Combined CYP1A1/GSTM1 at-risk genotypes are overrepresented in squamous cell lung carcinoma patients but underrepresented in elderly tumor-free subjects

Purpose: Polycyclic aromatic hydrocarbons are activated by cytochrome P450 1A1 (CYP1A1) and inactivated by glutathione S-transferase mu (GSTM1). Therefore, it is expected that a combination of proficient CYP1A1 genotype with deficient GSTM1 variant would result in particularly elevated lung cancer (LC) risk, especially for squamous cell carcinoma (SCC). This study was aimed to validate whether the CYP1A1-C ³⁸⁰¹ (CYP1A1*2) allele has an unfavorable significance alone and/or in combination with the GSTM1 deficiency. Methods: We compared the distribution of CYP1A1 and GSTM1 genotypes in LC patients (n=141), healthy donors (HD, n=204), and elderly tumor-free smokers and non-smokers (ED, n=246). Results: CYP1A1*2 allele carriers demonstrated a clear-cut association with SCC: the adjusted odds ratios (OR) were 2.22 (95% CI=1.06–4.63) and 2.27 (95% CI=1.14–4.52) when HD and ED were used as referents, respectively. CYP1A1*2(+)/GSTM1(-) combined genotypes were overrepresented in the SCC patients (14/70, 20.0%) and underrepresented in the ED (19/246, 7.7%) as compared to the intermediate prevalence in the HD (26/204, 12.7%); the adjusted OR for SCC versus ED reached 3.85 (95% CI=1.43–10.33). Conclusions: In agreement with some literature data, our results support the concerted role of CYP1A1 and GSTM1 at-risk genotypes in SCC predisposition.     

Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP2E1, GSTM1, and NAT2), drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer

Background Genetic polymorphisms of drug-metabolizing enzymes have recently been shown to affect susceptibility to chemical carcinogenesis. However, the molecular mechanisms of individual susceptibility to gastric cancer have not been fully understood. Therefore, we studied the relationship between the genetic polymorphisms of drug-metabolizing enzymes, drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer.Methods The genotypes of cytochromes P450 (CYP) 1A1 and 2E1, glutathione S-transferase (GST) M1, and N-acetyltransferase (NAT) were investigated by polymerase chain reaction (PCR), allele-specific PCR, or restriction fragment length polymorphism (RFLP) following PCR in 146 Japanese patients with gastric cancer (67 intestinal-type and 79 diffuse-type carcinomas) and 177 autopsied controls. In addition, p53 gene point mutations of exons 5 through 9 in gastric cancer tissues were determined.Results The frequency of either being a habitual drinker or having a CYP2E1^*1A/^*1A genotype was significantly higher in patients with intestinal-type gastric cancer than in control subjects. The difference between the frequencies of habitual drinkers with the CYP2E1^*1A/^*1A genotype and non-drinkers with the CYP2E1^*5B allele was much more significant in the intestinal-type cancer versus the control group. Among intestinal-type cancer patients with the CYP2E1^*1A/^*1A genotype, p53 point mutations were significantly more frequent in the group of habitual drinkers than in that of non-drinkers. On the other hand, the combination of GSTM1 null and CYP2E1^*1A/^*1A genotypes increased the risk for diffuse-type gastric cancer, but had no influence on the frequency of p53 gene mutations.Conclusions The present study suggests that individuals with both the CYP2E1^*1A/^*1A genotype and a history of habitual drinking have an increased risk of intestinal-type gastric cancer with a high frequency of p53 gene point mutations in the gastric mucosa.     

CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer

Purpose As risk-modifiers of alcohol and tobacco effects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN). Methods A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% confidence interval (CI). Results SCCHN risk was associated with high-levels of alcohol intake [OR = 3.50 (95%CI: 1.93–6.35) and OR = 6.47 (95%CI: 2.92–14.35) for 19–30 g/day and >30 g/day, respectively], cigarette smoking [OR = 3.47 (95%CI: 1.88–6.41) and OR = 7.65 (95%CI: 4.20–13.90) for 1–25 and >25 pack-years of smoking, respectively] and low-fruit and vegetables consumption (OR = 2.45; 95%CI: 1.53–3.92). No differences were observed for the genotypes or haplotypes distributions among cases and controls, and no biological interaction emerged from gene–gene and gene–environment interaction analyses. An attributable proportion (AP) due to biological interaction of 0.65 (95%CI: 0.40–0.90) was detected for heavy drinkers with a low intake of fruit and vegetables, and an AP of 0.40 (95%CI: 0.10–0.72) resulted forever smokers with low fruit and vegetables consumption. Conclusions Even in presence of high alcohol consumption or cigarette smoking, a high intake of fruit and vegetables might prevent the development of around one quarter of SCCHN cases. The lack of interaction between the studied polymorphisms and the environmental exposures suggests that chronic consumption of tobacco and alcohol overwhelm enzyme defences, irrespective of genotype.     

A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives

High penetrance genes such as BRCA1 or BRCA2 account for only a small proportion of familial breast cancer in Chinese population. Estrogen has been proposed to participate in the proliferation and carcinogenesis of breast cancer. To investigate the association between genetic polymorphisms in genes encoding estrogen metabolizing, estrogen biosynthesizing enzyme and estrogen receptor and the breast cancer risk in BRCA1/BRCA2 negative Shanghai women, we conducted a case-control study including 114 cases with early-onset breast cancer or affected relatives and 121 healthy controls. The genotypes of estrogen receptor alpha (ERα), aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed by direct DNA-sequencing. Compared with H/H genotype of COMT Val158Met, COMT Val158Met L/L genotype was associated with a nonsignificantly elevated risk of breast cancer (OR: 3.72; 95% CI: 0.99–13.96, P = 0.051). There was no statistically significant difference in genotype frequency of the ERα PvuII, ERα XbaI and CYP19 Arg264Cys polymorphism between controls and cases. When stratified by menopausal status, COMT Val158Met L/L (OR: 11.94; 95% CI: 1.48–96.03, P = 0.02) and ERα PvuII P/p genotypes (OR: 2.67; 95% CI: 1.01–7.05, P = 0.048) were associated with a significantly elevated risk of breast cancer in premenopausal women, and there was a association between ERα XbaI x/x genotype and the nonsignificantly increased risk of breast cancer in premenopausal women (OR: 6.88; 95% CI: 0.80–59.15, P = 0.079). The multigenic analysis showed maybe these high risk genotypes had combined effect on breast cancer risk. Our findings suggest that polymorphism of genes involving estrogen-metabolizing pathway, estrogen- biosynthesizing pathway and estrogen receptor pathway may play an important role in the etiology of BRCA1/2 negative breast cancer with hereditary predisposing factors. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Zhen Hu and Chuan-Gui Song contributed equally to the work.     

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40–50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated “DR3”) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated “DR4”). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7–20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12–7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated “DR2”; OR = 0.03; 95% CI, 0.01–0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (OR =10.31; 95% CI, 4.21–25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.     

Genotypes of CYP1A1, SULT1A1 and SULT1A2 and risk of squamous cell carcinoma of esophagus: outcome of a case–control study from Kashmir,India

Studies on associations of various polymorphism in xenobiotic metabolizing genes with different cancers including esophageal squamous cell carcinoma (ESCC) are mixed and inconclusive. To evaluate the association of CYP1A1*4, SULT1A1*2 and SULT1A2*2 genotypes with ESCC risk and their modifying effects on different risk factors of ESCC, we conducted a case–control study in Kashmir, India, an area with relative high incidence of ESCC. We recruited 404 histopathologically confirmed ESCC cases, and equal number of controls, individually matched for sex, age and district of residence to respective case. Information was obtained on various dietary, lifestyle and environmental factors in face‐to‐face interviews, using a structured questionnaire, from each subject. Genotypes were analyzed by polymerase chain reaction, restriction fragment length polymorphism and direct sequencing. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A higher risk was observed in the subjects who harbored variant genotype of CYP1A1*4 (OR = 2.06; 95% CI: 1.28–3.32); and the risk was further enhanced in ever smokers (OR = 3.47; 95% CI: 1.62–7.42), adobe dwellers (OR = 6.71; 95% CI: 3.02–14.89), and biomass fuel users (OR = 5.11; 95% CI: 1.34–19.50). We did not find any significant differences in the polymorphic variants of SULT1A1*2 and SULT1A2*2 between cases and controls. The study indicates that, unlike SULT1A1*2 and SULT1A2*2, the polymorphism of CYP1A1*4 is associated with ESCC risk. However, replicative studies with larger sample size are needed to substantiate our findings.     

Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population

Purpose: To investigate whether the common cyclin D1 (CCND1) A870G polymorphism is a risk factor for colorectal cancer (CRC) in an Indian population. Methods: In this study, 301 newly diagnosed CRC patients and 291 healthy control subjects were genotyped by the PCR-RFLP method. Genotype frequencies were compared between cases and controls, and the association of genotypes with CRC was studied. Results: The CCND1 870 A allele was more frequently observed in CRC patients than controls (0.63 vs. 0.56, P=0.01), and after adjustment for age, sex, smoking habits, family history, family income and the consumption of meat, fish, vegetables and fruit, an increased risk was observed for the AA genotype compared to the GG+AG genotype (OR=1.56; 95% CI: 1.10–2.21). The increased risk were also found for colon (OR=1.96; 95% CI: 1.08–3.57) and rectal cancer (OR=1.51; 95% CI: 1.04–2.19). No correlation was observed between genotypes and age of diagnosis of CRC (49.9, 48.7 and 49.4 years for the GG, AG and AA genotypes, respectively; P=0.84). Multivariate analysis also revealed a stronger positive association with the AA genotype among patients with high meat intake (OR=2.67; 95% CI: 1.29–5.51), and particularly significant inverse associations with the GG+AG genotypes were also found for those with high vegetable consumption (OR=0.46; 95% CI: 0.27–0.79 of 2–3 servings/day, and OR=0.31; 95% CI: 0.18–0.53 for >3 servings/day) and fish intake (OR=0.48; 95% CI: 0.28–0.82). Conclusion: These data support the hypothesis that the CCND1 A870G polymorphism may increase the risk of CRC in our Indian population.     

Genetic differences in CYP2C19 single nucleotide polymorphisms among four Asian populations

Background. This study was designed to compare genetic differences in single-nucleotide polymorphisms of the S-mephenytoin 4′-hydroxylation (CYP2C19) gene among four Asian populations. Methods. Polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) analysis of CYP2C19 was conducted in Japanese, Chinese, Thai, and Vietnamese populations. All genotype frequencies were analyzed. Wild-type homozygote and wild-type heterozygote genotypes were extensive proton pump inhibitor (PPI) metabolizers. Mutant-type heterozygote and mutant-type homozygote genotypes were poor PPI metabolizers. Results. No significant differences in CYP2C19 phenotype, calculated based on genotype frequencies, (P > 0.05) were found among the four populations. Conclusions. Many factors, including CYP2C19 polymorphisms, affect the success rate of Helicobacter pylori eradication with PPI-based therapy. We suspect that CYP2C19 polymorphisms may not be the main factor associated with differences among these four Asian populations in the success rates of H. pylori eradication with PPI-based therapy. Received: October 10, 2000 / Accepted: April 13, 2001     

Impact of pepsinogen C polymorphism on individual susceptibility to gastric cancer and its precancerous conditions in a Northeast Chinese population

Purpose  Human pepsinogen C (PGC) is an aspartic protease produced specifically by the gastric mucosa, and is considered as a mature marker of gastric epithelium. This study examined the contributions of PGC polymorphisms and the Helicobacter pylori (H. pylori) infection to the risk of gastric cancer (GC), and its precancerous conditions in a Northeast Chinese population. Methods  The PGC insertion/deletion polymorphism was evaluated by polymerase chain reaction analysis, followed by direct DNA sequencing in 564 cases of GC, atrophic gastritis (AG), gastric ulcer (GU) and superficial gastritis (as control). All cases were frequency-matched 1:1 by gender and age (±5). H. pylori infection was identified by serum anti-H. pylori IgG measurement through enzyme-linked immunosorbent assay. Results  Patients with a homozygous PGC allele 1 genotype had a significant risk of AG [adjusted odds ratio (OR) 3.11; 95% confidence interval (CI) 1.44–6.71] or of GC (OR 3.00; 95% CI 1.38–6.51), and a significantly elevated risk of intestinal metaplasia (OR 1.90, 95% CI 1.11–3.27). PGC polymorphism with H. pylori infection increased risk of GU (OR 8.69; 95% CI 1.01–74.69), and AG (OR 11.12; 95% CI 1.37–90.84) or GC (OR 10.61; 95% CI 1.28–87.79) in a super-multiplicative manner. The S value was 5.40, 6.48 and 4.34; and the AP value was 72.09, 7.00 and 69.69%, respectively. Conclusions  The PGC gene polymorphism increases an individual’s susceptibility to GC and its precancerous conditions. Moreover, the PGC gene polymorphism shows a positive link to H. pylori infection in the development of GC.     

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population

In this study, we investigated the contribution of vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes, age, and body surface area (BSA) on warfarin dose requirements and in an adult Turkish population. Blood samples were collected from 100 Turkish patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the therapeutic range. Genetic analyses for CYP2C9 genotypes (*2 and *3 alleles) and VKORC1 −1639 G>A polymorphism were performed and venous INR determined. The mean warfarin daily dose requirement was higher in CYP2C9 homozygous wild-type patients, compared to those with the variant *3 allele (P < 0.05), similar to those with the variant *2 allele (P > 0.05) and highest in patients with the VKORC1 −1639 GG genotype compared to those with the GA genotype and the AA genotype (P < 0.01). The time to therapeutic INR was longer in CYP2C9 homozygous wild-type patients compared with those with the variant *2 and *3 alleles (P < 0.01), and longer in patients with the VKORC1 (position −1639) GG genotype compared with those with the GA genotype and the AA genotype (P < 0.01). The multivariate regression model including the variables of age (R ² = 4.4%), BSA (R ² = 27.4%), CYP2C9 (R ² = 8.1%), and VKORC1 genotype (R ² = 34.1%) produced the best model for estimating warfarin dose (R ² = 60.4%). VKORC1 genotype and CYP2C9 polymorphism affect daily dose requirements and time to therapeutic INR in Turkish patients receiving warfarin for anticoagulation.     

Helicobacter pylori infection in combination with the serum pepsinogen I/II ratio and interleukin-1β-511 polymorphisms are independent risk factors for gastric cancer in Thais

Background Thailand has the lowest incidence of gastric cancer in the world. Helicobacter pylori infection, a low serum pepsinogen I/II ratio, and interleukin (IL)-1β-511 polymorphisms are suspected to be risk factors for gastric cancer. Methods A total of 167 Thais, comprising 56 cancer patients and 111 volunteers without cancer, underwent an esophagogastroduodenoscopic examination and three fixed-point biopsies; a cancer tissue biopsy was also done, and blood samples were collected. The subjects without cancer were divided into normal subjects and chronic gastritis patients. IL-1β-511 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism, and the serum levels of pepsinogen I and II were determined by a radioimmunoassay. Helicobacter pylori IgG antibody and tissue pathology were tested in all groups. Results The pepsinogen I/II ratio was significantly lower in the gastric cancer group than in the normal and chronic gastritis groups [odds ratio (OR), 2.3; 95% confidence interval (CI), 1.10–4.80; P = 0.025]. Gastric cancer patients were positive for the H. pylori IgG antibody more frequently than negative (OR, 2.946; 95% CI, 1.4–6.39; P = 0.005). However, only 15 (27%) cancer patients were both positive for H. pylori IgG antibody and had low serum pepsinogen I/II. The C/C genotype was found more frequently in the gastric cancer group than in the group with a normal gastric mucosa (OR, 0.64; 95% CI, 0.50–0.81; P = 0.014). Conclusions A low serum pepsinogen I/II ratio combined with positivity for H. pylori IgG, and a IL-1β-511 C/C genotype may be independent risk factors for gastric cancer in Thais. Presented at the 19th World Congress of the International Society of Digestive Surgery, Pacifico Yokohama, Japan, December 8–11, 2004 (Helicobacter pylori Symposium)     

Variant recurrent risk among stroke patients with different CYP2C19 phenotypes and treated with clopidogrel

Polymorphisms of CYP2C19 have been associated with variant risk of subsequent cardiovascular events in survivors of myocardial infarction (MI) receiving clopidogrel. This study evaluated the impacts of CYP2C19 polymorphisms on stroke recurrence and other vascular events in a cohort of Chinese patients receiving clopidogrel. From Nanjing Stroke Registry Program, 625 consecutive patients with ischemic stroke were enrolled between May 2008 and April 2010. CYP2C19 variants (*2, *3, and *17) were genotyped. Clinical outcomes were determined with three monthly follow-up. The primary endpoint was a composite of vascular death, non-fatal ischemic stroke, and non-fatal MI. The second endpoint was bleeding events. The median exposure to clopidogrel was 13.2 (interquartile range, 8.9–18.0) months. Primary endpoint was observed in 85 (13.6%) patients and secondary endpoint in 13 (2.1%) patients. Frequencies of CYP2C19*1, *2, *3, and *17 alleles were 61.2, 34.0, 3.8, and 1.0%, respectively, in this patient cohort. CYP2C19 loss-of-function allele (*2 and *3, LOF) carriers were observed with higher risk of subsequent vascular events compared with non-carriers (17.2 versus 8.1%, HR?=?2.16, 95% CI: 1.31–3.56, p?=?0.003). After adjusted for age, sex, major cardiovascular risk factors, and drug agent, CYP2C19 LOF carrier was independently associated with primary endpoint (HR?=?2.31, 95% CI: 1.39–3.84, p?=?0.001). No significant association between CYP2C19 gain-of-function (*17, GOF) and clinical events was detected. In Chinese stroke survivors treated with clopidogrel, carriers of CYP2C19 LOF allele may have increased risk of recurrence.     

CYP2E1 PstI/RsaI polymorphism and colorectal cancer risk: A meta-analysis

AIM: To clarify the association between CYP2E1 PstI/RsaI polymorphism and susceptibility to colorectal cancer.METHODS: A meta-analysis based on 10 eligible case-control studies involving 4979 cases and 6012 controls was carried out to summarize the data on the association between CYP2E1 RsaI/PstI polymorphism and colorectal cancer risk.RESULTS: In comparison of the homozygote c2c2 and c2 carriers (c1c2 + c2c2) and the homozygous wild-type genotype (c1c1), no association was found between CYP2E1 RsaI/PstI polymorphism and colorectal cancer risk [odds ratio (OR) = 1.24 (95% CI: 0.93-1.66) for c2c2; OR = 1.02 (95% CI: 0.88-1.19) for c2 carriers]. In stratified analysis, Caucasians with c2c2 homozygote appeared to have an increased risk of colorectal cancer (OR = 2.67, 95% CI: 1.03-6.89, P = 0.043), no significant associations were found in other groups.CONCLUSION: c2c2 homozygote of CYP2E1 PstI/RsaI polymorphism may be associated with the increased risk of colorectal cancer in Caucasians, which needs further investigations.     

Polymorphisms of matrix metalloproteinase-7 and chymase are associated with susceptibility to and progression of gastric cancer in Japan

Background  Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most macromolecules making up the extracellular matrix. MMPs are involved in not only the gastric mucosal inflammatory response but also the pathogenesis of Helicobacter pylori-associated diseases. In the renin-angiotensin system, chymase (CMA) is related to gastric carcinogenesis and angiogenesis in H. pylori-infected patients. We aimed to clarify the association of MMP-7-181 and CMA/B polymorphisms with susceptibility to gastric cancer and cancer progression in H. pylori-infected patients. Methods  We assessed the MMP-7-181 and CMA/B polymorphisms in H. pylori-positive patients with gastric cancer (n = 160), gastric ulcer (n = 157), duodenal ulcer (n = 121), and H. pylori-positive gastritis alone as controls (n = 156). Results  For gastric cancer risk, the age-and sex-adjusted odds ratio (OR) of the MMP-7-181 G allele carrier relative to the A/A genotype was significantly increased [OR, 2.32; 95% confidence interval (CI), 1.24–4.35], especially in patients with noncardia cancer (OR, 2.31; 95% CI, 1.22–4.36) and those with clinical stage III or IV cancer (OR, 3.66; 95% CI, 1.54–8.73). Carriage of the CMA/B A allele was significantly associated with gastric cancer development (OR, 1.73; 95% CI, 1.10–2.71). Simultaneous carriage of both the MMP-7-181 G allele and the CMA/B A allele dramatically increased the gastric cancer risk (OR, 8.18; 95% CI, 2.79–23.93). Conclusions  In Japan, carriage of the MMP-7-181 G allele and of the CMA/B A allele were each associated with an increased risk for H. pylori-related noncardia gastric cancer development. MMP-7-181 and CMA/B genotyping tests might be useful tools for screening for individuals with higher gastric cancer risk.     

Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus

To assess whether the CYP2C19 polymorphism modified the effect of cyclophosphamide on ovarian toxicity in Thai patients with SLE. We performed a case–control study of female patients with SLE who were treated with cyclophosphamide at Ramathibodi Hospital, Bangkok, Thailand. Cases were patient who had ovarian toxicity (sustained amenorrhoea >12 months or lack of menstruation for >4 months). CYP2C19 polymorphism was genotyped using PCR–RFLP method. Logistic regression was applied to assess CYP2C19 polymorphism as an effect modifier of cyclophosphamide. Seventy-one patients with SLE were enrolled, of which 36 (59.7%) had ovarian toxicity. CYP2C19*2 allele frequencies were 27.8 and 21.4% in the ovarian and non-ovarian toxicity groups. Patients with CYP2C19*1/*1 genotype and higher cumulative dose of cyclophosphamide (>23.75 g) had the highest odds of ovarian toxicity, i.e. 11.0 (95% CI: 1.2–99.1) times higher than patients with the CYP2C19*1/*2 or *2/*2 genotypes who received less cyclophosphamide (<23.75 g). After adjusting for age at start of treatment, this risk increased to 13.6 (95% CI: 1.1–162.2). Our results suggest that a cumulative cyclophosphamide dose of 23.75 g or higher carries a twofold higher risk of ovarian toxicity and the CYP2C19*1/*1 genotype increases the risk of toxicity a further fivefold.     

Two single nucleotide polymorphisms in ALOX15 are associated with risk of coronary artery disease in a Chinese Han population

Arachidonate 12/15-lipoxygenase (12/15-LOX) has been implicated in the pathogenesis of atherosclerosis, but with contradicting results. The aim of this study was to investigate the association of two polymorphisms in ALOX15 and the risk of coronary artery disease (CAD) in a Chinese Han population. A total of 519 unrelated CAD patients and 608 unrelated control subjects of the Chinese Han population were recruited in the case-control study. Two tagSNPs, rs7217186:T>C and rs2619112:G>A, were selected and genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The carriers of the C allele (the CC homozygote and the CT heterozygote) of rs7217186:T>C and the carriers of the A allele (the AA homozygote and the GA heterozygote) of rs2619112:G>A displayed elevated odds ratios (ORs) for CAD compared with the TT homozygotes and GG homozygotes, respectively, after adjusting for other potential confounders including age, sex, body mass index, systolic blood pressure, diastolic blood pressure, glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and smoking status (adjusted odds ratio [OR] = 3.2, 95% confidence interval [CI]: 1.335–7.665, P = 0.009 and adjusted OR = 3.5, 95% CI: 1.343–9.330, P = 0.011). In stratified analyses, after adjusting those aforementioned confounders, the CC and CT genotypes of rs7217186:T>C were associated with a greater risk of CAD in subjects <60 years (adjusted OR = 5.7, 95% CI: 1.557–21.097, P = 0.009) and in females (adjusted OR = 9.3, 95% CI: 1.048–82.213, P = 0.045). For rs2619112:G>A, subjects (<60 years) carrying the A allele had a greater risk of CAD than the GG homozygotes (adjusted OR = 4.9, 95% CI: 1.215–19.547, P = 0.025); the male carriers of A allele also had a greater risk (adjusted OR = 3.5, 95% CI: 1.136–11.006, P = 0.029). In summary, the present study shows that after adjustment for other confounding CAD factors, rs7217186:T>C and rs2619112:G>A of ALOX15 are associated with increased risk of CAD in this Chinese Han population.     

Warfarin Dose Adjustments Based on CYP2C9 Genetic Polymorphisms

Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0–3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.     

DNMT3B Promoter Polymorphism and Risk of Gastric Cancer

To investigate the association of single-nucleotide polymorphism (SNP) in DNA methyltransferase 3B (DNMT3B) gene and the risk of gastric cancer (GC), we detected -149C>T and -579G>T in the promoter region of the DNMT3B gene by polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing analysis. The DNMT3B genotype was determined in 259 gastric cancer patients and 262 healthy controls that were frequency matched for age and gender. Results showed that individuals with at least one -579G allele were also at significantly decreased risk of gastric cancer [odds ratio (OR), 0.43; 95% confidence interval (CI) 0.26–0.72] compared with those having a -579TT genotype. The -149C>T genotype distribution was irrelevant to the risk of gastric cancer (OR, 1.49; 95% CI, 0.17–17.94) in the studied Chinese population. In addition, data suggested that DNMT3B genetic polymorphism varied among different races, ethnic groups, and geographic areas.     

Ile<Superscript>105</Superscript>Val <Emphasis Type="Italic">GSTP1</Emphasis> polymorphism and susceptibility to colorectal carcinoma in Bulgarian population

Background and aims Etiologically, the sporadic colorectal cancer (CRC) is a complex and multifactorial disease that is linked to both exogenic and endogenic factors. Accumulating evidence indicates that susceptibility to cancers, including CRC, is mediated by genetically determined differences in the effectiveness of detoxification of potential carcinogens. A member of the glutathione-S-transferase (GST) family, GSTP1, is an important candidate for involvement in susceptibility to carcinogen-associated CRC. An A→G transition in exon 5 of the GSTP1 gene resulting in Ile¹⁰⁵Val amino acid substitution has been identified. This change leads to alteration in catalytic efficiency of variant enzyme. The aim of the current study was to evaluate the influence of Ile¹⁰⁵Val GSTP1 polymorphism on susceptibility to CRC. Materials and methods The GSTP1 genotyping was conducted in a case-control study of 80 ethnic Bulgarian CRC patients and 126 unaffected controls using polymerase chain reaction restriction fragment length polymorphism method. Results A statistically significant case-control difference in genotype frequencies was observed: 0.69 vs 0.54 for Ile/Ile, 0.22 vs 0.39 for Ile/Val, and 0.09 vs 0.07 for Val/Val (p = 0.049). The odds ratio (OR) for Val/Val was close to 1 (0.96, 95%CI: 0.35–2.66, p = 0.942), whereas the OR for Ile/Val was significantly lower, 0.45 (95%CI: 0.24–0.86, p = 0.016), compared to the referent Ile/Ile genotype. Although a prevalence of the GSTP1 variant allele-containing genotypes (Ile/Val or Val/Val) was found in controls than in patients (OR = 0.53, 95%CI: 0.30–0.96, p = 0.035), the allele frequencies did not show significant difference between cases and controls (p = 0.127). Conclusions Based on the obtained protective effect of Ile/Val GSTP1 genotype, we could suggest that Ile¹⁰⁵Val GSTP1 polymorphism may play some role in susceptibility to CRC.     

Obesity-related genes variability in Czech patients with sporadic colorectal cancer: preliminary results

Background  Genetic variability in obesity-related genes and the resulting phenotypes are being recognized as major risk factors for colorectal cancer and/or severity of the disease. Materials and methods  A total of 102 patients (aged 68 ± 10.2 years, 79 men and 23 women) and 101 age-matched (68.1 ± 5.4 years old) individuals without colorectal cancer, 59 men and 42 women, were recruited. All the individuals were genotyped for the following subset of polymorphisms in obesity-related genes: angiotensinogen gene (M235T and -6A/G), in IL-6 gene (-174 G/C and -596 A/G), in leptin gene (-2548 A/G), and polymorphism Gln223Arg within the leptin receptor (LEPR) gene. Results  A significant increase in frequency of double heterozygote genotype (MTAG) of both angiotensinogen polymorphisms in males with colorectal cancer was observed when compared to control men [odds ratio (OR) = 3.77, P _corr = 0.001]. A marginally significant difference in genotype distribution of -174 G/C IL-6 polymorphism between the patients in stage I–II compared to patients in III–IV was found (P _g = 0.05, P _a = 0.173). The GG genotype of -174 G/C IL-6 polymorphism in the patients in stage III–IV carries an increased risk compared to those in stage I–II (OR = 2.83, P _corr = 0.06). Similarly, a difference in genotype distribution of Gln223Arg in LEPR gene between the patients staged I–II compared to III–IV was observed (P _g = 0.05). The AA genotype was shown to be risky for the patients staged III–IV (OR = 3.35, P _corr = 0.06). Conclusions  The investigated single nucleotide polymorphisms within the genes encoding for obesity-related genes were observed to be associated both with clinical manifestation of colorectal cancer and with severity of the disease. Thus, we suggest that defined genetic variability in the genes might become DNA markers for colorectal cancer in the future.