Association of HLA class II (DRB1, DQA1, DQB1) alleles and haplotypes with myasthenia gravis and its subgroups in the Iranian population.

Heterogenic pattern of HLA associations with myasthenia gravis (MG) among different ethnicities and also among different MG subgroups has been the subject of debate in large series of many studies. One hundred and sixty Iranian MG patients were investigated for HLA class II (DRB1, DQA1, DQB1) associations compared to two hundred healthy controls from the same ethnic population. DRB1*11 DQA1*0501 DQB1*0301 haplotype was found to be protective for total (ocular plus generalized) MG (Pc=0.005, OR=0.49) and generalized MG (Pc=0.008, OR=0.49). DRB1*04 DQA1*0301 DQB1*0302 haplotype (Pc=0.03, OR=2.25) was predisposing for anti-acetylcholine receptor (AChR) antibody-positive MG, while DRB1*16 DQA1*0102 DQB1*05 (Pc=0.013, OR=4.28) was predisposing for anti-muscle specific tyrosine kinase (MuSK) antibody-positive MG. There was also a trend of positive association for DRB1*14 DQA1*0104 DQB1*05 haplotype with MuSK-positive MG (Pc=0.054, OR=3.97). Among other MG subgroups and with less significance, DRB1*0101 DQA1*0101 DQB1*05 haplotype (P=0.016, OR=3.68) had positive association with pure ocular MG, and DRB1*03 DQA1*0501 DQB1*0201 haplotype (P=0.024) had negative association with thymomatous MG. This study highlights the importance of appropriate MG subgrouping according to clinical and paraclinical characteristics in HLA studies among MG patients.

Association of interleukin 6 single nucleotide polymorphisms with allergic rhinitis.

OBJECTIVES: Allergic rhinitis (AR) is a polygenic inflammatory disorder of the nasal mucosa with an increasing prevalence worldwide. As interleukin 6 (IL-6) seems to be involved in development of allergic disorders, such as allergic rhinitis, this study was performed to evaluate the association of two promotor variants of IL-6 gene in the AR. METHODS: Ninety eight patients with AR were enrolled in this study. Genotyping was done for two polymorphisms in a promoter region of IL-6 gene (G/C at -174, rs1800795 and G/A at -597, rs1800797), using a PCR sequence-specific-primers method. RESULTS: Patients homozygous for the G allele of rs1800795 in IL-6 had a 3.35-fold risk of having AR than those with the C allele. AA genotype in rs1800797 of IL-6 was associated with the increased risk of developing AR. G/G haplotype for IL-6 (rs1800795, rs1800797) was significantly higher in the patient group. In some subgroups of patients, there were significant relationships between IgE levels, eosinophil count, eosinophil percentage, nature of sensitivity and persistency of disease and these two variants. CONCLUSION: We found that two promotor variants in IL-6, especially rs1800795, were predisposing factors for AR with a negative heterosis pattern. These SNPs could also affect the clinical parameters, the nature of sensitivity and persistency of the disease in some subgroups of the patients.

HLA-DRB1,-DQA1 and -DQB1 allele and haplotype frequencies in female patients with early onset breast cancer.

Based on the reports, few HLA class II alleles are associated with susceptibility or protection in breast cancer. Here we investigate the association between HLA class II alleles and breast cancer in Iranian women. 100 patients with pathologically proven breast cancer who referred to Cancer Institute were randomly selected and compared with a group of 80 healthy blood donor subjects. The patients were studied in two groups, group 1 includes patients aging 40 years or younger and group 2 include patients aging over 40 years. HLA class II alleles were determined by amplification of DNA followed by HLA-typing using sequence-specific primer (SSP) for each allele. In group 1, the most frequent alleles were HLA-DQA1*0301 (P = 0.002, OR = 3.3) and HLA-DQB1*0302 (P = 0.04, OR = 2.8). In group 2, the following alleles increased significantly than those in controls including HLA-DQA1*0301 (P = 0.001, OR = 3.4) and HLA-DRB1*0301 (P = 0.04, OR = 2.3). In complete group of patients, the frequency of HLA-DQA1*0301 (P = 0.001, OR = 3.4) and HLA-DRB1*1303 (P = 0.02, OR = 2.3) increased significantly than those in control group. HLA-DQA1*0505, HLA-DQA1*0101, HLA-DRB1*1301and HLA-DRB1*0101 alleles showed negative association with breast cancer. Our findings suggest that HLA-DQA1*0301 allele is mainly associated with increased risk of breast cancer including early-onset of the disease. HLA-DQA1*0505 and HLA-DRB1*1301 are involved in protection. We conclude that specific alleles of HLA class II influence breast cancer risk.

Cytokine gene polymorphisms in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia and an increased susceptibility to recurrent infections, autoimmunity and cancers. There are some conflicting results regarding the cytokine profile of CVID patients. While cytokine production could be associated with gene polymorphism, genetic profiles of a number of cytokines were analyzed in this study. The allele and genotype frequencies of the polymorphic genes coding for interleukin (IL)-2, IL-12, interferon-gamma and transforming growth factor (TGF)-beta were investigated in 30 patients with CVID in comparison with 140 controls. The genotype TGF-beta CG at position +915 was significantly overrepresented in the patient group, while the frequencies of the genotypes TGF-beta TT at +869 and GG at +915 were significantly decreased in the patient group in comparison with controls. TGF-beta TC and IL-2 GT were the most frequent haplotypes in the patients, whereas the TGF-beta TG haplotype was significantly decreased in the patient group. The allele and genotype frequencies of interferon-gamma at position UTR +5644 and also IL-12 at position -1188 were similar in patients and controls. Cytokine single nucleotide polymorphisms could play a role in the pathophysiology of CVID. Considering the significantly lower frequency of the high production haplotype (TG) and the higher frequency of the low production halplotype (TC) of TGF-beta, low production of this cytokine is expected in some CVID patients.

Proinflammatory cytokine gene polymorphisms among Iranian patients with asthma.

INTRODUCTION: Asthma is one of the most common respiratory diseases caused by acute and chronic inflammation of airways. Proinflammatory cytokines could contribute to this inflammatory process. This study was performed in order to analyze the genetic profile of proinflammatory cytokines in Iranian asthmatic patients. PATIENTS AND METHODS: The allele and genotype frequencies of a number polymorphic genes coding for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor (IL-1R), IL-1RA, and IL-6 were investigated in 60 patients with asthma in comparison with 140 controls using polymerase chain reaction with sequence-specific primers. RESULTS: The most frequent genotypes in our patients were TNF-alpha GA at position -308 (P = 0.001), TNF-alpha AA at position -238 (P = 0.01), IL-1 alpha TC at position -889 (P = 0.0001), IL-1 beta TC at position -511 (P = 0.0001), and IL-1RA TC at position Mspa-I 11100 (P = 0.001). In contrast, the frequencies of the genotypes TNF-alpha GG at position -308 (P = 0.001), IL-1 alpha CC at position -889 (P = 0.005), IL-1 beta CC at position -511 (P = 0.0001), and IL-1RA TT at position Mspa-I 11100 (P = 0.0001) in the patient group were significantly lower than controls. The most frequent haplotypes for TNF-alpha (positions 308, -238) was A/A in the patient group in comparison with controls (P = 0.0001). CONCLUSION: While environmental factors are important in the development of asthma, genetic factors could have a critical role in the expression of the disease. Considering the high frequency of presence of TNF-alpha AG genotype (-308), it seems that the production of TNF-alpha in the asthmatic patients could be higher than normal subjects.

HLA class II allele and haplotype frequencies in iranian patients with acute myelogenous leukemia and control group.

Previous studies have demonstrated some significant differences in HLA allele frequencies in leukemic patients and normal subjects. We have analyzed HLA class II alleles and haplotypes in 60 Iranian patients with acute myelogenous leukemia (AML) and 180 unrelated normal subjects. Blood samples were collected after obtaining informed consents. From the patients and control DNA extraction and HLA typing were performed using PCR-SSP method. Significant positive association with the disease was found for HLA-DRB1*11 allele (35% vs. 24.7%, p=0.033). Two alleles including HLA-DRB4 and -DQB1*0303 were found to be significantly decreased in patients compared to controls. Regarding haplotype analysis, no significant association was found between case and control groups. It is suggested that HLA-DRB1*11 allele plays as a presumptive predisposing factor while the HLA-DRB4 and -DQB1*0303 alleles are suggested as protective genetic factors against acute myelogenous leukemia. Larger studies are needed to confirm and establish the role of these associations with acute myelogenous leukemia.