TAP1 and TAP2 gene polymorphisms in Korean patients with allergic rhinitis

Antigen peptides are actively transported across the endoplasmic reticulum by the transporters associated with antigen presentation (TAP). TAP genes polymorphism could influence the selection process that determines which antigen peptides play a role in the pathogenesis of allergic rhinitis. The aim of this study was to investigate the association of TAP genes polymorphism with allergic rhinitis. TAP1 and TAP2 genotyping were performed on 110 allergic rhinitis patients and 107 healthy controls. TAP1 polymorphic residues at codons 333 and 637, and TAP2 polymorphic residues at codons 379, 565, 651, and 665 were analyzed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Analysis of TAP1 gene polymorphism demonstrated decreased frequencies of Ile/Val genotype at codon 333, Asp/Gly genotype at codon 637, and haplotype A and B in allergic rhinitis patients when compared to controls (p<0.05). However, there was no significant difference in the genotype, phenotype, or allele frequencies at four TAP2 codons between controls and allergic rhinitis patients. In conclusion, TAP1 gene polymorphism may be an important factor contributing to the genetic susceptibility in the development of allergic rhinitis in the Korean population.     

Transforming growth factor-beta1 polymorphisms in Korean patients with systemic sclerosis

Transforming growth factor-beta1 (TGF-beta1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate the role of TGF-beta1 gene polymorphisms in SSc, we genotyped six biallelic polymorphic positions (position -988, -800, and -509; and codons 10, 25, and 263) in 61 Korean SSc patients and in 148 healthy controls, using polymerase chain reaction-sequence-specific primers. Genetic polymorphisms were found at position -509 and codon 10 in Koreans. The allele frequencies of C/T at position -509 were 0.59/0.41 in patients and 0.56/0.44 in controls. The allele frequencies of C/T at codon 10 were 0.40/0.60 in patients and 0.50/0.50 in controls. In conclusion, no skewed distribution of TGF-beta1 gene polymorphisms was found in Korean patients with SSc.     

Association of TAP 1 and 2 gene polymorphisms with human immunodeficiency virus-tuberculosis co-infection

Major histocompatibility complex (MHC) class I binding peptides are carried from cytosol to the lumen of the endoplasmic reticulum (ER) by transporter associated with antigen processing (TAP), an integral ER membrane protein composed of two subunits, TAP1 and TAP2. Polymorphism in TAP genes may influence these proteins further affecting the antigen peptide presentation, indirectly resulting in the viral escape mechanism from cell-mediated immunity in human immunodeficiency virus (HIV). Our aim was to study the influence of these polymorphism in study groups with HIV-tuberculosis (TB) (n = 110), TB (n = 105), and HIV (n = 130) compared with healthy controls (n = 183), using the tetraprimer amplification refractory mutation system (ARMS)-polymerase chain reaction method. Our results demonstrated that the GG genotype at TAP1 position 333 and GA genotype at TAP1 position 637 were positively associated with HIV-TB co-infection and these genotypes may act as a risk factor for developing TB co-infection in HIV-positive individuals.     

No association of TAP2 polymorphisms in Korean patients with schizophrenia

OBJECTIVES: Polymorphisms of transporters associated with antigen-processing (TAP) genes might influence the susceptibility to schizophrenia by altering the antigen-processing pathway. The aim of this study was to verify the relationship between schizophrenia and the polymorphisms of TAP2 genes. METHOD: Two hundred and fifty-seven Korean patients diagnosed with schizophrenia according to DSM-IV and 184 normal controls participated in this study. TAP2 polymorphic residues at positions 379, 565 and 665 were typed using amplification refractory mutation system-polymerase chain reaction single-strand conformation polymorphism. RESULTS: Distribution of the alleles and genotypes in patients with schizophrenia was not significantly different from those of controls. CONCLUSIONS: This study did not show the association of the TAP2 gene with schizophrenia in the Korean population.     

Frequencies of TAP1 and TAP2 gene polymorphisms in the Anatolian population

Anatolia has a long and complex record of immigration from various regions. Here, we have used TAP1 and TAP2 gene polymorphisms as genetic markers to study the relationship between the Anatolian population and other populations. A neighbour‐joining tree was constructed indicating the relatedness of European populations and the Anatolian population with respect to TAP1 and TAP2 allele frequencies.     

Association of CTLA-4 gene promoter polymorphisms with systemic sclerosis in Iranian population

In a recent study, we were unable to show any association between CTLA-4 exon-1 polymorphism and systemic sclerosis (SSc) in Iranian population. In order to further explore the role of this immune inhibitory gene in SSc development, in the present study, the polymorphisms in the CTLA-4 promoter region (-1,722 T/C, -1,661 A/G and -318 C/T) were investigated in 83 SSc patients and 166 healthy controls. All genotypes and allele frequencies in patients were significantly different from the control group (P=0.022 for -1,722 T/C, P=0.03 for -1,661 A/G and P=0.014 for -318 C/T genotypes). The -1,722C, -1,661G and -318T alleles contributed to SSc with P=0.012, odds ratio (OR) 2.16, P=0.031, OR 1.82 and P=0.023, OR 2.45, respectively. A significant difference was observed in the frequency homozygous 'genotype combination' -1,722TT/-1,661AA/-318CC of these three polymorphisms (P(c)=0.003). The frequency of this genotype combination was significantly higher in the control group than in patients. Results of this investigation indicate that -1,722C, -1,661G and -318T alleles of CTLA-4 gene promoter appear to be associated with SSc, and individuals carrying these alleles may be more susceptible to this disease.     

Association of osteopontin regulatory polymorphisms with systemic sclerosis

To test the involvement of osteopontin gene (OPN) in systemic sclerosis (SSc) susceptibility, two OPN single nucleotide polymorphisms previously reported to be associated with systemic lupus erythematosus, namely −156G/GG (proximal promoter) and +1239A/C (3′ untranslated region (UTR)), were tested in 357 Italian patients and 864 matched control subjects. OPN serum levels were determined by enzyme-linked immunosorbent assay in 32 patients and 116 controls. Compared with the controls, in SSc patients there was a significantly increased frequency of the alleles −156G (p = 0.0086), and +1239C (p = 0.00064), paralleling the association reported for systemic lupus erythematosus. According to logistic regression analysis, this association is primarily due to the effect of +1239 single nucleotide polymorphism. OPN serum levels were significantly higher in SSc patients than in controls (p = 0.00025). These data suggest that OPN genetic variations have a role in SSc susceptibility, reporting for the first time an involvement of this molecule in SSc pathogenesis and emphasizing that SSc shares pathogenetic mechanisms with other autoimmune diseases.     

Interleukin-1 gene complex polymorphisms in systemic sclerosis patients with severe restrictive lung physiology

Increased concentrations of interleukin-1 (IL-1) were observed in bronchoalveolar lavage fluids from patients with systemic sclerosis (SSc), and their levels were correlated with the patients' forced vital capacity (FVC). Because IL-1 production is regulated at the genetic level, we hypothesized that IL-1 gene complex single nucleotide polymorphisms (SNPs) might be relevant to the progression of ventilatory restriction in SSc. Two-hundred four Italian SSc patients were genotyped for the following IL-1 gene complex SNPs: IL-1alpha C-889T, IL-1beta C+3962T, IL-1beta C-511T, IL-1R Cpst1970T, and IL-1Ra Cmspal11100T, as well as for the following SNPs of cytokines with regulatory functions on IL-1 production: IFNgamma AUTR5644T, TNFalpha A-308G, and IL-10 A-1082G. The SNPs were inserted in a Cox regression model with disease subset, gender, autoantibodies, age at onset of disease, and prior use of immunosoppresants as covariates and the presence of FVC<55% of predicted values as outcome measure; p values were corrected for the number of pairwise comparisons. Twenty-five patients (12.3%) developed a severe ventilatory restriction after 6.8+/-6.6 years (mean+/-standard deviation) from diagnosis. In our model, the relative risk to develop a severe ventilatory restriction was increased by the antitopoisomerase I antibody (p=0.01; HR=14.67, CI95=1.87-114.92), the dcSSc subset (p=0.007; HR=3.14, CI95=1.36-7.21) and the IL-1beta C+3962T SNP (p=0.003 TT vs CC; HR=6.61, CI95=2.28-19.15). The IL-1beta C+3962T SNP is associated with the presence of severe restrictive lung physiology in Italian SSc patients.     

Proximal interleukin-10 gene polymorphisms in Italian patients with systemic sclerosis

Interleukin-10 (IL-10) can favour the development of fibrosis by promoting a relative shift towards T helper 2 responses. Three single base pair substitutions in the 5' flanking region of the IL-10 gene (G/A -1082, C/T -819 and C/A -592) influence the amount of IL-10 secreted in cell cultures: the GCC haplotype is associated with an increased production, while the ACC and the ATA haplotypes are associated with intermediate and decreased production. Accordingly, three phenotypes have been individuated: high producers (GCC+/GCC+), medium producers (GCC+/GCC-) and low producers (GCC-/GCC-). We hypothesised that IL-10 haplotypes and genotypes are differently expressed in patients with systemic sclerosis (SSc) with the limited cutaneous SSc (lcSSc) subset or the diffuse cutaneous SSc (dcSSc) subset. One hundred and sixty-one unrelated Italian patients with SSc and 94 controls have been included. Their DNA was extracted and stored before being analysed by polymerase chain reaction with sequence-specific primers. The GCC haplotype is overrepresented in patients with SSc; subjects with dcSSc were the primary contributors to these results (dcSSc: 52.2% vs controls: 37.2%; chi2= 8.519, 2 d.f., corrected P= 0.04). In Scl70-positive patients, the GCC haplotype increased the likelihood of presenting the dcSSc subset [chi2= 12.56, P < 0.0005; odds ratio (OR) = 3.89, 95% confidence interval (CI(95)) = 1.69-9.08]; these results were confirmed at the phenotypic level (chi2= 11.67, 2 d.f., P= 0.003). In Scl70-positive patients, the high-producing phenotype was associated with poor survival, independently from disease subset and gender (hazard ratio = 9.9, CI(95)= 1.6-61.27, P < 0.05). The IL-10 haplotype and genotype associated with high IL-10 production may alter the susceptibility to SSc and/or its expression, increasing the prognostic value of other well-known markers of disease severity.     

Frequencies of TAP1 and TAP2 gene polymorphisms in the Anatolian population.

Anatolia has a long and complex record of immigration from various regions. Here, we have used TAP1 and TAP2 gene polymorphisms as genetic markers to study the relationship between the Anatolian population and other populations. A neighbour-joining tree was constructed indicating the relatedness of European populations and the Anatolian population with respect to TAP1 and TAP2 allele frequencies.     

HSP90B1基因多态性与系统性红斑狼疮易感性的关联研究

目的：探讨HSP90B1基因多态性与中国汉族人群系统性红斑狼疮(SLE)易感性的关系。方法：从医院收集360例对照和360例SLE患者,按照年龄和性别进行匹配。利用Multiplex SNaPshot分型技术对SNP位点分型。采用基于错误发现率 (FDR) 标准的本杰明-汉伯格 (BH) 法进行多重检验校正。结果：显性模型分析发现rs1165681的基因型频率分布在对照组和SLE组之间存在统计学差异(Crude OR = 0.621, 95%CI = 0.450-0.856, P=0.004; Adjusted OR = 0.619, 95%CI = 0.449-0.855, P=0.004);隐性模型分析发现rs10778306 (Crude OR = 0.568, 95%CI = 0.328-0.984,P = 0.044; Adjusted OR = 0.570, 95%CI = 0.329-0.988, P = 0.045)、rs2722188(Crude OR = 0.227, 95%CI = 0.076-0.681, P = 0.008; Adjusted OR = 0.227, 95%CI=0.076-0.682, P=0.008) 的基因型分布在两组之间存在统计学差异。BH法校正后,rs1165681基因型分布在两组之间有统计学差异 (P_BH = 0.044)。单倍型分析后CCATTAGGCAT(OR=0.323, 95%CI=0.154-0.680, P = 0.002)、CCCTTAGGCAC (OR = 1.324, 95%CI = 1.014-1.729, P =0.039)、TCCCTAGTCGC(OR = 0.465, 95%CI = 0.221-0.979, P = 0.039)和TTCTCGGGCAT(OR=0.443, 95%CI = 0.224-0.875, P = 0.016) 与SLE的发病风险有关;BH法校正后,CCATTAGGCAT在两组之间的分布有统计学差异(P_BH = 0.028),其他单倍型均无统计学差异 (P>0.05)。结论：HP90B1基因多态性可能与中国汉族人群的SLE发病有关。     

TAP1 and TAP2 gene polymorphisms and HLA-TAP haplotypes in Koreans based on 90 families

We have investigated the polymorphism of TAP genes and the distribution of human leukocyte antigen (HLA)-TAP haplotypes in 90 Korean families (180 parents and 233 children), previously typed for HLA class II alleles. TAP1 (codons 333 and 637) and TAP2 (codons 379, 565, 577, 651, 665, and 687) typings were carried out by use of polymerase chain reaction-restriction fragment length polymorphism method. For TAP1, four alleles (gene frequency: A 81.9%, B 15.0%, C 2.5%, D 0.5%) and for TAP2, nine alleles (A1 31.7%, A2 14.2%, B 32.5%, Bky2 6.1%, C 6.9%, D 2.5%, E 3.9%, G 0.8%, and H 1.4%) were detected. Sixteen different TAP1-TAP2 haplotypes were observed with frequencies > 0.5%, and we found that significant linkage disequilibrium was present between TAP1 and TAP2 loci (p < 0.001). When HLA-DRB1-DQB1 haplotypes were extended to TAP1 and TAP2 loci, much diversification of haplotypes was observed: 26 different DRB1-DQB1 haplotypes (frequencies > 0.8%) formed 90 different extended haplotypes. Eight recombinant haplotypes between DQB1 and DPB1 loci were observed, and most (seven of eight) of the recombinations occurred between TAP2 and DPB1 loci. These results add more evidence to the view that recombination hot spot is present within and around TAP gene region.     

Angiotensin-converting enzyme gene insertion/deletion polymorphism in Korean patients with systemic sclerosis

To determine whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with the development and clinical features of systemic sclerosis (SSc) in Korean, we studied seventy two Korean patients with SSc fulfilling the ACR preliminary classification criteria. The controls were 114 healthy, disease free Koreans. ACE I/D genotypes were determined by PCR method using oligonucleotides. Sixty eight patients (94.4%) were women and age at diagnosis was 43.5+/-12.6 yr old (mean+/-SD). Thirty nine patients (54.2%) had a diffuse type of SSc. There were no statistical differences in the frequencies of all ACE I/D genotypes and D allele between patients and controls, and neither between diffuse and limited types of SSc. ACE I/D gene polymorphism was not associated with the development of SSc in Korea. The investigation for the pathogenesis of SSc requires more studies about the role of other candidate genes such as endothelin, TGF-beta, nitric oxide, or angiotensin II receptor in addition to the ACE genes.     

TNF-alpha and TNF-beta gene polymorphisms in systemic sclerosis

Tumor necrosis factor (TNF)-alpha and TNF-beta, mediators of inflammatory responses, have been implicated in the pathogenesis of autoimmune diseases. The aim of this investigation was to determine whether two promoter region polymorphisms of the TNF-alpha gene (TNF-alpha -308 and TNF-alpha -238) and a determinant in the first intron of the TNF-beta gene (TNF-beta +252) affect susceptibility to systemic sclerosis (scleroderma) (SSc). Fifty patients and 60 healthy blood donors from Japan were genotyped for these markers by polymerase chain reaction-based methods. Fisher's exact test was used to test for significant associations. Because of very limited variation at the TNF-alpha -308 and TNF-alpha -238 loci in the Japanese people, statistical analyses with sufficient power could not be done for these genotypes. However, the two homozygous genotypes of the TNF-beta +252 locus were found to be significantly associated with SSc. Compared to controls, the frequency of the TNF-1 genotype was decreased, whereas that of TNF-2 was increased in SSc patients. The former implies an association with resistance, while the latter suggests an association with susceptibility to the disease. These results show that the TNF-beta +252 locus plays an important role in the etiopathogenesis of SSc.     

Association of interleukin-1 gene polymorphisms with multiple sclerosis: a meta-analysis

Background

Dysregulated levels of interleukin-1 (IL-1) were observed in patients with multiple sclerosis (MS). Previous studies have provided conflicting evidence implicating the IL-1 gene polymorphisms in MS risk.

Methods

A meta-analysis of 16 case–control studies involving 3,482 cases and 3,528 controls was conducted to evaluate this association.

Results

No association was found between the IL-1α ?889 (rs1800587), IL-1α +4,845 (rs17561), IL-1β ?511 (rs16944), IL-1β +3,953 (rs1143634), IL-1ra variable number tandem repeat (VNTR) polymorphisms and MS risk. However, in subgroup analyses for the IL-1ra VNTR polymorphism, we found that individuals carrying the 2 allele had a 32 % increased risk for bout-onset MS (relapsing remitting and secondary progressive MS) when compared to the LL homozygotes (OR = 1.32, 95 % CI = 1.06–1.66, P _z = 0.014).

Conclusion

Common variants in the IL-1 region are not associated with MS risk but our data suggest that the IL-1ra VNTR polymorphism might be associated with bout-onset MS subtype.     

Association with tryptophan hydroxylase 2 gene polymorphisms and autism spectrum disorders in Korean families

It was performed a family-based association study of 6 single nucleotide polymorphisms (SNPs) from the TPH2 with autism spectrum disorder (ASD) in 151 Korean trios. We found a significant association at the rs2129575 with ASD susceptibility (corrected p=0.006). Furthermore, after conducting with the quantitative scores in the Autism Diagnostic Interview-Revised, there were associations between restricted, repetitive, and stereotyped patterns of behavior (preoccupation with parts of objects or nonfunctional elements of materials) in ASD and SNPs in TPH2. These results suggest that TPH2 polymorphisms influence the phenotypic impairments of ASD and enhance ASD susceptibility.     

AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis

Mutations in the autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Systemic sclerosis (SSc) is a non-organ-specific autoimmune disease mainly characterized by cutaneous involvement, that is frequently associated with other autoimmune manifestations common to APECED. Nineteen SSc patients, 22 patients affected by SSc associated with autoimmune thyroiditis, and 100 healthy controls were analyzed. We identified 11 AIRE gene variants, one of which has never previously been described. Intronic polymorphism G11107A was significantly correlated to SSc/thyroiditis. Data show that variants of the AIRE gene might be correlated to different clinical manifestations in SSc patients.     

Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a lung inflammatory disease caused by the inhalation of a variety of antigens. Previous studies support the role of the major histocompatibility complex (MHC) class II genes in the susceptibility to develop HP. However, the putative role of other MHC loci has not been elucidated. Transporters associated with antigen processing (TAP) genes are located within the MHC class II region and play an important role transporting peptides across the endoplasmic reticulum membrane for MHC class I molecules assembly. The distribution of single nucleotide polymorphisms (SNPs) in TAP1 genes was analyzed in 73 hypersensitivity pneumonitis (HP) patients and 58 normal subjects. We found a significant association of the allele Gly-637 (GGC) (p=0.00004, OR=27.30, CI=3.87-548.04) and the genotypes Asp-637/Gly-637 (p=0.01, OR=16.0, CI=2.19-631.21), Pro-661/Pro-661 (p=0.006, OR=11.30, CI=2.28-75.77) with HP. A significant decrease in the frequency of the allele Pro-661 (CCA) (p=0.008, OR=0.06, CI=0-0.45), the genotype Asp-637/Asp-637 (p=0.01, OR=0.17, 95% CI=0.05-0.58) and the haplotype [Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro-661 (CCA)] was detected in HP patients compared with controls (p=0.002, OR=0.07, CI=0.0-0.57). These findings suggest that TAP1 gene polymorphisms are related to HP risk, and highlight the importance of the MHC in the development of this disease.