TRAF1 polymorphisms associated with rheumatoid arthritis susceptibility in Asians and in Caucasians

Objective

Recent genome‐wide association scans and replication studies of European populations have disclosed several single‐nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA) susceptibility. The aim of this study was to evaluate the RA‐associated loci by genotyping previously reported SNPs and additional tag SNPs in a Korean population.

Methods

A total of 1,316 unrelated RA patients and 1,006 controls were genotyped for 12 SNPs identified in genome‐wide scans and for 12 additional tag SNPs in IL2RB, OLIG3–TNFAIP3, PTPN22, and TRAF1–C5, and the findings were statistically compared.

Results

None of the SNPs tested was associated with RA susceptibility, except rs7021206 in TRAF1 intron 3 (P = 0.0032) and, among the SNPs previously reported, rs6457617 in HLA (P = 4.6 × 10⁻³⁵). The association of rs7021206 was positive in patients who were seropositive for rheumatoid factor (P = 0.0051) or for anti–cyclic citrullinated peptide autoantibodies (P = 0.0062). However, Korean patients were negative for the association of rs3761847 in the TRAF1–C5 intergenic region previously reported in Caucasians. Linkage disequilibrium between rs3761847 and rs7021206 was not as high in Koreans (r² = 0.37) as in Caucasians (r² = 0.67), which explains the lack of association of rs3761847 in Koreans. Accordingly, RA susceptibility was localized to an extended haplotype marked by rs7021206 rather than rs3761847, and SNPs highly correlated with rs7021206 (r² ≥ 0.81) extended from rs1953126 in the PHF19–TRAF1 intergenic region to rs2900180 in the TRAF1–C5 intergenic region, spanning 66 kb.

Conclusion

Our results demonstrate that within and around TRAF1, excluding PHF19 and C5, SNPs highly correlated with rs7021206, but not those correlated with rs3761847, are associated with RA in both Asians and Caucasians and are possibly correlated with causative variations.

     

Association of PTPN22 with rheumatoid arthritis among South Asians in the UK

OBJECTIVE: To compare the distribution and assess genetic associations of the PTPN22 R620W single-nucleotide polymorphism among South Asian (Asiatic Indian) patients with rheumatoid arthritis (RA) and ethnically matched controls. METHODS: DNA samples from 133 rheumatoid factor-positive South Asian RA patients and 149 control subjects from the East Midlands of the UK were genotyped for PTPN22 R620W polymorphism. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The PTPN22 *T allele frequency was lower than in the Caucasian populations, but the disease association was significant (odds ratio 5.87, 95% confidence interval 1.68-20.52). Similar association was observed for genotypes containing *T allele. CONCLUSION: Our results suggest that the T variant acts as a susceptibility allele for autoantibody-positive RA among South Asians.     

Genetic analysis of the glutathione s-transferase genes MGST1, GSTM3, GSTT1, and GSTM1 in patients with hereditary pancreatitis

Background Specific mutations in the cationic trypsinogen gene (PRSS1) are disease-causing in patients with hereditary pancreatitis, but the genetic background still remains mysterious in about 40% of patients with the disease. It has been suggested that oxidative stress contributes to pancreatic damage. The glutathione s-transferases (GSTs) represent major detoxification enzymes that protect cells from oxidative stress.Methods In the present study we tested whether mutations in the MGST1 and GSTM3 genes or common deletions in the GSTT1 and GSTM1 genes are associated with hereditary pancreatitis. We analyzed the entire coding region of MGST1 and GSTM3 in 30 patients that were tested negative for PRSS1 mutations, and we studied 55 controls. For GSTT1 and GSTM1, we investigated 75 hereditary pancreatitis patients who had been tested negative for PRSS1 mutations, 135 hereditary pancreatitis patients with a PRSS1 mutation, and 183 controls. Patients were further subclassified with regard to age of onset of disease as a marker of severity.Results No mutation was found in the MGST1 gene. In the GSTM3 gene, we detected a homozygous 670G > A polymorphism (V224I) with similar frequencies in patients and controls. We found no difference in the frequencies of the GSTT1 and GSTM1 null genotypes between patients and controls, and we detected no differences in age of onset in patients with or without GSTT1 and GSTM1 deletions.Conclusions We conclude that genetic alterations in the MGST1, GSTM3, GSTT1, and GSTM1 genes do not play a dominant role in hereditary pancreatitis.     

Association of Genetic Polymorphism of GSTT1, GSTM1 and GSTM3 in COPD Patients in a North Indian Population

Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). Cigarette smoking is the main etiological factor for decline in lung function in COPD. However, only 10–20% chronic smokers develop symptomatic COPD. Genetic susceptibility to COPD might depend upon the variation of enzyme activities that detoxify cigarette smoke components. We performed a case control study to assess the association of Glutathione- S-transferase T1(GSTT1),Glutathione- S-transferase M1 (GSTM1), and Glutathione-S-transferase M3(GSTM3) common polymorphisms with the susceptibility to COPD patient in a north India population. In the present study, the genotypes of 412 subjects, (204 COPD patients and 208 healthy controls) were analyzed. Statistical analysis revealed that the frequency of homozygous GSTM1 null genotype was found to be significant higher in COPD patients as compared with healthy controls (OR, 2.58; 95% CI, 1.73–3.84; P = 0.001), but there were no significant differences in the distribution of homozygous null GSTT1 and 3-bp deletion polymorphism (rs1799735) in intron 6 variant allele in GSTM3 between COPD patients and healthy controls. Our study results suggest that GSTM1 null polymorphism is associated with genetic susceptibility to COPD. Moreover, we also found association between this polymorphism with pulmonary function test in smokers as well as nonsmokers.     

Association of genetic polymorphism of GSTT1, GSTM1 and GSTM3 in COPD patients in a north Indian population

Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). Cigarette smoking is the main etiological factor for decline in lung function in COPD. However, only 10-20% chronic smokers develop symptomatic COPD. Genetic susceptibility to COPD might depend upon the variation of enzyme activities that detoxify cigarette smoke components. We performed a case control study to assess the association of Glutathione- S-transferase T1(GSTT1),Glutathione- S-transferase M1 (GSTM1), and Glutathione-S-transferase M3(GSTM3) common polymorphisms with the susceptibility to COPD patient in a north India population. In the present study, the genotypes of 412 subjects, (204 COPD patients and 208 healthy controls) were analyzed. Statistical analysis revealed that the frequency of homozygous GSTM1 null genotype was found to be significant higher in COPD patients as compared with healthy controls (OR, 2.58; 95% CI, 1.73-3.84; P = 0.001), but there were no significant differences in the distribution of homozygous null GSTT1 and 3-bp deletion polymorphism (rs1799735) in intron 6 variant allele in GSTM3 between COPD patients and healthy controls. Our study results suggest that GSTM1 null polymorphism is associated with genetic susceptibility to COPD. Moreover, we also found association between this polymorphism with pulmonary function test in smokers as well as nonsmokers.     

Patients' acceptance of antihypertensive therapy to prevent cardiovascular disease: a comparison between South Asians and Caucasians in the United Kingdom.

BACKGROUND: The importance of patients' involvement in decision-making is because of their right to know the risks and benefits they accept in undertaking treatment and the as yet unproven hope that this will improve compliance. The aim of this study was to establish local people's willingness to receive antihypertensive treatment for primary prevention of cardiovascular disease (CVD) and to explore the role of ethnicity. METHODS: In a cross-sectional study with face-to-face interview South Asian and Caucasian men and women aged 35-74, with and without history of CVD, were interviewed. Minimal clinically important differences were measured for three different baseline CVD risks (10, 20, and 40% in 10 years) using a standard method with risks presented both graphically and numerically and expressed in positive and negative terms. RESULTS: A total of 262 (110 South Asians) participants were interviewed. Overall, South Asians expressed smaller median minimal clinically important differences than Caucasians, 1 and 4%, respectively. Up to 17% of participants in both ethnic groups indicated that they would not take medication regardless of the benefits. The proportion of South Asian men unwilling to take medication regardless of benefit was higher than Caucasian men for all scenarios, 17.2 versus 10.7% for scenario 1 and 12.1 versus 5.6% for scenario 2, respectively. South Asians of both sexes who would consider therapy required less benefit for acceptance in all three scenarios compared with the Caucasians. CONCLUSION: South Asian participants were at least likely as Caucasians to accept antihypertensive treatment as the primary prevention therapy and they should be targeted for this type of therapy.     

Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias

Acute leukemias (ALs) are heterogeneous diseases. Functional polymorphisms in the genes encoding detoxification enzymes cause inter-individual differences, which contribute to leukemia susceptibility. The CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 polymorphisms in ALL (n = 156) and AML (n = 94) patients and 140 healthy controls were genotyped by PCR and/or PCR-RFLP using blood or bone marrow samples. No association was observed between the GSTT1 gene deletion and patients (OR = 0.8, 95% CI = 0.4-1.7 for AMLs and OR = 0.9, 95% CI = 0.5-1.6 for ALLs). Patients with ALL and AML had a higher prevalence of the GSTM1 deletions compared to controls but only the difference among adult AML patients (OR = 2.1, 95% CI = 1.0-4.2) was statistically significant. The CYP2D6*3 variant allele frequency was lower in the overall acute leukemia patients (0.6%) compared to controls (P = 0.03). CYP2D6*1/*3 genotype frequency also showed a protective association in AML patients (OR = 0.09, 95% CI = 0.01-1.7; P = 0.04). We also found a risk association for CYP2E1*5 in ALL and AML (OR = 3.6, 95% CI = 1.4-9.4 and OR = 3.9, 95% CI = 1.4-10.5, respectively). No association was found for the studied CYP2D6*4, CYP1A1*2A, and GSTT1"null" variants and the risk of acute leuke-mia (ALL or AML). This case-control study suggests a contribution of CYP2E1, CYP2D6, and GSTM1 "null" variants to the development of acute leukemias.     

Polymorphic variants of GSTM1, GSTT1, and GSTP1 genes in childhood acute leukemias: A preliminary study in Argentina

Abstract

Background and Aim

Despite recent major advances in leukemia research, the etiopathogenesis of childhood leukemias remains far elusive. Individual predisposing factors, including polymorphisms in detoxification enzymes, have been implicated in the molecular pathogenesis and heterogeneity of the disease. Genetic polymorphisms of glutathione S-transferases (GSTs) that alter enzyme activity could be an additional factor that increases the risk of acute leukemia, but data are lacking in Argentina. We assessed the association of GST polymorphisms and the susceptibility to childhood leukemia in Argentina by conducting an exploratory case-control study and correlated patients’ genotype to clinical and biological features.

Methods

Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.313A>G (rs1695; p.105Ile>Val) were genotyped by PCR-RFLP in 36 patients and 133 healthy individuals.

Results

GSTM1-null genotype was associated with a lower risk of developing acute leukemia (P = 0.013; OR: 0.31; CI: 0.12–0.80), while GSTP1-GG variants displayed an increased risk (P = 0.01; OR: 3.9; CI: 1.85–8.2). However, no differences were found for GSTT1 gene.

Conclusion

These preliminary results, to be validated in a larger population from Argentina, suggest that the development of pediatric leukemia may be differentially influenced by polymorphic variants in GST genes.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom

OBJECTIVE: To undertake a systematic whole-genome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA). METHODS: Two hundred fifty-two RA-affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single-point and multipoint analysis. RESULTS: Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA-DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 x 10(-4)) was identified on chromosome 6q by single- and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single-point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis. CONCLUSION: Linkage to the MHC region was confirmed. Eleven non-HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome-wide threshold for significant linkage (P = 2.2 x 10(-5)). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.     

Characterization of MTHFR,GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia

The role of methylenetetrahydrofolate reductase (MTHFR C677T), glutathione S-transferases (GSTM1 and GSTT1 null, GSTP1 Ile105Val), and cytochromes p450 (CYP1A1*2A) genotypes in the etiology of childhood leukemia was simultaneously investigated. 144 Turkish children with acute lymphoblastic leukemia (ALL) and 33 with acute nonlymphoblastic leukemia (ANLL) were studied and compared with 185 healthy pediatric controls. The frequency of MTHFR genotype was insignificantly higher in ALL (7.7%) and ANLL (6.3%) than in controls (4.4%). Equal distribution of the GSTM1 null genotype was detected between ALL patients and controls (55%), while its incidence was slightly higher in ANLL patients (61.3%). Although GSTT1 null genotype was insignificantly lower in ALL patients (20.9%) than controls (22.7%), it was significantly underrepresented in ANLL patients (6.5%) (P = 0.05, OR 0.24, 95% CI 0.05-1.03). The homozygous frequency of GSTP1 genotype did not differ significantly between groups of ALL (3.7%), ANLL patients (9.1%) and controls (4.9%). Homozygous CYP1A1*2A genotype was underrepresented in ALL patients (1%) as compared to control (4.8%) but the differences did not reach to statistical significance (OR 0.21; 95% CI 0.03-1.72). Homozygosity for this genotype was not detected in ANLL patients. No particular association was noted between different combinations of combined genotypes and risk of development of childhood ALL and ANLL. These results suggested that there are no significant associations between the studied genotypes and the risk of developing either form of acute leukemia except GSTT1 null and homozygosity for CYP1A1 genotypes that may play protective roles in the development of ANLL in Turkish children.     

新疆哈萨克族人群谷胱甘肽S转移酶M1、T1基因多态性

目的 探讨谷胱甘肽S转移酶M1、T1基因多态性在新疆哈萨克族人群中分布的特点.方法通过多重聚合酶链反应对新疆哈萨克族264例个体 GSTM1、GSTT1基因型进行检测.结果 GSTM1、GSTT1基因缺失型在新疆哈萨克族人群中频率分别为47%及36.4%,同时为GSTM1、GSTT1基因缺失型的频率为20.5%.结论 新疆哈萨克族人群GSTM1、GSTT1基因多态性与汉族及其他少数民族存在一定差异.     

Association of GSTT1/GSTM1 and ApoE variants with left ventricular diastolic dysfunction in thalassaemia major patients

Background: Cardiomyocytes are particularly susceptible to complications from iron loading. The blood transfusions in thalassaemia major create loading of iron that cannot be naturally excreted. Apolipoprotein E and Glutathione S-transferase act as the scavenger of free radicals, which are generated due to excess iron. The variants of Apolipoprotein E (ApoE) and Glutathione S-transferase (GST) may play a role in oxidative damage-induced cardiomyopathy, so we aimed to study the association of genetic variants of these genes on diastolic dysfunction in our patients.

Materials and methods: One hundred and five β-thalassaemia patients older than 10 years were enrolled for the study. Two-dimensional and M-mode echocardiography analysis was done in all patients. Genotyping of the genetic variants of aforementioned genes was done using the PCR–RFLP method. Serum Glutathione S-transferase levels were estimated by ELISA.

Results: Diastolic dysfunction was observed in 24 (22.8%) patients, whereas left ventricular hypertrophy was present in 37(35.2%) patients. There was a significant association of GSTM1 null allele with diastolic dysfunction only. Serum GST levels were also positively correlated with e/a and e/e′ ratio. Positive association of ApoE E2 allele with the diastolic dysfunction was also seen.

Conclusions: Patients having Glutathione S-transferase M1 allele and Apolipoprotein E E2 allele are predisposed to oxidative stress-induced cardiac injury.     

Association analyses of genetic polymorphisms of GSTM1, GSTT1, NQO1, NAT2, LPL, PRSS1, PSTI, and CFTR with chronic alcoholic pancreatitis in Japan

Background: Excessive consumption of alcohol is involved in the onset of pancreatitis. However, most of heavy drinkers do not always develop chronic pancreatitis. Various genetic factors appear to be involved in these individual differences in onset of chronic alcoholic pancreatitis. Here we investigated a possible association of alcoholic pancreatitis with polymorphisms of the various genes belong to the phase II detoxification enzymes responsible for metabolism of the oxidative compounds, and the several genes that have relevance to inherited pancreatitis. Methods: The subjects consisted of 53 patients with chronic alcoholic pancreatitis, 54 alcoholic patients without pancreatic dysfunction, and 42 healthy individuals. DNA was extracted from the peripheral nucleated blood cells of all subjects and genetic mutations and subtypes were analyzed by the PCR and RFLP methods. We examined the correlation between chronic alcoholic pancreatitis and variants of the phase II detoxification enzymes such as Glutathione S-transferase M1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), NADPH-quinone oxidoreductase 1 (NQO1), and N-acetyl transferase (NAT2). In addition, genes of lipoprotein lipase (LPL), cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (PSTI), and cystic fibrosis transmembrane conductance regulator (CFTR) were also analyzed. Results: Frequencies of the gene deletion of GSTM1 and GSTT1 in addition to the C-allele frequency of NQO1 tended to be higher in the alcoholic patients with (AlCP) or without pancreatic dysfunction (Alc) than in the healthy controls although the difference was not significant. The NAT2 gene showed no relation with Alc and AlCP patients. PSTI, LPL, PRSS1, and CFTR genes presented no association with chronic alcoholic pancreatitis. Conclusions: All genes analyzed in the present study lacked association with chronic alcoholic pancreatitis. However, the gene deletion of GSTM1 and GSTT1, and the C-allele of NQO1 cannot be ruled out for association with alcoholism.