Caspase 9 promoter polymorphisms and risk of primary lung cancer

Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [-1263A>G, -905T>G, -712C>T and -293_-275delCGTGAGGTCAGTGCGGGGA (-293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the -1263 AA genotype or combined -1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42-0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46-0.97, P=0.01, respectively]. For the -712C>T polymorphism, individuals with at least one -712T allele were at a significantly increased risk of lung cancer compared with those harboring the -712 CC genotype (adjusted OR=1.42, 95% CI=1.06-1.89, P=0.02). Consistent with the results of genotype analyses, the -1263G/-712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47-0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45-0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17-0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; P(trend)<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the -1263G/-712T and -1263A/-712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.     

Polymorphisms in the caspase-8 gene and the risk of lung cancer

Caspase-8 (CASP-8) is an initiator CASP in the cell death receptor-mediated apoptotic pathway, and plays an important role in the development of cancer. Polymorphisms and their haplotypes in the CASP-8 gene can result in alterations in CASP-8 expression and/or activity, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we examined the association of -678_-673delAGTAAG (-678del) and IVS12-19G-->A polymorphisms and their haplotypes with the risk of lung cancer in a Korean population. The CASP-8 genotypes were determined in 432 lung cancer patients and 432 healthy age- and gender-matched control subjects. The distributions of the CASP-8 -678del and IVS12-19G-->A genotypes were not significantly different between the overall lung cancer cases and the controls. When the cases were categorized by tumor histology, however, the IVS12-19 AA genotype and the combined IVS12-19 GA + AA genotype were associated with a significantly decreased risk of small cell carcinoma (SmCC) compared with the IVS12-19 GG genotype [adjusted odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.03-0.64, P = 0.01; and adjusted OR = 0.56, 95% CI = 0.33-0.96, P = 0.03, respectively]. Consistent with the genotyping analyses, the -678del-/IVS12-19A haplotype containing 94% of the IVS12-19A allele in the study population was associated with a significantly decreased risk of SmCC compared with the -678del-/IVS12-19G (adjusted OR = 0.58, 95% CI = 0.36-0.93, P = 0.023, and Pc = 0.046). These findings suggest that the CASP-8 gene may contribute to an inherited predisposition to SmCC of the lung.     

Analysis of Single Nucleotide Polymorphisms in the NOS2A Gene and Interaction with Smoking in Age‐Related Macular Degeneration

Age‐related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P= 0.035). A significant interaction with smoking was detected at rs2248814 (P= 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD.     

The −675 4G/5G PAI-1 polymorphism confers genetic susceptibility to systemic lupus erythematosus,its clinical manifestations,and comorbidities in Mexican-Mestizo population

Abstract

Systemic lupus erythematosus (SLE) involves a broad range of factors that contribute to the development of the disease and its comorbidities. Genetic predisposition influences the development of SLE, and the ?675 4G/5G PAI-1 polymorphism has been associated with several pathologies with a chronic inflammatory component. Our objective was to investigate the genetic association between the ?675 4G/5G PAI-1 polymorphism with SLE, its clinical manifestations, and comorbidities in a Mexican-Mestizo population. The ?675 PAI-1 polymorphism was determined by PCR-RFLP in 716 subjects: 293 SLE patients and 423 control subjects. Significant associations for SLE genetic susceptibility were found in carriers of 4G/5G (OR = 2.63; CI 1.81–3.87; p?<?.001) and 4G/4G (OR = 2.70; CI 1.62–4.51; p?<?.001) genotype in comparison with the 5G/5G genotype; 4G allele carriers also presented genetic risk for SLE (OR = 1.63; CI 1.31–2.03; p?<?.001) compared to the 5G allele. Following a dominant genetic model, a similar association was found with the 4G allele to SLE (OR = 2.66; CI1.84–3.84; p?<?.001). The 4G/5G genotype was associated with shorter disease duration (p?=?.039), as well as lower levels of haemoglobin (p?=?.001) and haematocrit (p?=?.009); the need for prednisone treatment (p?=?.001), higher BMI (p?=?.03), presence of type 2?DM (p?=?.015), clinical activity (Mex-SLEDAI = 57%; p?=?.047), Chronicity (SLICC-ACR = 0; p?=?.015) and CRP levels (p?=?.015) were associated with 5G/5G genotypes. In conclusion, the ?675 4G/5G and 4G/4G PAI-1genotypes were found as genetic risk markers of susceptibility for SLE in the Mexican-Mestizo population, and each genotype could influence the clinical manifestations and comorbidities differently in SLE.     

Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

The tumor necrosis factor-α (TNF-α) promoter ? 238A/G polymorphism has been repeatedly associated with systemic lupus erythematosus (SLE), but findings are not consistent across studies. Our aim was to do a meta-analysis to assess the association between TNF-α promoter ? 238A/G polymorphism and SLE. Eleven published studies of this polymorphism with SLE in different ethnic groups were identified using a Medline search. Meta-analysis was performed for genotypes AA versus GG, GA versus GG, AA versus GG+GA, GA+AA versus GG, and A allele versus G allele in a fixed/random effect model. The overall odds ratio (OR) of the AA versus GG+GA genotypes was 3.46 (95% CI = 1.35–8.83, P = 0.01), and a similar result was found in Caucasian population (OR = 4.62, 95% CI = 1.20–17.80, P = 0.03); the overall OR of the AA versus GG genotypes was 3.36 (95% CI = 1.32–8.55, P = 0.01), and a similar result was found in Caucasian population (OR = 4.29, 95% CI = 1.11–16.53, P = 0.03); the OR of the GA versus GG genotypes was 0.48 (95% CI = 0.30–0.75, P = 0.001) in Caucasian population. In conclusion, this meta-analysis demonstrates the association between TNF-α promoter ? 238A/G polymorphism and SLE, especially in Caucasian population.     

Meta-Analysis of Associations Between Interleukin-10 Polymorphisms and Susceptibility to Vasculitis

Objective: This study determined whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to vasculitis.

Methods: A meta-analysis was conducted of the associations between the IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and the haplotype of the IL-10-1082 G/A, -819 C/T, -592 C/A polymorphisms and vasculitis.

Results: A total of 21 comparative studies involving 4121 patients and 5504 controls were considered in the meta-analysis. Meta-analysis revealed no association between the IL-10-1082 G allele and vasculitis in all study subjects (OR?=?0.927, 95% CI?=?0.780–1.102, p?=?0.389). However, disease-specific meta-analysis showed an association between Wegener’s granulomatosis (WG) and the IL-10-1082 G allele (OR?=?0.729, 95% CI?=?0.547–0.971, p?=?0.031). Meta-analysis revealed an association between vasculitis and the IL-10-819 C allele (OR?=?0.804, 95% CI?=?0.706–0.916, p?=?0.001) in all study subjects and Behcet’s disease (BD) (OR?=?0.724, 95% CI?=?0.679–0.781, p?<?1.0?×?10^?9). Meta-analysis of the IL-10-592 C allele showed an association with vasculitis in all study subjects (OR?=?0.805, 95% CI?=?0.619–0.938, p?=?0.005) and BD (OR?=?0.718, 95% CI?=?0.661–0.781, p?<?1.0?×?10^?9). Meta-analysis of the IL-10 haplotype revealed an association between the GCC haplotype and vasculitis in Europeans (OR?=?1.239, 95% CI?=?1.105–1.513, p?=?0.035).

Conclusions: This meta-analysis showed that IL-10 polymorphisms are associated with vasculitis susceptibility, especially in WG and BD.     

RANTES Gene Polymorphisms Are Not Associated with Rheumatoid Arthritis and Atopic Dermatitis: A Meta-Analysis

Background: A few recent studies have suggested that regulated on activation, normal T cell expressed and secreted (RANTES) polymorphisms (-403 G/A, -28C/G) are associated with rheumatoid arthritis (RA) and atopic dermatitis (AD). However, there still existed studies that did not confirm this correlation. Objective: The objective of this study was to evaluate the relationships of RANTES and RA and AD using a meta-analysis. Methods: Pubmed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers, and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Results: Eight studies were enrolled, including a total of 548 RA cases and 493 controls of -403G/A, 305 RA cases and 303 controls of -28C/G, and 705 AD cases and 578 controls of -403G/A in this meta-analysis. In RA, the overall OR and 95% CI of -403A were 1.41, 1.10–1.82 (p = 0.391) and 2.18, 1.30–3.66 (p = 0.335) in dominant and recessive models, respectively. The overall OR and 95% CI of -28G in RA were 1.35, 0.91–2.01 (p = 0.707) and 3.32, 1.29–8.52 (p = 0.559) in dominant and recessive models, respectively. Moreover, the overall OR and 95% CI of -403A in AD were 1.38, 1.08–1.76 (p = 0.421) and 1.06 and 0.65–1.72 (p = 0.361) in dominant and recessive models, respectively. Conclusions: This meta-analysis showed that RANTES -403G/A and -28C/G were not associated with RA and AD.     

Association of Monocyte Chemoattractant Protein‐1 (MCP‐1)‐2518A>G Polymorphism with Susceptibility to Coronary Artery Disease: A Meta‐Analysis

We attempted to systematically elucidate the association between monocyte chemoattractant protein‐1 (MCP‐1) ‐2518A>G polymorphism and risk of coronary artery disease (CAD). Eligible studies were identified through PubMed, EBSCO, and Web of Science Databases. The magnitude of MCP‐1 polymorphism effect and its possible mode of action on CAD were estimated. The odds ratio (OR) with 95% confidence intervals (CI) were pooled in a specific genetic model to assess the association. A total of 21 studies were involved. There was significant gene effect on CAD risk in the overall population (likelihood ratio test: p < 0.0001). Patients with GG and AG genotypes had 1.435 (95% CI: 1.183–1.740) and 1.087 (95% CI: 1.008–1.172) times higher risk of CAD than those with AA genotype. These gene effects suggested a recessive model to be appropriate. The pooled OR was 1.362 (95% CI: 1.137–1.631; p_uncorrected = 0.001, p_FDR = 0.005) in the recessive model. In the ethnicity‐stratified analysis, significant association was observed in the Caucasian population (OR = 1.492; 95% CI: 1.106–2.014; p_uncorrected = 0.009, p_FDR = 0.015), whereas no statistical significant association was detected in the Asian population (adjusted p = 0.124). The results suggested that MCP‐1 ‐2518A>G polymorphism may be associated with susceptibility to CAD, especially in Caucasians.     

APOBEC3B deletion impacts on susceptibility to acquire HIV‐1 and its advancement among individuals in western India

APOBEC3B deletion polymorphism has been associated with risk of HIV‐1 acquisition and its progression. Therefore, we aimed to investigate the association of APOBEC3B ins/del polymorphism with risk of acquisition of HIV‐1 and its progression. In the present case–control study, we enrolled a total of 150 HIV‐infected individuals and 150 healthy controls. Polymorphism for APOBEC3B gene was genotyped by PCR. APOBEC3B ID, DD genotypes, and D allele were associated with higher risk of acquisition of HIV‐1 (p = 0.004, OR = 4.96; p = 0.03, OR = 3.55; and p = 0.004; OR = 1.60). The individuals with ID genotypes and combined genotype ID+DD of APOBEC3B in the presence of tobacco and alcohol showed the higher risk of advancement of HIV disease; however, risk could not reach statistical significance (OR = 1.14, 95% CI: 0.59–2.18; OR = 1.33, 95% CI: 0.83–2.15 and OR = 1.44, 95% CI: 0.77–2.69; OR = 1.50, 95% CI: 0.94–2.40). Individuals in advanced HIV disease stage and ID genotype and combined genotype ID + DD of APOBEC3B were more likely to be associated with advanced HIV disease stage but risk could not reach significant (OR = 1.50, 95% CI: 0.94–2.40; OR = 1.27, 95% CI: 0.88–1.84). Individuals with ID and DD genotype of APOBEC3B had influence on susceptibility to acquisition of HIV‐1. This suggests that APOBEC3B deletion may attenuate innate cellular immunity against HIV‐1 and thus confer the host persistence for HIV infection.     

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility

Aim: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. Methods: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. Results: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). Conclusion: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.     

Association of the IL‐10 receptor A536G (S138G) loss‐of‐function variant with multiple sclerosis in Tunisian patients

Interleukin‐10 (IL‐10), a potent anti‐inflammatory T‐cell cytokine, has been shown to be a regulatory cytokine that is associated with disease remission in multiple sclerosis (MS) and exerts its activity through its cognate cell surface receptor complex, IL‐10 receptor 1 (IL‐10R1) and IL‐10R2. The purpose of this study was to investigate the IL‐10R1 S138G loss‐of‐function polymorphism (A536G: rs3135932) for possible influence on susceptibility and outcome of MS in Tunisian patients. A total of 103 Tunisian MS patients and 160 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL‐10R1 gene by multiplex allele‐specific polymerase chain reaction. Associations between G allele [odds ratio (OR) = 5.57; 95% confidence intervals (CI) = 3.26–9.54; p = 10^?7], GG genotypes [OR = 10.41; 95% CI = 2.28–47.58; p = 0.0007] and AG genotype [OR = 4.14; 95% CI = 2.16–7.93; p = 0.000016] with the risk development of MS were found. In contrast, the AA genotype seemed to be associated with protection against MS [OR = 0.17; 95% CI = 0.09–0.30; p = 10^?7]. No association was found between S138G SNP and clinical features or disease activity of MS patients. In conclusion, our results suggest that S138G loss‐of‐function polymorphism of the IL‐10R1 may be important risk factor in increasing susceptibility to MS.     

Hepatitis B virus genotype G: prevalence and impact in patients co-infected with human immunodeficiency virus

Relatively little is known about the role of hepatitis B virus (HBV) genotype G (HBV/G) in patients co‐infected with human immunodeficiency virus (HIV) and HBV. This study examined the prevalence and association of HBV/G to liver fibrosis in co‐infected patients. HBV genotypes were determined by direct sequencing of the HBV surface gene or Trugene® HBV 1.0 assay in 133 patients infected with HIV/HBV. Quantitative testing of HBV‐DNA, HBeAg, and anti‐HBe were performed using the Versant® HBV 3.0 (for DNA) and the ADVIA®Centaur assay. The non‐invasive biomarkers Fib‐4 and APRI were used to assess fibrosis stage. Genotype A was present in 103/133 (77%) of the cohort, genotype G in 18/133 (14%) with genotypes D in 8/133, (6%), F 2/133 (1.5%), and H 2/133 (1.5%). Genotype G was associated with hepatitis B e antigen‐positivity and high HBV‐DNA levels. Additionally, HBV/G (OR 8.25, 95% CI 2.3–29.6, P = 0.0012) was associated with advanced fibrosis score using Fib‐4, whereas, being black was not (OR 0.19, 95% CI 0.05–0.07, P = 0.01). HBV/G in this population exhibited a different phenotype than expected for pure G genotypes raising the question of recombination or mixed infections. The frequent finding of HBV/G in co‐infected patients and its association with more advanced fibrosis, suggests that this genotype leads to more rapid liver disease progression. Further studies are needed to understand why this genotype occurs more frequently and what impact it has on liver disease progression in patients with HBV/HIV. J. Med. Virol. 83:1551–1558, 2011. © 2011 Wiley‐Liss, Inc.     

The polymorphism ‐2548 G/A in leptin and severity of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by airway obstruction that is not fully reversible, and there is evidence of a hereditary component in COPD. We aimed to determine whether the polymorphisms ‐2548G/A of leptin (LEP) gene were associated with COPD and its severity in Chinese. A total of 456 subjects with COPD and 422 healthy controls from West China Hospital were enrolled in this study. COPD patients had been undergone a spirometry and a physical examination to refer the GOLD I–IV stages. The polymorphisms in the leptin promoter region at position ‐2548 G/A were detected by Polymerase chain reaction‐restriction fragment length polymorphism analysis. The genotypes and alleles were scored, and the frequencies of the alleles and genotypes in patients and controls were compared. A significantly higher risk for COPD was observed for carriers of the LEP ‐2548 AA genotype [odds ratio (OR) = 7.87, 95% confidence interval (CI) 4.19–14.77, P < 0.001] and carriers of the LEP ‐2548 GA genotype (OR = 2.98, 95% CI 1.57–5.66, P = 0.001). The LEP ‐2548 A allele: frequency was significantly higher in the patient group compared with the control group (OR = 2.75, 95% CI: 2.20–3.44, P < 0.001). We also found a significant relationship between leptin gene polymorphism and the severity of COPD. In the present case–control study, we found an association between the ‐2548 G/A variant of the leptin gene and pathogenesis, severity of COPD in the Chinese population. It suggests that leptin ‐2548 G/A should be used as a genetic marker of COPD severity.     

Interleukin-18 promoter polymorphisms in patients with Behçet's disease

Beh?et's disease (BD) is an idiopathic systemic inflammatory disease and is considered to be a T helper 1 (Th1) type cytokine driven disorder. Moreover, levels of interleukin-18 (IL-18), a pivotal mediator of Th1 cytokine response, have been reported to be upregulated in BD. Therefore, we investigated the distribution of IL-18 promoter -607 C/A and -137 G/C polymorphisms in 103 BD patients (mean age 41.0 years; 48 male, 55 female) using allele-specific-polymerase chain reaction. As compared with healthy control subjects, BD patients had a significantly higher frequency of the -607 CC genotype (42.7% vs 23.3%, odds ratio [OR] = 2.455, 95% confidence interval [CI] = 1.350-4.461, p(c) = 0.021) and a higher frequency of the -607 C allele (60.7% vs 48.1%, OR = 1.668, 95% CI = 1.129-2.464, p = 0.0101). Haplotype analysis showed that BD patients had significantly less -607A/-137G haplotype (27.3% vs 44.2%, OR = 0.469, 95% CI = 0.268-0.820, p(c) = 0.032) and -607A/-137G haplotype homozygote (5.8% vs 20.4%, OR = 0.242, 95% CI = 0.096-0.612, p(c) = 0.014) than control subjects. In addition, the frequency of -607C/-137G haplotype homozygote was significantly higher in BD patients than control subjects (48.5% vs 20.4%, OR = 3.684, 95% CI = 1.997-6.791, p(c) = 0.0014). Although there were no associations between the polymorphisms and clinical manifestations or severity, patients with the -607 CC genotype or -607C/-137G haplotype homozygote showed significantly earlier symptom development (p = 0.034 by ANOVA; p = 0.009 by t-test, respectively) than those with other genotypes or diplotypes. These results suggest that the IL-18 promoter gene is a candidate susceptibility gene in BD patients.     

MMP9基因单核苷酸多态性与鼻咽癌遗传易感性的关系

目的研究MMP9基因单核苷酸多态性与广东人鼻咽癌患病风险及临床病理分期的关系。方法以聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）分析方法检测433例鼻咽癌患者和437例健康对照MMP9基因C-1562T和第6外显子R279Q基因型。结果吸烟显著增加鼻咽癌的患病风险（OR=4．01,95％CI=2．86—5．63）。MMP9基因C．1562T和R279Q基因型频率病例组与对照组相似,均未能增加鼻咽癌的发病风险,-1562CT／TF基因型相对于cc基因型AdOR=0．99,95％CI=0．70—1．39;279RQ／QQ基因型相对于RR基因型OR=0．96,95％C1=0．70～1．32;而且与吸烟增加鼻咽癌发病风险无交互作用。鼻咽癌病例组中,-1562CT／TT和RQ／QQ基因型并未表现出更高的T分期（经年龄、性别和吸烟校正后的OR值分别为1．23和0．84,P〉0．05）和淋巴结转移潜能（经年龄、性别和吸烟校正后的OR值分别为0．88和0．68,P〉0．05）。结论MMP9基因C-1562T和第6外显子R279Q多态性与广东地区鼻咽癌患病风险无关,可能不是广东人鼻咽癌发病遗传易感因素。     

Glutathione S‐Transferase M1 and T1 Gene Polymorphisms and the Outcome of Chronic Hepatitis C Virus Infection in Egyptian Patients

We analysed the distribution of GSTM1 and GSTT1 gene polymorphisms in Egyptian patients with chronic hepatitis C, and investigated their relationship to the clinical outcome of chronic hepatitis C virus (HCV) infection. This study included 169 patients with chronic HCV infection and 145 healthy and matched controls.GSTM1 and GSTT1 polymorphisms were genotyped by multiplex polymerase chain reaction. Individual GSTM1 null and GSTT1 null genotypes were more frequent in patients versus control subjects [OR, 4 (95% CI, 2.5–6.4); P ? 0.001] and [OR, 1.7 (95% CI, 1.1–2.6); P = 0.025], respectively. The patient group showed a higher frequency of the combined GSTM1/GSTT1 double‐null genotype than the control group [OR, 1.8 (95% CI, 1.1–2.9); P = 0.016]. The distribution frequencies of the combined GSTM1/GSTT1 double‐null genotype were significantly different [OR, 0.5 (95% CI, 0.25–0.99); P = 0.049] between F0–F3 and F4. There were no significant differences between the two groups with regard to other genotypes. The combined GSTM1/GSTT1 double‐null genotype was significantly increased in Child‐Pugh C patients in comparison to Child‐Pugh A+B (P = 0.02). There was no significant difference between different classes with regard to other genotypes. In conclusion, we identified an association between the combined GSTM1/GSTT1 double‐null genotype and advanced liver fibrosis and outcome of chronic HCV infection in Egyptian patients.     

Meta-Analysis: The Relationship Between CTLA-4 +49 A/G Polymorphism and Primary Biliary Cirrhosis and Type I Autoimmune Hepatitis

Objectives: CTLA-4 exon-1 +49A?>?G (rs231775) polymorphism has been reported to influence the risk for primary biliary cirrhosis (PBC) as well as type I autoimmune hepatitis (AIH-1) in many studies; however, the results still remain controversial and ambiguous. This study aimed to determine more precise estimations for the relationship between CTLA-4 +49 A?>?G polymorphism and the risk for PBC and AIH-1 by using a meta-analysis.

Design and Methods: PubMed, EMBASE and MEDLINE were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.

Results: Fifteen studies including 3661 patients with PBC and 4427 controls as well as seven studies including 1270 patients with AIH-1 and 1614 controls were identified. Our pooled analysis revealed that G allele of CTLA-4 gene +49A/G polymorphism may confer an increased risk of PBC in overall (p?=?0.001, OR?=?1.29; 95% CI?=?1.13–1.47) and Caucasians (p?=?0.001, OR?=?1.32; 95% CI?=?1.21–1.44). At genotypic level, the codominant, dominant and recessive models showed no significant association with PBC. With respect to AIH-1, the AG genotype demonstrated a trend for association with increased risk of AIH-1 (p?=?0.04, AG vs. AA, OR?=?1.20; 95% CI?=?1.01–1.43). However, the CTLA-4 alleles as well as genotypes in dominant and recessive models were not associated with a risk for AIH-1 in both Caucasians and Asians.

Conclusions: This meta-analysis concluded that the CTLA-4 G allele and the AG genotype were associated with an increased risk for PBC and AIH-1, respectively, suggesting the CTLA-4 +49 A/G polymorphism as a candidate of susceptibility locus to PBC and AIH-1.     

Association between Functional CYP2D6 Polymorphisms and Susceptibility to Autoimmune Diseases: A Meta-Analysis

Objective: This study aimed to explore whether functional CYP2D6 polymorphisms are associated with susceptibility to autoimmune diseases.

Methods: A meta-analysis was conducted on associations between autoimmune diseases and functional CYP2D6*4 1934 A/G and *3 polymorphisms and CYP2D6 phenotypes.

Results: Twelve studies with 1,472 patients and 3,328 controls were included. Autoimmune disease and the CYP2D6 1934 A allele were significantly associated in the overall group, consistent with the Hardy–Weinberg equilibrium (OR = 1.227, 95% CI = 1.071–1.406, p = 0.003); stratification by ethnicity indicated that the CYP2D6 1934 A allele and autoimmune diseases were associated in Caucasians (OR = 1.225, 95% CI = 1.010–1.485, p = 0.039). The CYP2D6*3 allele was also associated with autoimmune diseases in Caucasians (OR = 1.977, 95% CI = 1.125–3.472, p = 0.018). Stratified by autoimmune disease type revealed that the CYP2D6 1934 AA genotype was associated with systemic lupus erythematosus (SLE; OR = 2.007, 95% CI = 1.170–3.442, p = 0.011) and ankylosing spondylitis (AS; OR = 2.317, 95% CI = 1.422–3.774, p = 0.001). The CYP2D6 PM+IM phenotype was significantly associated with autoimmune diseases in Caucasians (OR = 1.526, 95% CI = 1.038–2.246, p = 0.032) and with SLE (OR = 1.778, 95% CI = 1.249–2.532, p = 0.001).

Conclusions: This meta-analysis indicates that CYP2D6*4 and *3 polymorphisms and the CYP2D6 phenotype are associated with susceptibility to autoimmune diseases in Caucasians; particularly, the CYP2D6*4 polymorphism and CYP2D6 PM+IM phenotype are risk factors for SLE development.     

PDCD1 polymorphism amplifies the predisposing effect conferred by CTLA4 polymorphism in chronic hepatitis B virus infection

Programmed cell death 1 (PDCD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) both negatively regulate the T-cell response in chronic hepatitis B virus (HBV) infection. This study determined genotypes of PDCD1 -606 G/A and +8669 G/A and CTLA4 -318 C/T and +49 A/G polymorphisms in 172 chronic HBV patients and 145 healthy controls and analyzed the interaction between these polymorphisms of the 2 genes. The results indicated that carriage of the PDCD1 +8669 A allele was increased in HBV patients carrying the CTLA4 -318 CC genotype and carrying the CTLA4 +49 AA genotype compared with controls carrying the CTLA4 -318 CC genotype (80.2% vs 64.8%, p = 0.002, odds ratio [OR] = 2.202, 95% confidence interval [95% CI] = 1.326-3.656) and carrying the CTLA4 +49 AA genotype (18.6% vs 9.7%, p = 0.024, OR = 2.139, 95% CI = 1.093-4.187), respectively. More obviously, carriage of the PDCD1 +8669 AA genotype was significantly increased in HBV patients carrying the CTLA4 +49 AA genotype compared with controls carrying the same CTLA4 +49 genotype (14.0% vs 3.4%, p = 0.001, OR = 4.541, 95% CI = 1.686-12.230). These results suggest that the PDCD1 +8669 A allele and AA genotype may amplify the predisposing effect conferred by the CTLA4 polymorphism through PDCD1 and CTLA4 gene interaction in chronic HBV infection.