GSTT1 and GSTM1 gene deletions are not associated with hepatotoxicity caused by antitubercular drugs

Background and objective: Susceptibility to antitubercular drug (ATD)‐induced hepatotoxicity may be genetically mediated, with variant alleles of genes such as N‐acetyltransferase (NAT2) and CYP2E1 reported as risk factors. Two studies of Asian populations have reported that GSTM1*0/*0 (null) genotype was a likely predictor of hepatotoxicity, whereas another of a Caucasian population implicated GSTT1*0/*0. We undertook a prospective case–control study to investigate whether GSTM*0/*0 and GSTT1*0/*0 were risk factors for ATD‐induced hepatotoxicity. Methods: Pulmonary tuberculosis patients on isoniazid, rifampicin and pyrazinamide who developed hepatotoxicity using defined criteria were prospectively identified. These cases were then matched with at least one control subject on the same drugs but without hepatotoxicity. Genotyping for GSTM1 and GSTT1 was performed by multiplex PCR on genomic DNA. The odds ratios for the frequency of specific GSTM1 and GSTT1 homozygotes in the case and control subjects were calculated to test for association between the genotypes and hepatotoxicity. Results and discussion: Hundred and fifty‐one subjects (51 cases, 100 controls) were enrolled. Odds ratio for GSTM1 null genotype was 1·00 (95% CI 0·51–1·97) and GSTT1 null was 2·02 (95% CI 0·39–10·39), respectively, showing that these genotypes are not associated with hepatotoxicity. Conclusion: GSTM1 *0/*0 or GSTT1 *0/*0 or both null genotypes, do not appear to be associated with ATD‐induced hepatotoxicity in our Indian population.     

Relevance of glutathione S-transferase M1 and cytochrome P450 1A1 genetic polymorphisms to the development of head and neck cancers.

BACKGROUND: Cytochrome P450 (CYP) and glutathione S-transferase (GST) gene variants have been intensively investigated for their implication in the development of different neoplasms. METHODS: In the present study, we analyzed genetic polymorphisms of CYP1A1, GSTM1, GSTP1, and GSTT1 in 127 head and neck cancer patients and 151 hospital controls. RESULTS: No significant increase in risk in patients with the GSTM1 null genotype (OR=1.52, 95% CI: 0.93-2.49) or CYP1A1 462Val alleles (OR=1.60, 95% CI: 0.73-3.52) or GSTP1 105Val alleles (OR=0.97, 95% CI: 0.59-1.58) was observed. The GSTT1 null genotype was found in 30.5% of the controls and 21.3% of the head and neck cancer patients (p=0.15). The estimated head and neck cancer risk for the combination of either CYP1A1 Ile462Val or CYP1A1 Val462Val genotype with either GSTP1 Ile105Val or Val105Val genotype (OR=2.89, 95% CI: 0.71-11.71) and for the combination of either CYP1A1 Ile462Val or CYP1A1 Val462Val genotype with GSTT1 null genotype (OR=2.62, 95% CI: 0.64-10.85) suggested the absence of the modifying effect of combined variant alleles on head and neck cancer susceptibility. The joint effect of either CYP1A1 Ile462Val or CYP1A1 Val462Val genotype with GSTM1 null genotype significantly increased the risk of head and neck cancer (OR=7.15, 95% CI: 1.49-34.32). CONCLUSIONS: Our findings corroborate metabolic genes interactions, especially for CYP1A1 462Val alleles and GSTM1 homozygous deletion, in the development of head and neck cancer in the investigated population groups in Poland.     

Association of GSTT1, GSTM1 and CYP1A1 polymorphisms with susceptibility to systemic lupus erythematosus in the Chinese population

BackgroundGSTT1, GSTM1, CYP1A1 are enzymes responsible for the detoxification of the toxicant which may be involved in the development of systemic lupus erythematosus (SLE). We examined the relationship between the risk of SLE and the polymorphisms of these genes in the Chinese population.MethodsSamples from 298 SLE patients and 284 healthy controls were collected. Polymerase chain reaction-restriction fragments length polymorphism (PCR–RFLP) was used to analyze the genotypes of CYP1A1 m2 and m4, while multiplex PCR was used to analyze the genotypes of GSTT1 and GSTM1.ResultsStatistically significant difference was observed in genotypes for GSTM1 (p = 0.003, OR 1.66 [95% CI 1.19–2.32]), but not for GSTT1 (p = 0.119, OR 0.77 [95% CI 0.56–1.07]), in the SLE patients as compared with the controls. Combinational analysis for double-null deletion of both GSTT1 and GSTM1 showed no significant difference (p = 0.863, OR 1.03 [95% CI 0.70–1.52]). Significant difference was observed in the genotype frequencies (p = 0.013), but not in the allele frequencies (p = 0.444, OR 0.90 [95% CI 0.70–1.17]), of CYP1A1 m2. All candidates have a wild-type genotype for CYP1A1 m4.ConclusionsPolymorphisms of GSTM1 are associated with SLE in the Chinese population.     

The roles of GSTM1 and GSTT1 null genotypes and other predictors in anti‐tuberculosis drug‐induced liver injury

What is known and Objective: Anti‐tuberculosis drugs (ATD), although highly effective, often cause liver injury. Glutathione S‐transferases (GST) play a crucial protective role in the detoxifying mechanisms of drugs. Several studies have investigated the genetic null variants of GSTM1 and GSTT1 as possible risk factors for ATD‐induced liver injury; however, those findings are inconsistent. We investigated GSTM1 and GSTT1 null genotypes in Brazilian patients with tuberculosis (TB), adjusting for other possible predictors of ATD‐induced liver injury. Methods: This was a prospective cohort study with patients who were treated for TB from 2006 to 2011. GSTM1 and GSTT1 gene deletions were analysed from genomic DNA by polymerase chain reaction (PCR). Demographic, clinical and laboratory data were extracted from medical records and possible predictors of liver injury were evaluated. Results and Discussion: This study enrolled 177 patients. Anti‐tuberculosis drugs‐induced liver injury incidence was 33·3%. Hepatitis B infection (HBV) and increased alanine aminotransferase (ALT) baseline were significant predictors. Neither GSTM1 nor GSTT1 null genotypes were associated with ATD‐induced liver injury; nevertheless, the comparison among four different liver toxicity grades showed that GSTM1 non‐null genotype was significant more frequent among the higher grades of liver toxicity. What is new and Conclusion: GSTM1 and GSTT1 null genotypes do not seem to play important roles in ATD‐induced liver injury in Brazilians. However, there was evidence that GSTM1 polymorphisms were possibly related to the intensity of toxicity. Active HBV and initial high ALT could predict ATD‐induced liver injury.     

骨髓增生异常综合征患者GSTT1、GSTM1基因分布频率和NQO1基因多态性分析

目的探讨谷胱甘肽S转移酶（GST）基因T1、M1（GSTY1、GSTM1）和苯醌氧化还原酶基因（NQO1C609T）多态性与骨髓增生异常综合征（MDS）易感性及MDS染色体核型异常的关系。方法用多重PCR方法检测52例MDS患者和241名与患者无血缘关系的正常人GSTF1和GSTM1基因型，用PCR-限制性片段长度多态性（RFLP）方法分析NQO1C609T基因型。结果与正常人对照组相比，MDS患者GSTT1和GSTM1无效型（nu11）比例明显增高（P值均〈0．01），其比值比（OR）分别为2．873（95％可信区间：1．491～5．537）和3．591（95％可信区间：1．717～7．508）。染色体核型正常的MDS患者GSTT1无效型比例较正常人对照组显著增高（OR=5．336，P〈0．01），而GSTM1无效型比例与正常人对照组比较差异无统计学意义染色体核型异常的MDS患者GSTM1无效型比例较正常人对照组显著增高（OR=3．740，P〈0．01），而GSTT1无效型比例与正常人对照组比较差异无统计学意义MDS患者的NQI1C609T各基因型与正常人对照组差异无统计学意义。结论GSTT1和GSTM1基因无效型可能与MDS发生相关，对判断MDS患者是否出现染色体核型异常有一定意义。     

Genetic polymorphism of GSTT1 and GSTM1 and susceptibility to chronic obstructive pulmonary disease (COPD)

Background

Chronic obstructive pulmonary disease (COPD) represents a major public health care problem worldwide due to its increasing prevalence, morbidity and mortality. Chronic obstructive pulmonary disease is known to be the fourth leading cause of death and the only cause of death, which is increasing. It is generally accepted that cigarette smoking is the most important risk factor for COPD. Nevertheless, only 10% to 20% of chronic smokers develop the severe impairment of pulmonary functions associated with COPD. This indicates the presence of genetic predisposing factors in its pathogenesis.

Objective

To test the hypothesis that genetic polymorphism of glutathione S-transferase θ 1 (GSTT1)and/or glutathione S-transferase μ 1 (GSTM1) is associated with COPD in smokers.

Materials and Methods

A case-control study was done on 34 patients with COPD and 34 matched controls. DNA was extracted from white blood cells by salting out method. GSTT1 and GSTM1 genotypes were amplified by polymerase chain reaction. The fragments were then analyzed by agarose gel electrophoresis. Statistical analysis was done using SPSS program.

Results

The frequency of carriers of null GSTT1 genotype was 50% among cases compared to 44.1% in the control group. Carriers of null GSTT1 were at minor risk of developing COPD when compared with carriers of the wild GSTT1 genotype (OR, 1.3; 95% CI, 0.5-3.3). In case of GSTM1, the frequency of carriers of null GSTM1 genotype was 52.9% among cases compared to 26.5% in controls. Carriers of null GSTM1 were at much higher risk of developing COPD (OR, 3.13; 95% CI, 1.1-8.6). Furthermore, the risk of developing COPD was increased among carrier of null GSTT1 &; GSTM1 haplotype (OR, 3.6; 95% CI, 1.1-11.6).

Conclusion

Carriers of null GSTM1 genotype were at high risk of developing COPD especially when they were null GSTT1 and GSTM1 haplotype.     

Influence of glutathione S-transferase M1 and T1 genotypes on larynx cancer risk among Korean smokers.

Glutathione S-transferase (GST) isoenzymes are involved in the detoxification of major carcinogens present in tobacco smoke. It is thus conceivable that deficiency in GST activity due to homozygous deletions of the GSTM1 and GSTT1 genes (the null genotypes) may modulate susceptibility to smoking-induced cancers. The influence of the GSTM1 and GSTT1 null genotypes on larynx cancer risk among the Korean population were evaluated using peripheral blood DNA from 82 larynx cancer patients and 63 healthy controls, all of whom were male current smokers. Increased larynx cancer risk was related to the GSTM1 null genotype (odds ratio (OR)=3.53, 95% confidence interval (CI)=1.27-9.83). The OR associated with the GSTT1 null genotype was also increased, but did not reach statistical significance (OR=1.83, 95% CI=0.70-4.79). Individuals lacking both the GSTM1 and GSTT1 genes were at a significantly higher risk for larynx cancer than individuals with both genes present (OR=4.04, 95% CI=1.33-12.30). These data confirm that the GSTM1 null genotype is an important risk modifier for larynx cancer among Korean smokers and combined GSTM1 and GSTT1 null genotypes could be a useful predictor of genetic susceptibility to larynx cancer.     

GSTT1 and GSTM1 allelic polymorphisms in head and neck cancer patients from Italian Lazio Region

BACKGROUND: The association between head and neck squamous cell carcinoma (HNSCC) and allelic variants of glutathione S-transferase M1 (GSTM1) and -T1 (GSTT1) is currently controversial. The present study investigates the prevalences of GSTT1 and GSTM1 polymorphism in a cohort of 100 head and neck cancer patients, 100 healthy donors and 200 controls with non-neoplastic head and neck diseases from Italian Lazio Region. METHODS: The patients with benign head and neck pathologies, as well as the healthy donors were matched for age, sex, cigarette smoke (yes/no) and alcohol consumption (yes/no). Molecular definition of GSTT1 and GSTM1 genotype has been performed by means of allele-specific PCR technique. RESULTS: A significant association between head and neck cancer and GSTM1 null genotype was observed both considering benign disease controls (p=0.001, OR=2.613; 95% C.I.=1.48-4.62), and healthy donors (p=0.0003, OR=3.35; 95% C.I. 1.69-6.67) while no significant association was found with GSTT1 null genotype (p>or=0.14). No interactive association was observed when combining the different genotypes of the two polymorphisms. These results were confirmed after correction for daily number of cigarettes and period of tobacco exposure. CONCLUSIONS: The present study confirms a role for genetic alterations of GSTM1 detoxifying enzyme as a risk factor for the development of HNSCC in patients from the Italian Lazio Region, independently of age, sex and other confounding variables.     

Polymorphisms of glutathione S-transferase M1, T1, and P1 in patients with HBV-related liver cirrhosis, chronic hepatitis, and normal carriers

OBJECTIVES: Persistent hepatitis B virus (HBV) infection often leads to the development of chronic hepatitis and cirrhosis. The role of host genetic factors in chronic HBV infection is not fully understood. We studied the influence of glutathione S-transferase (GST) M1, T1, and P1 polymorphisms in patients with different stages of HBV infections. METHODS: The sample population included 41 HBV normal carriers, 37 patients with chronic hepatitis, and 38 patients with cirrhosis (infected with HBV) compared to a control group (n = 59). PCR-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Odds ratio analysis tests were used for statistical evaluation. RESULTS: We found that the frequency of GSTP1-Val (105)/Val (105) genotype was significantly higher in patients with liver cirrhosis (27%) than HBV normal carriers (2.4%; OR 14.8, 95% CI 1.8-122.5) and the frequency GSTP1-Val (105)/Ile (105) genotype was significantly higher in patients with liver cirrhosis (59.5%) than HBV normal carriers (19.5%; OR 6.1, 95% CI 2.1-16.7). The genotype GSTP1-Val (105)/Val (105) was more frequent in patients with chronic hepatitis (19.4%) than HBV normal carriers (2.4%; OR 9.65, 95% CI 1.1-82.8). Patients with cirrhosis also had a higher frequency of the GSTM1 null genotype (71.1%) than HBV normal carriers (27.5%; OR 6.5, 95% CI 2.4-17.4) and the GSTM1 null genotype was more frequent in patients with chronic hepatitis (64.9%) than HBV normal carriers (27.5%OR 4.9, 95% CI 1.8-12.8). The frequency of GSTT1 genotype was similar in all groups. CONCLUSION: These results suggest that in HBV infection, inheritance of the null GSTM1 and GSTP1-Val (105) polymorphisms involves a host genetic factor that is relevant to disease progression.     

Cytochrome P450 2D6 and glutathione S-transferase M1 genotypes and migraine

BACKGROUND: Migraine is thought to be a disease of the brain and trigeminovascular system. Migraine patients often claim that stress, food, and beverages trigger their attacks. Chemical substances in these foodstuffs with the property of triggering migraine attacks have not yet been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental compounds. The genes exhibit genetic polymorphism that is associated with altered enzyme activity. The aim of this study was to determine if the genotypes of these two enzymes are associated with migraine. MATERIALS AND METHODS: The study included 100 female patients and 245 female controls from the general population. Genomic DNA was isolated from whole blood. Allele specific PCR methods were used to identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (-) variants. All samples positive for GSTM1 were further analysed for the presence of allelic variants GSTM1*A and GSTM1*B. RESULTS: None of the CYP2D6 and GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5-3.6) and for the GSTM1 null genotype of 1.0 (95% CI = 0.6-1.5). CONCLUSION: The results of this study indicate that deficient metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important in the aetiology of migraine.     

Significance of white blood cell count and its subtypes in patients with acute coronary syndrome

Background Inflammation plays a role in the pathogenesis of coronary atherosclerosis. Materials and methods Six hundred twenty‐three patients with acute coronary syndrome (ACS) referred for coronary angiography for the first time in our hospital were enrolled in this study. White blood cell and its subtypes were measured on admission. The study population was divided into three groups based on total white blood cell count and followed up. Clinical end points were major adverse cardiac events (MACEs), including cardiogenic death, stroke, heart failure, non‐fatal myocardial infarction, rehospitalization for angina pectoris. Results The median age was 68 years (range 31–92) and 64·2% of the patients were men. The median white blood cell count was 6·48 × 10⁹ L⁻¹ (range 2·34–27·10 × 10⁹ L⁻¹). The median follow‐up duration was 21 months (range 1–116) and MACEs occurred in 167 patients. The multivariable Cox proportional hazards regression model revealed that neutrophil count [Relative risk = 1·098, 95% Confidence interval (CI): 1·010–1·193, P = 0·029) was a risk factor for MACEs. The logistic regression model revealed that lymphocyte count [Odds ratio (OR) = 1·075, 95% CI: 1·012–1·142, P = 0·018] and monocyte count (OR = 8·578, 95% CI: 2·687–27·381, P < 0·001) were predictive of stenosis ≥ 75%; Neutrophil proportion (OR = 1·060, 95% CI: 1·007–1·115, P = 0·026), monocyte count (OR = 12·370, 95% CI: 1·298–118·761, P = 0·029) were predictive of the presence of multivessel disease. Kaplan–Meier analysis of short‐term and long‐term cumulative survival showed no significant statistical differences among three groups. Conclusions Neutrophil count adds prognostic information to MACEs in ACS. Monocyte count and lymphocyte count are predictive of severity of coronary atherosclerosis.     

Genetic influence in antithrombotic actions of atorvastatin in hypercholesterolaemia

Background Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized‐low‐density lipoprotein cholesterol (ox‐LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox‐LDL lectin‐like receptor‐1 (LOX‐1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment. Materials and methods A prospective 4‐year study involving 1039 event‐free subjects (643 males, 396 females) treated with atorvastatin (10–40 mg day^?1) to reach the appropriate Adult Treatment Panel‐III LDL target of 3·36 mmol L^?1. Enrolled subjects were evaluated every 6 months or at a clinical event. LOX‐1 3′UTR/T‐C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic‐colorimetric method, ox‐LDL by enzyme linked immunosorbent assay, platelet activation by P‐selectin (P‐sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C‐reactive protein (CRP) by sensitive nephelometric technique. Results LOX‐1 3′UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4·90, 95% CI 3·19–6·98, P < 0·00001). Smoking influenced events in LDL‐targeted subjects (P < 0·0001). Ox‐LDL and P‐sel were better indicators than LDL or other variables according to 3′UTR/C genotype regardless of the magnitude of LDL reduction (OR 4·21, 95% CI 2·29–6·70 P < 0·0001). Conclusions LOX‐1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activity.     

Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation

What is known and objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12‐hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). Results: There were no significant differences in the dose‐adjusted area under the plasma concentration–time curve (AUC_0–12) and maximum plasma concentration (C_max) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co‐administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose‐adjusted AUC_0–12 and C_max of tacrolimus were associated with CYP3A5*3/*3 and co‐administration with lansoprazole. What is new and conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long‐term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.     

Inflammatory markers in relation to insulin resistance and the metabolic syndrome

Background Inflammation has repeatedly been demonstrated to be associated with the metabolic syndrome (MetS) and insulin resistance, but the relative importance of different aspects of the inflammatory process is largely unexplored. Design We measured circulating interleukins (IL‐1α, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10); other cytokines (tumour necrosis factor‐α, interferon gamma and monocyte chemotactic protein‐1), cell adhesion molecules [vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1, E‐selectin, P‐selectin, l ‐selectin], and systemic inflammation markers [C‐reactive protein (CRP) and leukocyte count] in 943 70 year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. We related these biomarkers to MetS and the homeostasis model assessment insulin resistance index (HOMA‐IR). Results In a multivariable model including all inflammatory markers conjointly together with sex, log VCAM‐1 [odds ratio (OR), 1·45; 95% confidence interval (CI), 1·22–1·72 per 1 SD increase; P < 0·0001], log E‐selectin (OR, 1·33; 95% CI, 1·12–1·57 per 1SD increase; P = 0·001), and log CRP (OR, 1·41; 95% CI, 1·20–1·66 per 1‐SD increase; P < 0·0001) were independently associated with MetS. These biomarkers were also independently associated with HOMA‐IR. Conclusions Among 17 inflammatory biomarkers, most of them previously not examined in relation to MetS and insulin resistance, VCAM‐1, E‐selectin and CRP demonstrated the strongest associations with MetS and insulin resistance in our community based sample of the elderly. The relative importance of these biomarkers in predicting the development of MetS, insulin resistance and cardiovascular disease needs to be further examined in a longitudinal setting.     

慈溪市常见恶性肿瘤与代谢酶基因多态性关系的研究

目的 探讨慈溪市居民常见恶性肿瘤与代谢酶基因多态性关系.方法 分层随机抽取108对研究对象,总计216例血样,剔除不合格研究对象,最后有100对配对个体共200例研究对象完成基因型的检测.采用DNA抽提采用改良盐析法和基因多态性检测.结果 非GSTM1缺陷型有231 bp的片段,非GSTF1缺陷型有120 bp的片段,而所有的样品都有268 bp的-球蛋白的DNA片段.CYP2E1基因第1019CT点突变使RsaI识别位点消失,CYP2E1基因第1259GC点突变产生RsaI识别位点.CYP2EIRsaI CC,CT,TT基因型分布在对照人群中的频率分别为64.0%,35.0%和1.0%,CYP2E1PstI GG,GC,CC基因型分布在对照人群中的频率分别为70.0%,30.0%,0.0%.GSTT1缺陷型与常见恶性肿瘤患病风险没有观察到有统计学意义的相关性效应,OR值分别为1.22(95%CI:0.70～2.13)和0.65(95%CI:0.36～1.20);以CYP2E1PstI野生型(GG基因型)作为参照,CYP2E1RsaI杂和型(GC基因型)患肿瘤的风险增高,其OR值为1.11(95%CI:0.61～2.03).结论 慈溪市正常人群中四个基因位点GSTM1,GSTF1,CYP2E1RsaI,CYP2E1PstI的多态基因型分布与国内报道基本一致,四个位点基因多态性与慈溪市常见恶性肿瘤易感性无统计学意义的关联.     

Association of β‐1 and β‐2 adrenergic receptor gene polymorphisms with myocardial infarction

Both β₁‐ and β2‐adrenergic receptors (β₁‐ and β₂‐AR) have important roles in heart function mainly in response to catecholamines. Some specific polymorphisms in the β₁‐ and β₂‐AR genes, named ADRB1 and ADRB2, respectively, have been implicated in several cardiovascular and noncardiovascular phenotypes. In this study, we aimed to investigate the possible relationship between Ser49Gly and Arg389Gly polymorphisms of the ADRB1 and Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene with ST elevation myocardial infarction (MI) in a Turkish population. One hundred patients with ST elevation MI and 100 healthy control subjects were genotyped using the PCR‐RFLP method. Although the Arg389 allele of the ADRB1 gene was associated with an elevated risk of MI, the Glu27 allele of the ADRB2 gene was associated with a decreased risk of MI. Carriers of the ADRB1 Arg389 allele (heterozygotes+homozygotes) had an approximately 3.5‐fold increased risk for MI than Gly389 homozygotes (OR=3.59, 95% CI=0.96–13.47, P=0.045). For the ADRB2 Gln27Glu polymorphism, subjects having one or two copies of the Glu27 allele showed a decreased risk of MI compared with Gln27 homozygote subjects (OR=0.48, 95% CI=0.24–0.94, P=0.03). Haplotype analysis of these polymorphisms showed no significant differences between groups. These results suggest that the Arg389Gly and Gln27Glu polymorphisms may be associated with an altered risk of MI in this Turkish population. J. Clin. Lab. Anal. 23:237–243, 2009. © 2009 Wiley‐Liss, Inc.     

CYP7A1 polymorphism influences the LDL cholesterol‐lowering response to atorvastatin

What is known and Objective: Response to the lipid‐lowering effect of the statins is known to show significant inter‐individual variability. Our aim was to investigate whether genetic variants of the CYP3A5 gene, CYP7A1 gene and ABCG8 gene influence the lipid‐lowering response to atorvastatin. Methods: One hundred and seven unrelated Chinese Han hypercholesterolemia patients were recruited from among the inpatients and outpatients of Tangshan Gongren Hospital of Hebei, China. Three polymorphisms of the CYP3A5 gene, seven polymorphisms of the CYP7A1 gene and seven polymorphisms of the ABCG8 gene were selected using a tagging single‐nucleotide polymorphism (tSNP) strategy and genotyped using Snapshot platform. Results: SNP rs8192870, located in the first intron of the CYP7A1 gene, was associated with the LDL level lowering response to atorvastatin. The LDL levels were reduced by 27·89% for the GG/GA genotype carriers and 35·26% for the AA genotype carriers, respectively, after atorvastatin treatment (P = 0·021). The significance remained after adjusting for covariates. In addition, we observed that rs4148222 in the 11th intron of the ABCG8 gene significantly associated with the baseline levels of HDL (P = 0·046). What is new and Conclusion: CYP7A1 gene polymorphism influences the LDL‐lowering effects of atorvastatin in Chinese Hans. If replicated by others, identification of the tagged functional variant would be needed.     

Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum gamma-glutamyltransferase in valproic acid-treated patients

BACKGROUND: This study was designed to verify whether the glutathione S-transferase (GST) genotypes affect mild hepatotoxicity in valproic acid (VPA)-treated patients. METHODS: The association between the GSTM1 and GSTT1 genotypes, and the levels of aminotransferases and total bilirubin was retrospectively investigated in 149 Japanese epileptic patients treated with VPA. RESULTS: The adjusted odds ratio (OR) of the GSTM1- vs. GSTM1+ genotype and the GSTM1-/GSTT1-vs. GSTM1+/GSTT1+ genotypes for gamma-glutamyltransferase (GGT) increase over the upper limit of normal were 2.8 [95% confidence interval (CI): 1.1-7.2] and 6.5 (95% CI: 1.5-28.0), respectively. The GSTT1 genotypes alone did not significantly affect the liver function tests. The alanine aminotransferase, aspartate aminotransferase and (gamma-glutamyltransferase) GGT levels in patients treated with VPA >6 months were significantly higher in the GSTM1- than GSTM1+ genotype. The GGT levels were significantly higher in the older subjects receiving polytherapy, and the effects of the polytherapy and age were greater in the GSTM1- genotype. CONCLUSIONS: The GSTM1- and GSTM1-/GSTT1- genotypes may be a genetic risk factor for the increase of GGT in VPA-treated patients. However, it was not possible to clarify whether the GGT increase was caused by VPA-induced hepatotoxicity or not.     

Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy

Background and aims. The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO‐production can be affected by polymorphisms in the endothelial NO‐synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients.

Patients and methods. A total of 1510 Finnish and Swedish T1D patients were included in a cross‐sectional case‐control study. Incipient DN was defined as an albumin excretion rate (AER) of 20–200?µg/min (n = 336). Overt DN = AER>200?µg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration ?20 years, AER<20?µg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27?bp repeat (NOS4ab) and Glu298Asp (rs1799983).

Results. Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu‐allele of the Glu298Asp‐polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12–1.91). The variables smoking (OR = 2.13; 95% CI = 1.63–2.78), male sex (OR = 1.61; 95% CI = 1.23–2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02–1.03), systolic (OR = 1.05; 95% CI = 1.04–1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02–1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a‐allele was not associated with DN.

Conclusions. The Glu/Glu‐genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.