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PubMed2004

Association of genetic variants in the calcium-sensing receptor with risk of colorectal adenoma.

OBJECTIVE: Evidence suggests that calcium prevents colorectal cancer, possibly mediated through the calcium-sensing receptor (CASR). We assessed the associations between CASR gene variants and risk for colorectal adenoma, a cancer precursor. We further investigated gene-diet interactions between the CASR variants and calcium intake on adenoma risk. METHODS: Individuals with advanced distal adenomas (n = 716) and controls with a negative sigmoidoscopy exam (n = 729) were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Three nonsynonymous variants in the intracellular signaling region of CASR (A986S, R990G, Q1011E) were analyzed by Taqman. RESULTS: Compared with the most common diplotype (haplotype pair), the odds ratios for advanced adenoma were 0.80 [95% confidence interval (CI), 0.60-1.06], 0.79 (95% CI, 0.55-1.13), and 0.56 (95% CI, 0.36-0.88) for the other three common diplotypes (>5% frequency). Although calcium intake was inversely associated with adenoma risk, CASR diplotypes did not modify this association. However, the power to investigate interactions was limited. CONCLUSION: Variants in the CASR intracellular signaling region were significantly associated with the risk of advanced adenoma.

Adenoma↗
PubMed2006

Selected polymorphisms of DNA repair genes and risk of pancreatic cancer.

BACKGROUND: Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis. O(6)-methylguanine-DNA methyltransferase (MGMT) is the major protein that removes alkylating DNA adducts, and apurinic/apyrimidinic endonuclease 1 (APE1) and X-ray repair cross-complementing group 1 (XRCC1) play important roles in the base excision repair pathway. METHODS: We investigated the association between polymorphisms of MGMT (Leu(84)Phe and Ile(143)Val), APE1 (Asp(148)Glu), and XRCC1 (Arg(194)Trp and Arg(399)Gln) and risk of pancreatic cancer in a case-control study. Exposure information from 384 patients with primary pancreatic ductal adenocarcinoma and 357 cancer-free healthy controls were collected and genomic DNAs were genotyped for five markers. Controls were frequency matched to patients by age at enrollment (+/-5 years), gender, and race. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by using unconditional logistic regression models. RESULTS: There was no significant main effect or interaction with smoking of these genetic variants on the risk of pancreatic cancer. However, the XRCC1(194) polymorphism had a significant interaction with the APE1(148) (p=0.005) or MGMT(84) polymorphism (p=0.02) in modifying the risk of pancreatic cancer. CONCLUSIONS: This study suggests that polymorphisms of genes involved in the repair of alkylating DNA adduct and DNA base damage may play a role in modulating the risk of pancreatic cancer. Larger studies are required to validate these preliminary findings. The mechanism of the combined genotype effects remains to be elucidated.

Adult↗
PubMed2001

Role of HPC2/ELAC2 in hereditary prostate cancer.

The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.

Adult↗
PubMed2006

Influence of genetic polymorphisms on bone disease of preterm infants.

Bone disease is an important complication among very low birth weight (VLBW, <1500 g) infants. In adults, osteoporosis is associated with polymorphisms of vitamin D receptor (VDR), estrogen receptor (ER), and collagen Ialpha1 (COLIA1) genes. However, limited information is available regarding the role of these polymorphisms in bone disease in premature infants. We have investigated the possible association between bone disease and the allelic polymorphisms of these three genes in 65 VLBW infants. Twenty infants (30.8%) were diagnosed with bone disease based on high activity of bone formation (serum alkaline phosphatase and osteocalcin), bone resorption (urinary excretion of calcium and pyridinium crosslink) markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA)(n)] allelic variant of ER gene and bone disease was observed. Infants without bone disorder more often carried a high number of repeats [(TA)(n) >18] [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.05-0.55]. A low number of repeats [(TA)(n) <19] was found more frequently in infants suffering from bone disease (OR: 6.00, 95% CI: 1.77-20.31). Significant interaction (p = 0.009) between VDR and COLIA1 genotypes was observed. In a logistic regression model, bone disorder of preterms significantly correlated with male gender (p = 0.002), lower gestational age (p = 0.015), homozygous allelic variants of high number of (TA)(n) repeats (p = 0.006), and interaction between VDR and COLIA1 genotype (p = 0.009).

Adult↗
PubMed2001

CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk.

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protective effect on the incidence of colon neoplasia. However, polymorphisms in NSAID-metabolizing enzymes may alter this effect. NSAIDs, particularly aspirin, are glucuronidated by UGT1A6 and some classes of NSAIDs are also metabolized by cytochrome P450 (CYP) 2C9. Both of these enzymes have slow-metabolizing, variant forms. We tested the hypothesis that the slow alleles of these enzymes can modify the inverse association between NSAIDs and colon neoplasia in the Minnesota Cancer Prevention Research Unit (CPRU) adenomatous polyp case-control study. CYP2C9 and UGT1A6 genotypes were determined for 474 adenoma cases and 563 controls. NSAID use was inversely associated with adenoma risk [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.44-0.90 for aspirin; and OR, 0.50; 95% CI, 0.31-0.82 for nonaspirin NSAID]. However, this association was absent in aspirin users who carried the CYP2C9 variant alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type UGT1A6 (OR, 0.86; 95% CI, 0.50-1.50). Carriers of both of these alleles who use aspirin were also not at reduced risk of adenomatous polyps (OR, 1.59; 95% CI, 0.68-3.73). The variants of these enzymes did not influence the association between nonaspirin NSAIDs and adenoma risk. These data indicate that the effectiveness of chemopreventive drugs can be modulated by the genotype of metabolizing enzymes.

Adenoma↗
PubMed2002

Predictors of outcome after the Fontan operation: is hypoplastic left heart syndrome still a risk factor?

OBJECTIVE: This study was undertaken to evaluate factors contributing to a decrease in early mortality and morbidity after the Fontan procedure between January 1, 1992, and December 31, 1999. METHODS: Outcomes evaluated were early survival, duration of pleural effusions, and duration of hospitalization. Potential predictors evaluated included anatomic diagnosis, presence of a common atrioventricular valve, preoperative pulmonary artery pressure, type of Fontan operation, type of intentional right-to-left shunt or baffle fenestration, and use of modified ultrafiltration. RESULTS: The modified Fontan procedure was performed in 332 patients at a median age of 22 months (range, 11-380 months) and a median weight of 11 kg (range, 5.8-120 kg). Prior stage I reconstructive surgery for classic or variant hypoplastic left heart syndrome had been performed in 205 (53%) of 332 patients, and 318 (96%) had undergone an interim superior cavopulmonary connection. A lateral-tunnel Fontan operation was performed in 281 patients, and an extracardiac conduit Fontan operation was performed in 51 patients. An intentional right-to-left shunt was created in 298 (90%) patients. Between 1992 and 1999, the outcome after the modified Fontan operation improved significantly. Overall mortality was 6.6% (22/332), with only 2 deaths since 1994. Morbidity was also reduced, with a decreased duration of pleural effusions and decreased hospital stay. In a multivariable analysis of the entire cohort, only the presence of a common atrioventricular valve (odds ratio, 7.64; 95% confidence limits, 2.07-28.14; P =.0002) and increased preoperative pulmonary artery pressure (odds ratio, 1.46/1 mm Hg increase; 95% confidence limits, 1.2-1.78; P <.001) increased the risk of early death, whereas use of a single-punch fenestration in a lateral-tunnel Fontan (odds ratio, 0.06; 95% confidence limits, 0.01-0.65; P =.02) and use of modified ultrafiltration (odds ratio, 0.14; 95% confidence limits, 0.03-0.72; P =.019) decreased the risk of death. The risk of prolonged pleural effusions (>3 days) was increased in patients with hypoplastic left heart syndrome (odds ratio, 1.73; 95% confidence limits, 1.07-2.81; P =.03) and was decreased by use of a single-punch fenestration in a lateral-tunnel Fontan operation (odds ratio, 0.17; 95% confidence limits, 0.07-0.4; P <.001), as well as by the use of modified ultrafiltration (odds ratio, 0.25; 95% confidence limits, 0.15-0.40; P <.01). CONCLUSIONS: In a contemporary series of Fontan operations performed largely in patients with hypoplastic left heart syndrome or variants, systemic ventricle morphology had no effect on mortality. Some patient characteristics, however, continue to influence outcome. The decrease in mortality and morbidity in the current era is attributed to changes in management strategies, specifically the use of modified ultrafiltration and baffle fenestration.

Cohort Studies↗
PubMed2006

BAT1, a putative anti-inflammatory gene, is associated with chronic Chagas cardiomyopathy.

BACKGROUND: It is not understood why only a subset of individuals infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC). Patients with CCC display high levels of circulating proinflammatory cytokines. Heart-infiltrating lymphocytes from patients with CCC also express proinflammatory cytokines (tumor necrosis factor- alpha and interferon- gamma ) that are detectable in biopsy samples and surgical heart-tissue samples. BAT1, a putative anti-inflammatory gene, presents functional polymorphisms in its promoter region that influence its transcriptional level. METHODS: We assessed, by polymerase chain reaction restriction fragment-length polymorphism analysis, BAT1 variants in the promoter region at positions -22C/G and -348C/T in 154 patients with CCC and in 76 T. cruzi-infected but asymptomatic (ASY) patients. RESULTS: Of the patients with CCC, 16% were homozygous for the -22C allele, compared with 4% of the ASY patients (P=.004; odds ratio [OR], 4.7 [95% confidence interval {CI}, 1.4-16]). A similar trend was observed for the -348C homozygotes (P=.01; OR, 1.9 [95% CI, 1.0-3.5]). Susceptibility to CCC was conferred by the C variants at nt -22 (P=.003; OR, 1.8 [95% CI, 1.2-2.8]) and at nt -348 (P=.02; OR, 1.7 [95% CI, 1.0-2.8]). CONCLUSIONS: BAT1 variants previously associated with reduced expression of HLA-B-associated transcript 1 are predictive of the development of CCC. These variants may be less efficient in down-regulating inflammatory responses and may contribute to the elevated production of proinflammatory cytokines in patients with CCC.

Brazil↗
PubMed1995

Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample.

OBJECTIVE: To establish the prevalence of Fc epsilon RI-beta polymorphisms Leu181 and Leu181/Leu183 on chromosome 11q13 in the general population and to examine whether when maternally inherited they confer a risk of atopy. DESIGN: A population based survey for measures of atopy (skin prick test reactions, specific IgE titres, total serum IgE concentration), bronchial hyperresponsiveness, and carriage of Fc epsilon RI-beta Leu181 and Leu181/Leu183. SETTING: The rural coastal town of Busselton, Western Australia. SUBJECTS: 1004 members of 230 two generation families identified through adults aged under 55. RESULTS: Fc epsilon RI-beta Leu181/Leu183 was identified in 45 subjects (4.5%). All 13 children who had inherited the variant maternally were atopic. Six had asthma and nine rhinitis. The odds ratio of a positive skin prick test reaction to house dust mite or grass pollen in these children compared with the other 523 children was 7.37 (95% confidence interval 1.62 to 33.60). The 95% confidence interval for the odds ratio of a positive specific IgE response (radio-allergosorbent test) was 3.00 to infinity, and the odds ratio for bronchial hyperresponsiveness was 3.70 (1.21 to 11.60). By contrast, the eight children who had derived the variant paternally had negative skin prick and radioallergosorbent test results and did not have increased bronchial responsiveness. CONCLUSION: Fc epsilon RI"' beta Leu181/Leu183 when inherited maternally identifies a genetic risk factor for atopy and bronchial hyperresponsiveness.

Adolescent↗
PubMed2006

Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China.

Germline mutations in MSH2, MLH1, E-cadherin and MutY (MYH) genes have been implicated in the occurrence of gastric cancer (GC). Epidemiological investigation was performed by recruiting patients with GC onset during 2002 in Jiangsu province, China. We identified suspected hereditary GC patients based on either the GC family history or GC onset at early ages. We have screened germline variations in 101 suspected hereditary GC patients at the coding sequences of MSH2, MLH1, E-cadherin and MYH genes with polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC) analysis and DNA sequencing. The result showed that about 40% of patients carried germline variations, predominantly with missense mutations. Of the variations detected are 2 base pair substitutions, c.53C > T and c.74G > A, which is predicted to generate missense mutations of p.Pro18Leu and p.Gly25Asp, respectively, and occurred at the same allele of MYH gene. The frequency of variant haplotype T/A in patients was higher than that in the control group (p = 0.021, odds ratio [OR] = 4.43, 95% confidence interval [95% CI] = 1.33-14.72). Difference in the frequency of the silent mutation p.Asn751Asn in E-cadherin gene was also found between patients and controls (p = 0.009, OR = 2.54, 95% CI = 1.30-4.95). Moreover, 6 types of variations were detected in MSH2 and MLH1 genes in 14 of 101 patients. Most of them occurred at exon7 of MSH2, frequently c.1168C > T, resulting in mutation of p.Leu390Phe. In summary, germline mutation at MSH2, MLH1, E-cadherin and MYH genes is a frequent event in the familial GC. They may form a genetic basis for the familial GC susceptibility in Chinese population.

Adaptor Proteins, Signal Transducing↗
PubMed1993

DNA regeneration in the polymerase chain reaction.

This paper is an analysis of a model of the regeneration of damaged DNA during the polymerase chain reaction (PCR) made to estimate the degree to which recombination between similar but not identical sequences ("jumping PCR") compromises the results obtained with the technique. The analysis is applicable to museum or field-weathered specimens and also to the damage, such as single-strand nicks, which can occur during storage. Two main results are derived: (i) oligonucleotide priming competes extremely effectively against regeneration derived from priming by overlaps of damaged DNA strands. (ii) Extending result (i), it is shown that jumping PCR is not likely to cause inaccurate sequence determination in standard PCR protocols. One exception arises where it is required to determine the sequence of one specified variant of a piece of DNA which is present in many thousand copies. But, generally, experiments can be performed with confidence that the results are very rarely distorted by jumping PCR. The basic model is extended to investigate how to increase the average length of DNA fragments input to PCR experiments. Increased input of less-damaged material to the PCR can theoretically be achieved by performing several cycles of denaturation, re-association and replication on the sample DNA in the absence of exogenous primers. Experimental work will be necessary to confirm this. However, jumping PCR may occur at substantial frequencies during such pretreatment. This problem cannot be avoided but can be reduced in pretreatment protocols by studying sequences (such as mtDNA or rDNA) where multiple copies are subjected to evolutionary homogenizing processes.

Animals↗
PubMed1999

Genetic risk factors of thrombophilia in ischaemic childhood stroke of cardiac origin. A prospective ESPED survey.

UNLABELLED: Ischaemic stroke is a rare event in childhood. In approximately one-fourth of cases an underlying cardiac disease can be detected. We investigated the importance of genetic risk factors of venous thromboembolism in childhood or stroke in adulthood as risk factors for ischaemic stroke in children in a multicentre survey focusing on patients with a cardiac disease. 38 of 162 white infants and children (neonate-18 years) with ischaemic stroke were suffering from a cardiac disorder. An age-matched group of 100 children from the same geographic areas as the patients served as controls. Patients and controls were analysed for increased lipoprotein (a) levels > 30 mg/dl, for the presence of the factor V (FV) G1691A mutation, the prothrombin (PT) G20210 A variant, and deficiencies of protein C, protein S, and antithrombin. The following frequencies (patients vs. controls), odds ratios (OR) and confidence intervals (CI) of single risk factors were found: Lp(a) > 30 mg/dl (18.4% vs. 5%; OR/CI: 4.3/1.3-14.4; p = 0.03), FV G1691A (13.2% vs. 4%; OR/CI 3.63/0.92-14.3; p = 0.12) protein C type I deficiency (15.8% vs. 1%; OR/CI: 18.5/2.15-16.0; p = 0.0017), anticardiolipin antibodies (10.5% vs. 0%; p = 0.0051). No protein S or antithrombin deficiency was found. Combinations of haemostatic disorders were found in 10.5% of cases but in none of the controls (Fisher 0.005). CONCLUSION: While FV G1691A and prothrombin G20210 A mutations show no significant data in our study, lipoprotein (a) levels >30 mg/dl protein C deficiency, anticardiolipin antibodies and combined prothrombotic disorders seem to be important risk factors for manifestation of ischaemic strokes in children with underlying cardiac disorders.

Adolescent↗
PubMed2006

Genetic variation in the interleukin-6 gene in relation to risk and outcomes in acute coronary syndrome.

BACKGROUND: The concept of inflammation in the acute coronary syndrome (ACS) is today well established. Interleukin-6 (IL-6), a pleiotropic, proinflammatory cytokine, seems to play an important role in the development and progression of ACS. AIM: The aim was to investigate whether IL6 polymorphisms are associated with patient/control status, outcome in patients with ACS and plasma concentrations of IL-6 and C-reactive protein (CRP). METHODS: Samples for citrated plasma and DNA were obtained on admission from 3027 patients with non-ST-elevation ACS in the FRISC-II study. A group of 447 healthy controls of similar age and gender as the patients was also recruited. Eight IL6 polymorphisms were genotyped and plasma concentrations of IL-6 and CRP measured in patients and controls. RESULTS: No associations between patient/control status, clinical outcome, ST-depression, troponin-T elevation or a history of myocardial infarction and IL6 polymorphisms were observed. In the full patient group, there was a trend towards association of the -572 G>C polymorphism with plasma concentrations of IL-6 (p=0.07). This association was statistically significant in patients with available high-sensitivity measurements of IL-6 (p=0.01). The -572 CG genotype was predictive for IL-6 levels above 5 ng/L in patients with a subsequent cardiovascular event, 2.3 (1.1-4.3) (adjusted odds ratio, 95% confidence interval). Comparison with data from HapMap showed that our panel of polymorphisms covered information on approximately 30 other IL6 variants. CONCLUSION: The -572 G>C and other polymorphisms in the study were not associated with outcome in ACS patients. However, the -572 CG genotype may contribute to a more distinct inflammatory response in patients with ACS.

Acute Disease↗
PubMed2006

Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk.

BACKGROUND: Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use. METHODS: A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk. RESULTS: Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A1*2C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A1*3 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A1*2 genotype: the SULT1A1*2 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use. CONCLUSIONS: Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss.

BACKGROUND: It has been reported recently that obstetric complications are associated with thrombophilias. Our objective was to investigate the association between pregnancy complications and the guanine 20210 adenine (G20210A) mutation in prothrombin gene. METHODS: Two hundred and twenty-two women (study group) with obstetric complications were tested for the prothrombin mutation. Indications for testing were: severe preeclampsia, mild preeclampsia, intrauterine growth retardation, severe abruptio placentae, unexplained stillbirth, second trimester loss, and three or more consecutive spontaneous abortions. We also tested 156 healthy women who had at least one normal pregnancy and comprised the control group. RESULTS: Demographic data of the study and control groups were similar. Twenty-eight women of the study group (13%) were found to be heterozygous carriers of the 20210 variant of the prothrombin gene compared to five (3.2%) of the control group, p=0.001, odds ratio (OR) 2.9; 95% confidence interval (CI) 1.3-6.5. Compared to the control women, the prothrombin gene mutation was significantly more prevalent in women with IUGR, abruptio placentae, and second trimester loss but not in women with mild or severe preeclampsia, stillbirth and habitual abortion. CONCLUSIONS: Our data demonstrate that the mutation in the prothrombin gene is associated with specific pregnancy complications.

Abortion, Spontaneous↗
PubMed2003

Polymorphisms in the DNA repair gene XRCC1, breast cancer risk, and response to radiotherapy.

The study goal was to examine the association of three polymorphisms in the XRCC1 gene (Arg194Trp, Arg280His, and Arg399Gln) involved in repairing DNA damage produced by ionizing radiation, a known breast cancer (BC) risk factor, with BC incidence and the possibility of developing an adverse radiotherapy response. Genomic DNA from 254 BC cases, 70 of whom were adverse radiotherapy responders [radiation-sensitive breast cancer (RS-BC) patients], and 312 female blood donors were genotyped using either TaqMan technology or variant specific restriction enzyme digestion. Neither the exon 6 codon 194Trp allele [BC versus controls: odds ratio (OR), 1.03; 95% confidence interval (CI) 0.62-1.67] nor the exon 10 codon 399Gln allele (BC versus controls: OR, 0.95; 95% CI, 0.74-1.23) alone was associated with an increased BC risk. The exon 9 codon 280His allele was associated with an increased risk (OR, 1.8; 95% CI, 1.07-3.05) in both the radiation-sensitive and non-radiation-sensitive cases and, in combination with the 399Gln allele, was found more frequently in cases than in controls (OR, 2.54; 95% CI, 1.04-6.22). The exon 6 194Trp allele was associated with the risk of developing an adverse response to radiotherapy (RS-BC versus non-radiation-sensitive BC: OR, 1.98; 95% CI, 0.92-4.17). This allele, in combination with the 399Gln allele, was found more frequently in RS-BC cases than in the non-radiation-sensitive BC cases (OR, 4.33; 95% CI, 1.24-15.12). Distinct combinations of XRCC1 polymorphisms appear to be associated with either an increased BC risk or the possibility of developing an adverse radiotherapy response seen in some BC patients.

Adult↗
PubMed1998

Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2E1.

Genetic polymorphisms in enzymes involved in carcinogen metabolism have been shown to influence susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for the bioactivation of many low molecular weight carcinogens, including certain nitrosamines, whereas glutathione S-transferases (GSTs) are involved in detoxifying many other carcinogenic electrophiles. Esophageal cancer, which is prevalent in China, is hypothesized to be related to environmental nitrosamine exposure. Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility. DNA samples were isolated from surgically removed esophageal tissues or scraped esophageal epithelium from cases with cancer (n = 45), cases with severe epithelial hyperplasia (n = 45), and normal controls (n = 46) from a high-risk area, Linxian County, China. RFLPs in the CYP2E1 and the GSTP1 genes were determined by PCR amplification followed by digestion with RsaI or DraI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was examined by a multiplex PCR. The CYP2E1 polymorphism detected by RsaI was significantly different between controls (56%) and cases with cancer (20%) or severe epithelial hyperplasia (17%; P < 0.001). Persons without the RsaI variant alleles had more than a 4-6-fold risk of developing severe epithelial hyperplasia (adjusted odds ratio, 6.0; 95% confidence interval, 2.3-16.0) and cancer (adjusted odds ratio, 4.8; 95% confidence interval, 1.8-12.4). Polymorphisms in the GSTs were not associated with increased esophageal cancer risk. These results indicate that CYP2E1 may be a genetic susceptibility factor involved in the early events leading to the development of esophageal cancer.

Adult↗
PubMed1999

Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease.

BACKGROUND: Genes encoding components of the renin-angiotensin system have been associated with elevated blood pressure (BP) and an increased risk of coronary artery disease. To explore the role of the angiotensinogen (AGT) gene in coronary atherosclerosis and thrombosis, we studied the effect of the AGT M235T gene variant on plasma AGT levels and BP in patients with coronary artery disease and in the subgroup of survivors of myocardial infarction as compared with angiographically defined control subjects. METHODS AND RESULTS: This was a case-control study of 301 white male subjects examined at Frankfurt University medical center. Plasma AGT levels increased stepwise according to the number of T235 alleles present (no T235 allele, 14.8 +/- 3.9 nmol/L; 1 allele, 15.7 +/- 5.1 nmol/L; 2 alleles, 17.3 +/- 4.7 nmol/L; P =.006). In a multivariate model, circulating AGT emerged as the most important predictor of diastolic pressure (P =.001). In addition, AGT M235T gene polymorphism remained a significant predictor of diastolic BP in a multivariate model adjusted for age, body mass index, fasting glucose, apolipoprotein B, presence of coronary artery disease, and treatment with antihypertensive agents ( P <.05). Finally, homozygosity for T235 was associated with increased univariate risk of coronary artery disease and myocardial infarction (odds ratio estimates 1.5; 95% confidence intervals 1.1 to 2.1, P =.03, and 1.0 to 2.1, P =.05, respectively). CONCLUSIONS: The significant relations observed between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating AGT in the pathogenesis of coronary artery disease.

Alleles↗
PubMed2003

Genotyping of the MTHFR gene polymorphism, C677T in patients with leukemia by melting curve analysis.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in folate metabolism and displays common genetic polymorphisms affecting the enzyme activity. The MTHFR genetic polymorphisms have been associated with a decrease in the risk of developing the lymphoid but not myeloid form of pediatric and adult leukemias. AIM: In this study we describe the genotyping of the MTHFR C677T polymorphism by melting curve analysis with the LightCycler in a case-controlled study of patients with acute lymphocytic leukemia (ALL), myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), and assess the effect of this common polymorphism on the leukemia risk in adult patients in Turkey. METHODS: DNA from peripheral blood lymphocytes was used for genotyping in the LightCycler PCR by melting curve analysis. The risk of leukemia associated with the MTHFR polymorphism was evaluated by comparing the genotype frequencies between the control and patient groups. RESULTS: The frequency of the homozygote variant genotype (677TT) was lower than that in healthy individuals in all three leukemia groups. The 677TT genotype did not appear to have a protective effect in patients with ALL (Odds ratio [OR] = 0.78 with a 95% confidence interval [CI] = 0.24-2.59), compared with healthy controls. The difference was higher (4.3-fold) in patients with AML, but still non-significant (OR = 0.23 with a 95% CI = 0.03-1.83). In patients with CML, the frequencies of both heterozygous (677CT) and homozygote variant genotypes were lower (OR = 0.72 and 0.66, respectively). CONCLUSIONS: Our results suggest that the MTHFR C677T polymorphism displays a similar distribution pattern in lymphoid and myeloid leukemias and that the frequency of the homozygote variant genotype (677TT) is lower in all leukemia types.

Adolescent↗