PDCD1 single nucleotide genes polymorphisms confer susceptibility to juvenile-onset systemic lupus erythematosus

Abstract

Juvenile-onset systemic lupus erythematosus (JSLE) is a multisystem autoimmune disease in which both the genetic and environmental factors seem to be involved in the etiopathogenesis of the disease. The aim of this study was to evaluate the association of programmed cell death 1 (PDCD1, also called PD-1) gene polymorphisms with JSLE susceptibility in Iranian population. In this case-control association study, three PDCD1 SNPs, including PD-1.1 G/A, PD-1.3 G/A and PD-1.9 C/T were genotyped in 50 Iranian patients with JSLE and 202 healthy unrelated controls, using PCR-RFLP method. The PD-1.1 A allele was found to be more frequent in the case group compared with controls (6% vs. 1.5%, p?=?0.024). Moreover, the GG genotype was less frequent in cases than in controls (88% vs. 97%, p?=?0.021). The other PDCD1 SNPs did not show association. At the haplotypic level, no significant differences was recognized between the two groups of case and control neither for the GAC (PD-1.1 G, PD-1.3 A, PD-1.9 C) nor for the GGC haplotype (PD-1.1 G, PD-1.3 G, PD-1.9 C). Our findings support the influence of the PD1.1 A SNP on the development of JSLE in Iranian population.     

Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population

Programmed cell death 1 (PDCD1) is a necessary negative regulator to maintain peripheral tolerance and is a key molecule in the development of autoimmune diseases. Although PDCD1 gene polymorphisms and haplotypes were reported to be associated with rheumatoid arthritis (RA), replication studies later on showed conflicting results. Here, we analyzed the association of PDCD1 with RA using a large series of Japanese RA patients and population-based controls. DNA samples were obtained from 1,504 RA patients and 449 sex-matched controls. All samples were genotyped for three SNPs on PDCD1 (PD-1.1, PD-1.3 and PD-1.5) using the TaqMan fluorogenic 5′ nuclease assay. Chi-square testing was performed for a case-control study, and the PENHAPLO program was used for haplotype estimation. We could not observe any significant association of PD-1.1 or PD-1.5 polymorphisms between RA. PD-1.3, which was reported to be involved in susceptibility to RA in patients of European descent, was non-polymorphic in the Japanese population. We conclude that polymorphisms in the PDCD1 gene analyzed here are not associated with RA in a Japanese population.     

Tumor necrosis factor gene polymorphisms in ankylosing spondyiitis

Abstract: Despite the strength of the association of ankylosing spondyiitis (AS) with HLA-B27, other genetic elements could play a possible role in the pathophysiology of AS. In view of its gene location, in the proximity of the HLA-B locus, and biological effects, tumor necrosis factor (TNF) genes are potential candidates for additive susceptibility factors to AS. TNFα and TNFβ genotypes were analyzed by PCR-RFLP in 57 patients with AS, 102 random controls and 30 HLA-B*27-positive controls. No significant differences of TNFα promoter variations at position -308 and -238 were found in AS patients in comparison with controls. The -244 polymorphism was not detected in our population. The TNFβ genotype frequency was significantly different between AS patients and random controls. However, when the distribution of the TNFβ genotype was compared in B*27-positive AS patients and controls, these differences disappeared. In addition, we demonstrated that the TNFβ*l was in strong linkage disequilibrium with the B*27 allele, which may explain the differences observed for the TNFβ genotype among AS patients and random controls. Our data suggest that the polymorphisms of TNFα and TNFβ genes do not have an independent effect on AS susceptibility.     

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.     

Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus

A regulatory single nucleotide polymorphism (SNP) PD1.3G/A located on programmed cell death 1 (PDCD1) gene, was shown to be involved in susceptibility to systemic lupus erythematosus (SLE) in Swedish, European American, and Mexican cases. However, association to childhood-onset SLE has not been analyzed. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with susceptibility to childhood-onset SLE in Mexican population. Three PDCD1 SNPs, PD1.3G/A, PD1.5C/T, PD1.6G/A, were analyzed in 250 childhood-onset SLE Mexican patients and 355 healthy controls in a case-control association study. Polymorphisms were genotyped by TaqMan technology. Stratification analysis was performed on the SLE cohort to investigate the SNP association with renal disorder. In addition, haplotypes were constructed with these three SNPs. The PD1.3A allele was significantly associated to childhood-onset SLE (P=0.0019, odds ratio (OR) 2.73, 95% confidence interval (95% CI) 1.35-5.56). The other PDCD1 SNPs did not show association. A total of 155 patients (62%) had nephritis, and no association was observed with PDCD1 SNPs. The ACG haplotype (PD1.3A, PD1.5C, PD1.6G) included almost all PD1.3A alleles, and it was more frequent in SLE patients (5.5%) than in controls (2.1%) (P=0.003; OR 2.73, 95% CI 1.37-5.46). The haplotype structure in Mexican controls was significantly different from those reported in Spanish and Swedish. Our results support association of the PD1.3A SNP to susceptibility of childhood-onset SLE in Mexican population and does not show association to lupus nephritis in this age group.     

中国大陆汉族人群强直性脊柱炎患者骨保护素基因多态性研究

目的：通过骨保护素（OPG）基因单核苷酸多态性（SNPs）位点的筛查,分析中国大陆汉族人群中OPG基因多态性与强直性脊柱炎（AS）易感性的相关性。方法：采集2008年1月至2012年1月在我院就诊的AS患者195例（AS组）及203例性别、年龄与之匹配的健康体检者（对照组）的外周血样本,并提取基因组DNA。所有样本采用TaqMan探针法对OPG基因SNP rs2073618、rs4355801位点进行基因型鉴定。比较AS组与对照组之间不同等位基因及基因型的分布差异,并分析其与AS易感性的相关性。结果：OPG基因SNP rs2073618、rs4355801位点的等位基因及基因型分布均符合Hardy—Weinberg平衡。AS组与对照组等位基因频率分别如下。rs2073618（G）：71．0％、71．9％,（C）：29．0％、28．1％;rs4355801（G）：27．7％、26．4％,（A）：72．3％、73．6％。两组在基因型频率的分布上显示,m2073618（CC）：9．2％、8．9％,（GC）：39．5％、38．4％,（GG）：51．3％、52．7％;rs4355801（AA）：52．3％、52．7％,（AG）：40．0％、41．9％,（GG）：7．7％、5．4％。以上数据组间比较差异均无统计学意义（P〉0．05）。经关联性分析,未发现AS发病的风险等位基因或基因型。结论：中国大陆汉族人群中OPG基因SNP rs2073618、rs4355801单核苷酸多态性与AS的易感性之间没有相关性。     

Association study of LMP gene polymorphisms in Mexican patients with spondyloarthritis

To evaluate the role of LMP (low molecular weight protein) genes as susceptibility markers for spondyloarthritis (SpA), LMP gene polymorphisms were analyzed in 223 Mexican patients with SpA (81 undifferentiated SpA [U-SpA], 117 with ankylosing spondylitis [AS], 25 with reactive arthritis) and in 139 ethnically matched healthy individuals. LMP genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The LMP2 and LMP7 allele frequencies were similar in patients and healthy controls. Genotype analysis revealed an increased frequency of LMP2 R/R genotype in the whole group of SpA (pC = 0.003, OR = 2.06, 95%CI = 1.3–3.25) and in the clinical subgroups of AS (pC = 0.039, OR = 1.88, 95%CI = 1.1–3.22) and U-SpA (pC = 0.003, OR = 2.56, 95%CI = 1.37–4.8) compared with healthy controls. Analysis in the LMP7 did not reveal significant differences in patients and healthy controls. The HLA-B27-negative AS subgroup also showed an increased frequency of LMP2 R/R genotype (pC = 0.027, OR = 4.81, 95%CI = 1.21–22.13). The LMP2-R/R AS patients were younger than LMP2-H/R and H/H patients at onset of the disease (16.0 ± 6.8 years for R/R, 22.0 ± 11.2 years for H/R and 28.6 ± 10.9 years for H/H) (p < 0.05). The data suggest that, besides HLA-B27, LMP2 genotypes are also involved in the genetic susceptibility to develop AS in Mexicans. Furthermore, the age at onset of this disease might also be influenced by genotypes of this gene.     

Association of programmed death‐1 gene polymorphisms with the risk of basal cell carcinoma

Environmental and genetic factors play a fundamental role in the pathogenesis of basal cell carcinoma (BCC) defined as the most common cancer of skin. Programmed death‐1 (PD‐1), encoded by programmed cell death‐1 (PDCD1) gene, serves as an inhibitory molecule in the suppression of immune responses and a risk factor in the development of different cancers. In this study, we investigated the role of two single nucleotide polymorphisms (SNPs) within PDCD1 gene, and haplotypes defined by these SNPs, in the development of BCC in an Iranian population. Whole blood samples were obtained from 210 BCC and 320 healthy subjects. Genomic DNA was extracted from whole blood samples, polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used to genotype determinations of PD1.3 (rs11568821) and PD1.5 (rs2227981) SNPs, and 4 haplotypes were constructed by PDCD1 SNPs. The frequency of G allele of PD1.3 was significantly higher in BCC patients than healthy subjects (p < 0.02), while these significant differences were not observed in the frequencies of PD1.5 alleles between BCC and healthy subjects. Moreover, we found that there were no statistically significant differences in PD1.3 and PD1.5 genotypes between BCC and control groups. Of all estimated haplotypes for PDCD1, only AC haplotype was associated with BCC (OR = 0.22, 95% CI = 0.06–0.79, p < 0.01). These findings suggest that PD1.3G allele and AC haplotype of PDCD1 contribute to BCC in the Iranian population. However, further studies in different populations with larger sample size are required to confirm this study.     

SLC22A12基因第8外显子和第8内含子多态与中国汉族人原发性高尿酸血症关联研究

目的 研究原发性高尿酸血症患者SLC22AI2基因第8内含子和第8外显子单核苷酸多态(single nucleotide polymorphism,SNP)位点与原发性高尿酸血症遗传易感性的关系.方法 选择山东沿海地区原发性高尿酸血症患者215例,正常对照人群323名.提取基因组DNA,PCR扩增SLC22A12基因第8内含子和第8外显子,对PCR扩增产物进行测序.结果 序列分析发现:(1)SLC22AI2基因第8外显子存在T1309C单核苷酸多态,第8内含子存在-103A＞G单核苷酸多态,这2个多态位点完全连锁.(2)高尿酸血症组-103A＞G G等位基因频率和T1309C C等位基因频率明显高于正常对照组(均为51.9%vs.42.4%,P＜0.01);(3)高尿酸血症组GG+GA基因型频率和CC+CT基因型频率显著高于正常对照组(均为80.0%vs.69.0%,P＜0.01).(4)-103 A＞G和T1309C基因多态中,含有等位基因G的基因型GG+GA及含有等位基因C的基因型CC+CT均使高尿酸血症的发病危险性上升了1.79倍(OR=1.79,95%CI:1.19～2.70).结论 SLC22A12基因第8外显子T130gC及第8内含子-103A＞G SNP与原发性高尿酸血症密切相关.     

Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis

T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV.     

A single-nucleotide polymorphism marker within the FCRL5 gene and HLA-B27 positive Han Chinese ankylosing spondylitis patients

The aim of this study was to determine whether FCRL5 genes in concert with human leukocyte antigen-B27 (HLA-B27) genotypes are associated with susceptibility to ankylosing spondylitis (AS) in Chinese population. One hundred and sixty-nine HLA-B27-positive AS patients (107 males and 62 females) and 184 HLA-B27-positive matched controls (112 males and 72 females) were analyzed from Han Chinese populations by case–control design, and their samples were genotyped using a panel of two single-nucleotide polymorphism (SNP) markers (rs6427384, rs12036228) within the FCRL5 gene by ligase detection reactions (LDRs) and the HLA-B27 subtypes were determined by polymerase chain reaction (PCR) using sequence-specific primer (SSP) methods. Our results show that in addition to B27 , the SNPs rs6427384 and rs12036228 were associated with AS, and the C-T haplotype was higher in cases with AS than in the control population [74.8% vs 63.6%, Fisher's P = 0.003, odds ratio (OR) = 1.660,95% confidence interval (CI) = 1.184−− 2.326]. Our results suggest that, in addition to HLA-B27 , a novel polymorphism within the FCRL5 gene confers susceptibility to AS in Han Chinese population.     

KCNQl基因多态性与2型糖尿病易感性相关研究

目的探讨KCNQ1基因单核苷酸多态性（SNPs）与2型糖尿病易感性的关系。方法应用基质辅助激光解吸附电离飞行时间质谱（MALDFFOF—Ms）平台以及MassARRARY—iPLEX技术,分别对238例2型糖尿病患者和240例正常对照组KCNQl基因的三个单核苷酸多态性位点（rs231361、rs231359和rs2237892）进行基因分型,并分析KCNQI基因位点在两组间的差异。结果rs2237892存在CC、TC、TT三种基因型多态性,在对照组中的基因型频率分别为45．5％、40．7％、13．8％,在病例组中的基因型频率分别为44．4％、49．6％、6．0％,该位点在对照组和病例组中分布差异有统计学意义（x2=9．334,P=0．009）。相较于cc基因型,TT基因型其OR（95％CI）分别为0．416（0．206-0．840）（P=0．014）。位点rs231361和rs231359均存在三种多态性,但在病例组和对照组间差异无统计学意义。结论KCNQ1基因位点rs2237892与2型糖尿病易感性相关,位点rs231361和rs231359与2型糖尿病易感性不相关。     

Allelic variation at the TAP 1 locus influences disease phenotype in HLA-B27 positive individuals with ankylosing spondylitis

Abstract: The objective was to determine the role of the TAP 1 gene in influencing the phenotype of disease in adult patients with ankylosing spondylitis (AS). The distribution of TAP 1 gene alleles was determined using the PCR RFLP method and restriction enzymes Bcl I and Ace I. The study population included 115 HLA-B27 positive patients with well-documented AS and 41 HLA-B27 positive normal controls. No significant difference in distribution of TAP 1 alleles was noted in comparisons of all AS patients with normal controls. However, AS patients with extraspinal disease were noted to have a significantly increased prevalence of the TAP 1B allele (17.0%) as compared to AS patients without extraspinal disease (2.9%) (P=0.005) or normal controls (1.9%) (P=0.005). Polymorphism at the TAP 1 locus may influence disease outcome in patients with AS.     

E-钙黏蛋白基因多态性与上皮性卵巢癌发病风险关系的研究

目的 探讨E-钙黏蛋白基因(E-cadherin gene,CDH1)单核苷酸多态性(single nucleotide polymorphism,SN-P)与上皮性卵巢癌发病风险的关系.方法 采用聚合酶链反应-限制性片段长度多态性方法分析207例上皮性卵巢癌患者和256名健康对照的CDH1基因启动子区-160C/A、-347G/GA和3′UTR+54C/T3个SNP位点基因型频率分布;采用免疫组织化学方法检测携带3′UTR+54C/T SNP位点不同基因型的卵巢癌患者癌组织CDH1基因的表达情况.结果 CDH1基因-160C/A和-347G/GA 2个SNP位点的基因型和等位基因频率分布在患者组与健康对照组间差异无统计学意义(P＞0.05).3′UTR+54C/T SNP 位点的基因型与等位基因频率分布在患者与健康对照组间差异有统计学意义,患者组中CC基因型和C等位基因频率(65.2%,89.1%)明显高于对照组(52.7%,64.5%)(P＜0.01);CC基因型可能显著增加上皮性卵巢癌的发病风险(比值比为1.85,95%可信区间为1.27～2.69);且免疫组化研究表明CC基因型患者癌组织CDH1基因的表达明显低于T等位基因(CT+TT)携带者(P＜0.05).采用2LD软件分析显示-160C/A、-347G/GA两位点间存在连锁不平衡(D′=0.999 582),-160A/-347GA单倍型仅在患者组中检测到(5.1%),-160C/-347GA单倍型可能明显降低卵巢癌的发病风险(比值比为0.66,95%可信区间为0.45～0.96).结论 CDH1基因-160C/A、-347G/GA SNP可能与上皮性卵巢癌的发病风险无关,但两位点的单倍型可能改变上皮性卵巢癌的发病风险.3′UTR+54C/T多态CC基因型可能成为上皮性卵巢癌发病的潜在危险因素.     

Association of three single nucleotide polymorphisms of the E-cadherin gene with susceptibility to epithelial ovarian carcinoma]

OBJECTIVE: To investigate the association of three single nucleotide polymorphisms (SNPs), i.e. -160C/A, -347G/GA and 3'UTR+ 54C/T, in the promoter region of E-cadherin gene (CDH1) with the risk of epithelial ovarian carcinoma. METHODS: The SNPs of CDH1 gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 207 epithelial ovarian carcinoma patients and 256 unrelated healthy women; immunohistochemistry was used to measure the level of CDH1 in different genotypes of 3'UTR+ 54C/T locus. RESULTS: There were no significant difference in the frequencies between patients and control women in the two loci (-160C/A, -347G/GA) of CDH1 gene (P> 0.05). However, there was significant difference in the frequency of CDH1 3'-UTR+ 54C/T genotypes (CC, CT and TT) between patients and controls (P< 0.05). The frequencies of the CC genotype and the C allele in patients (65.2%, 89.1%) were significantly higher than that in controls (52.7%ì64.5%) (P< 0.01). The CC genotype significantly increased the risk to epithelial ovarian carcinoma, with adjusted odds ratio of 1.85 (95%CI= 1.27-2.69). In the ovarian tissues of patients, the expression of CDH1 from CC genotype was significantly lower than that with the other genotypes (CT+ TT) (P< 0.05). The -160C/A and -347G/GA polymorphisms were in linkage disequilibrium (D'= 0.999582) by analyzing with 2LD software. The -160A/-347GA haplotype was only observed in patients (5.1%), the -160C/-347GA haplotype decreased susceptibility to epithelial ovarian carcinoma, with adjusted odds ratio of 0.66 (95%CI= 0.45-0.96). CONCLUSION: CDH1 -160C/A and -347G/GA polymorphisms were not associated with the risk of epithelial ovarian carcinoma. However, the haplotype may have impact on the risk of epithelial ovarian carcinoma. The CC genotype of 3'-UTR + 54CT may be a potential risk factor for the epithelial ovarian carcinoma.     

Lack of association between interleukin-1 alpha,beta polymorphisms and Parkinson's disease

The associations between interleukin-1 alpha (IL-1α-889) and beta (IL-1β-511) single nucleotide polymorphisms (SNPs) and the risk for Parkinson's disease (PD) are still controversial and ambiguous. The aim of this study was to determine a more precise estimation of the relationship by meta-analysis. We searched databases through March 2010 for all publications on the association between these variations and PD. A total of 11 studies including 2803 PD patients and 2539 healthy controls were identified. The overall and geographic subgroups analysis was conducted, and odds ratios (OR) and 95% confidence intervals (95% CI) were calculated in the fixed- or random-effects model. We found that the overall OR (95% CI) for TT and CT genotypes versus CC genotype for IL-1α-889 was 1.01 (0.88–1.16), while the overall OR (95% CI) for TT and CT genotypes versus CC genotype for IL-1β-511 was 1.19 (0.87–1.62). The sensitivity analysis strengthened our confidence in the validity of these null associations. There was no publication bias observed in this study. To sum up, there were no associations found between the SNPs of IL-1α-889, IL-1β-511 and risk for PD.     

The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet''s disease

Beh?et's disease is known to be associated with HLA-B51 in many different populations. Genetic evidence supports that the susceptible gene for Beh?et's disease is the HLA-B51 allele at the HLA-B locus. This study was aimed to determine the HLA-B51 nucleotide sequence variation in three Beh?et's disease patients and three healthy controls in order to elucidate if any disease specific mutations or polymorphisms may exist in the HLA-B51 gene of patients. Long-range polymerase chain reaction (PCR) was first carried out to give a PCR-amplified product of 9.5 kb which was then used as a template for nested PCR to give a final amplified product of 4.2 kb. This final product containing the 1.3-kb promoter/enhancer region and the entire HLA-B gene except for a 363-bp 3' terminal end segment encoding the 3' untranslated region was subcloned by the BP cloning technique and sequenced. The sequencing results showed that all the patients possessed the HLA-B*51011 allele, and there were no differences in the exonic nucleotide sequences between the three Beh?et's disease patients and the three healthy controls. The HLA-B*51011 intronic and promoter/enhancer nucleotide sequences from the three patients had 22 single nucleotide polymorphisms (SNPs), a single insertion of 6 bp and a single deletion of 2 bp. On the other hand, the three healthy controls had 24 SNPs in their intronic and promoter/enhancer regions. However, none of these polymorphisms in the patients were specific for the disease. Therefore, these results clearly demonstrate that the HLA-B exonic sequence that encodes the HLA-B51 allele is the real pathogenic factor in Beh?et's disease.     

Association of the MSX2 gene polymorphisms with ankylosing spondylitis in Japanese

Several genes have been implicated in the etiology of ankylosing spondylitis (AS); however, the significance of these genes except HLA-B27 remains to be elucidated. In this study, we examined the association of AS with novel candidate genes and previously reported genes other than HLA-B27. We examined a total of 45 single nucleotide polymorphisms (SNPs) in 15 genes by a sequential screening. We first genotyped 170 Japanese AS patients and 896 controls for the SNPs (first screen). Then, we genotyped eight SNPs with P < 0.05 in the first screen for 108 additional Japanese patients (second screen). We checked the replication of the association of the most significant SNP by genotyping 219 Taiwanese AS patients and 185 controls. When the first and second screens were combined, four SNPs showed nominal significance of P < 0.05. An intronic SNP (IVS1 + 996G > A) in MSX2, a novel candidate gene, showed the most significant association (P = 0.0030). The association was not replicated in our Taiwanese population; however, there was the same trend with the Japanese population in the allelic frequency distribution of the SNP. In the genes previously reported to have association with AS, only one synonymous SNP, c.963T > G in ANKH, showed a marginal association in the Japanese population (P = 0.045). Tatsuya Furuich and Koichi Maeda contributed equally to this work.     

HSP70 gene polymorphisms in ankylosing spondylitis

Abstract: Despite the strength of the association of ankylosing spondylitis (AS) with HLA-B27, other genetic elements could play a possible role in the pathophysiology of AS. Because of the localization, in the proximity of the HLA-B locus, and the involvement of heat shock proteins (HSP) in the immune response, we analyzed the influence of HSP70 gene polymorphism on the susceptibility to AS. HSP70-1, HSP70-2 and HSP70-hom genotypes were analyzed by PCR-RFLP in patients with AS and in healthy controls. The results obtained in the present study showed that there are not significant differences in the distribution of HSP70-hom genotypes, whereas significant differences in HSP70-1 and HSP70-2 genotypes between AS patients and random controls were found. However, when the distribution of these genotypes were compared in B*27-matched AS patients and controls, the differences disappeared. These data suggest that the polymorphism of HSP70 genes was not independently associated with AS, and that the differences in HSP70-1 and HSP70-2 genotypes among AS patients and controls appears to be due to the linkage disequilibrium between HSP70 alleles and HLA-B*27.     

Association between ERAP1 gene polymorphisms and ankylosing spondylitis susceptibility in Han population

Purposes: The present study was designed to investigate the relationship between endoplasmic reticulum amino peptidase 1 (ERAP1) gene polymorphisms and ankylosing spondylitis (AS) in Han population of Shaanxi province. Methods: 100 AS patients and 100 healthy people were enrolled in present study as case and control groups respectively, and the control group was matched with the case group by age and gender. ERAP1 gene rs27434 and rs7711564 polymorphisms were test by TaqMan probe genotyping method. SHEsis software was used to operate linkage disequilibrium (LD) and haplotype analysis between the two single nucleotide polymorphisms (SNPs). χ² test was employed to compare the differences of the genotype, allele and haplotype frequencies between the case and control groups. Relative risk of AS was represented by odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: In ERAP1 rs27434 and rs7711564 polymorphisms, the frequencies of AA and CC genotypes in case group were significantly higher compared to those in control group (P=0.036; P=0.039), and so were the frequencies of A and C alleles (OR=1.589, 95% CI=1.070-2.359, P=0.028; OR=1.535, 95% CI=1.021-2.308, P=0.050). Linkage disequilibrium test and haplotype analysis of the alleles of the two SNPs showed that the frequency of A-C haplotype was higher in case group than that in control group (P=0.005), which indicated that A-C might be the susceptible haplotype to AS. Conclusions: ERAP1 gene rs27434 and rs7711564 polymorphisms may increase the risk of AS.