benign serous ovarian tumors, patients with Ile/Val and Val/Val revealed a 7.2- and 10.5-fold higher risk of having ovarian carcinoma (95% CI 2.22-23.40 and 2.16-51.19), respectively. In the benign mucinous ovarian carcinoma patients, the frequency of Ile/Val was found to be statistically significant with an OR of 5.15 (95% CI 1.75-15.16). However, no patient with Val/Val genotype was observed in this group and no statistical distribution was performed. Among borderline tumors, CYP1A1 Ile/Val genotype significantly increased the risk for patients (OR 5.15, 95% CI 1.75-15.16). However, only one patient was observed with the Val/Val allele and the frequency of this genotype was not found to be statistically different with an OR of 2.50 (95% CI 0.27-22.64). Among ovarian cancer patients, there were statistically differences in the distribution of CYP1A1 Ile/Val and Val/Val genotypes (OR 5.73, 95% CI 3.04-10.76; and OR 7.42, 95% CI 2.80-19.66), suggesting that patients carrying these genotypes were at increased risk for ovarian carcinoma. In serous carcinoma, patients with CYP1A1 Ile/Val and Val/Val revealed a 6.5- and 10-fold higher risk of having ovarian cancer (OR 7.09, 95% CI 3.30-15.22; and OR 8.77, 95% CI 2.83-27.14). In mucinous carcinoma, patients with CYP1A1 Ile/Val and Val/Val also revealed a 5.4 and 10.5 times higher risk of having ovarian cancer. There were no statistical significance in the distribution of Val allele among endometroid-type cancer patients. CONCLUSIONS: Our data, although based on a small number of subjects, suggest that variant alleles of CYP1A1 gene in ovarian epithelial cells, directly or through other components, may contribute to initiation of ovarian carcinogenesis.

Adenocarcinoma, Mucinous↗
PubMed2004

A common variant of the AMPD1 gene predicts improved survival in patients with ischemic left ventricular dysfunction.

BACKGROUND: A recent retrospective study suggested that the adenosine monophosphate deaminase (AMPD)-1 gene variant C34T predicts outcome in heart failure patients. This variant might lead to ischemic preconditioning by increasing tissue adenosine. We tested whether the survival benefit of C34T occurs preferentially in the setting of ischemic left ventricular dysfunction. METHODS AND RESULTS: A consecutive cohort of patients (n=390) with left ventricular ejection fraction <40% was evaluated. In the ischemic patient subgroup (n=210) multivariate analysis identified AMPD1 T allele carriage (hazard ratio=0.43, confidence interval=0.20-0.94, P=.035) as an independent predictor of transplant-free cardiovascular survival. No benefit was found in the nonischemic group although the number of events was too small to reliably exclude a benefit by genotype. CONCLUSION: The AMPD1 C34T polymorphism influences transplant-free cardiovascular survival in the setting of ischemic left ventricular dysfunction.

AMP Deaminase↗