ETS1 variants confer susceptibility to ankylosing spondylitis in Han Chinese

Introduction

ETS1 is a negative regulator of the Th17 differentiation gene and plays a central role in the pathogenesis of autoimmune diseases. We aimed to investigate whether polymorphisms in ETS1 confer susceptibility to ankylosing spondylitis (AS) in Han Chinese.

Methods

We selected seven single nucleotide polymorphisms (SNPs) within ETS1 based on HapMap data and previous genome-wide association study. Genotyping involved the TaqMan method in 1,015 patients with AS and 1,132 healthy controls from Shandong Province, and 352 AS patients and 400 healthy controls from Ningxia, a northwest region in China. Gene expression was determined by real-time PCR.

Results

The SNP rs1128334 was strongly associated with AS (odds ratio 1.204, 95% confidence interval 1.06-1.37; P = 0.005). This association was confiexrmed in the Ningxia population (P = 0.015). Carriers of the haplotype TAT for rs12574073, rs1128334 and rs4937333 were associated with increased risk of AS and haplotype CGC with reduced risk as compared to controls. In addition, ETS1 expression was lower in AS patients than controls. The risk allele A of rs1128334 and haplotype A-T of rs1128334 and rs4937333 were associated with decreased expression of ETS1.

Conclusions

Common variants in ETS1 may contribute to AS susceptibility in Han Chinese people.     

Association between promoter variants of interleukin-18 and schizophrenia in a Han Chinese population

An increasing amount of evidence suggests that interleukin-18 (IL-18) plays a pivotal role in the pathophysiology of schizophrenia. However, association between single nucleotide polymorphism of IL-18 and the risk of schizophrenia has not been clarified. This study examined whether two promoter polymorphisms -137 G/C (rs187238) and -607 C/A (rs1946518) of IL-18 were associated with schizophrenia and six clinical symptoms (disorder of perception, thought disorder, disturbance of emotion, disorder of behavior and volition, suicide action, and aggressive action) to provide data for screening high-risk Han Chinese individuals. Three hundred seventy-two schizophrenic patients and 353 healthy controls from a Han Chinese population were examined to assess their genotype and allele frequencies of the two promoter polymorphisms of IL-18. The genotype distributions in both patients and controls were within Hardy-Weinberg equilibrium. No significant differences were observed in the genotype or the allele frequencies of the two single-nucleotide polymorphisms between patients and controls. However, genotype frequencies of -607 C/A showed significant differences between patients and controls in the appearance of perception disorder (χ2 = 6.153, p = 0.046). A significant difference was detected in -137 G/C between patients and controls in the appearance of aggressive action (χ2 = 3.909, p = 0.048). In conclusion, IL-18 gene promoter polymorphisms may not contribute to the susceptibility of schizophrenia in a Han Chinese population, but two single-nucleotide polymorphisms, -137 G/C and -607 C/A, may play a role in the development of perception disorder and aggressive action, respectively.     

Association study of common variations of FBN1 gene and essential hypertension in Han Chinese population

Fibrillin-1 (FBN1) was reported to have impact on the physiological arterial stiffness and vascular remodeling with hypertension of recent years. In the previous study we reported the association of four functional single nucleotide polymorphisms (SNPs) of FBN1 gene and hypertension. Here, we further investigate the association of four tagging SNPs (tagSNPs) which covered remain genetic variation blocks of FBN1 gene with hypertension, blood pressure and efficacy of antihypertensive in a South Han Chinese population. A case–control study including 2,012 hypertension cases and 2,116 controls age- and sex-matched controls was conducted from a community-based population and four candidate tagSNPs of the FBN1 gene were genotyped. Association analysis by multiple logistic regression was conducted for allele, genotype and haplotype and hypertension, blood pressure trait and control status with antihypertensive. General linear model was applied to compare blood pressure levels between genotypes. The association of rs17361868 and hypertension was statistically significant and that was further observed in female, ≥55 years, non-smoking and non-drinking populations (P < 0.05). Significant association of rs668842, rs11635140 and hypertension were observed in <55 years population as well as the later in female and non-smoking populations respectively. Haplotype G-T constructed of rs668842 and rs11635140 was significantly associated with hypertension comparing to reference haplotype A-C (P = 0.022). Normally distributed square root of TGF-β1 (pg/ml) of hypertension cases (148.56 ± 66.46) was significantly higher than that of control (128.52 ± 65.11), P = 0.008. Furthermore, TGF-β1 was significantly correlated with SBP (r = 0.135, P = 0.018) and DBP (r = 0.154, P = 0.007) respectively whereas no statistical difference of blood pressure or TGF-β1 was observed between genotypes. Remarkably, rs17361868 were significantly associated with the status of blood pressure in the patients taking three of the antihypertensive drugs, Zhen Ju Jiang Ya tablets, Jiang Ya tablet and compound reserpine (P < 0.05). The present study provides further association evidence of FBN1 gene polymorphisms and hypertension, antihypertensive efficacy. Further replication of these results via association or prospective studies conducted in other populations is warranted.     

Genetic variants on 17q21 are associated with asthma in a Han Chinese population

A genome-wide study has shown an association between SNPs located on 17q21 and asthma. Such associations have been identified in several populations, but little is known about the Han Chinese population. We conducted a case-control study in a Han Chinese population to investigate the relationship between SNPs located on 17q21 and asthma; 241 asthmatic patients and 212 healthy controls were recruited from the outpatient clinics of the Nanfang Hospital, Guangdong Province, southern China. We genotyped six SNPs (rs8067378, rs8069176, rs2305480, rs4795400, rs12603332, and rs11650680) located on 17q21 with the Sequenom MassARRAY iPLEX platform. For two of these six loci (rs2305480 and rs8067378), there was evidence of association with asthma, and there was a weak association of asthma with rs8069176. We confirm that genetic variants on 17q21 are associated with asthma in the Han Chinese population.     

Evidence for significant overlap between common risk variants for Crohn's disease and ankylosing spondylitis

Background

A multicenter genome-wide association scan for Crohn''s Disease (CD) has recently reported 40 CD susceptibility loci, including 29 novel ones (19 significant and 10 putative). To gain insight into the genetic overlap between CD and ankylosing spondylitis (AS), these markers were tested for association in AS patients.

Principal Findings

Two previously established associations, namely with the MHC and IL23R loci, were confirmed. In addition, rs2872507, which maps to a locus associated with asthma and influences the expression of the ORMDL3 gene in lymphoblastoid cells, showed a significant association with AS (p = 0.03). In gut biopsies of AS and CD patients, ORMDL3 expression was not significantly different from controls and no correlation was found with the rs2872507 genotype (Spearman''s rho: −0.067). The distribution of p-values for the remaining 36 SNPs was significantly skewed towards low p-values unless the top 5 ranked SNPs (ORMDL3, NKX2–3, PTPN2, ICOSLG and MST1) were excluded from the analysis.

Conclusions

Association analysis using risk variants for CD led to the identification of a new risk variant associated with AS (ORMDL3), underscoring a role for ER stress in AS. In addition, two known and five potentially relevant associations were detected, contributing to common susceptibility of CD and AS.     

Association study of AGER gene polymorphism and hypertension in Han Chinese population

Background

Advanced glycation end products (AGEs) are produced by non-enzymatic glycation or glycoxidation of proteins, lipids and nucleic acids. The bond of AGEs and the receptor of AGE (AGER) in a pro-oxidant environment could induce immune and inflammation reaction involved in progress of microvascular disease. Accumulated evidence warrant further study on AGE–AGER pathway and genetic susceptibility to hypertension (HT).

Methods

We designed a two-stage association study to evaluate the association of AGER polymorphism and HT. In stage 1, seven tagSNPs were tested in 524 cases and 531 controls and the significant SNPs (P < 0.05) would enter into stage 2 including 807 cases and 869 controls. Furthermore, joint analysis was performed for all 2731 subjects including 1331 cases and 1400 controls, and meta-analysis was applied to evaluate combined estimations from the subgroups of stage 1 and stage 2.

Results

In stage 1, rs204994 had significant association with HT (P < 0.05) and enter stage 2. Neither joint analysis nor meta-analysis found statistical association of rs204994 with HT after adjusted for the covariates in the whole population. However, further stratification analysis found that rs204994 was significantly associated with HT in < 50 years and ≥ 50 years groups, ORs (95%CI) of dominant model were 1.623 (1.054–2.500) and 0.721 (0.546–0.952) respectively. No significant correlation was found between blood pressure and the polymorphisms of rs204994.

Conclusions

Our data suggests that age might modulate the genetic effects of variation of rs204994 in AGER on HT and further replications in other populations and functional studies should be warranted.     

Association study of CRP gene polymorphism and hypertension in Han Chinese population

Background

Serum C-reactive protein (CRP) and genetic variation of CRP gene have been reported as a strong, independent predictor of myocardial infarction and stroke. But there is rare association evidence of CRP genetic variation and hypertension (HT).

Methods

A community-based case–control study including 1331 cases with HT and 1400 controls was used to evaluate the association of tagSNPs covered CRP gene, CRPP1 gene and 40 kb upstream with HT in a Chinese Han population. Haplotypes and stratification analysis were applied to further evaluate relationships between the screened SNPs and HT and general linear model (GLM) was applied to compare blood pressure levels between genotypes.

Results

In stage 1, five SNPs had positive association with HT (P < 0.05) and entered stage 2 and two SNPs rs876537 and rs10737175 polymorphisms showed significant association with HT in joint sample. Haplotype analysis showed that comparing with common haplotype T–C which was constructed by rs6677719 and rs10737175, haplotype T–T significantly associated with HT after adjusted covariates. Stratification analysis found significant associations of HT for rs876537, rs2808630, rs6677719 and rs10737175 in ≥ 50 years group, rs876537, rs10737175 in female, rs876537 and rs10737175 in non-smoking and non-drinking populations as well as rs2808630 in non-drinking population. Furthermore, quantitative trait analysis indicated significant differences of SBP and DBP between the genotypes of rs10737175, rs876537 and rs2808630 in non-treatment hypertensive cases and control population.

Conclusions

The findings of this study support that CRP gene polymorphisms have significant association with genetic susceptibility of HT and quantitative traits of blood pressure.     

BMP2 variants in the risk of ankylosing spondylitis

The purpose of the study was to explore the genetic effects of bone morphogenetic protein (BMP2) polymorphisms on the susceptibility to ankylosing spondylitis (AS) in Chinese Han population. The case-control study included 120 AS cases and 110 healthy controls. Hardy-Weinberg equilibrium test was performed in control group. BMP2 rs235768 and rs3178250 polymorphisms were analyzed by polymerase chain reaction and direct sequencing. Additionally, the χ² test was used to estimate association strength between BMP2 genetic polymorphisms and AS susceptibility, and the results were assessed via odds ratio (OR) with the corresponding 95% confidence interval (95%CI). Results adjustment was performed using logistic regression analysis. AA, AT, TT genotype and A, T allele frequencies of BMP2 rs235768 polymorphism presented no significant differences between case and control groups (P > .05 for all). TC genotype of rs3178250 polymorphism showed significantly higher in case group than that in control group (P = .048). After adjusting, TC genotype was a risk factor for AS (OR = 2.095; 95%CI = 1.086-4.038; P = .027). BMP2 rs3178250 polymorphism may increase individual susceptibility to AS in Chinese Han population.     

Prevalence of ankylosing spondylitis and HLA-B27 in a North American Indian population: a pilot study.

The value of an epidemiologic approach to the diagnosis of ankylosing spondylitis was assessed in a pilot study of an Amerind population. In 103 adult volunteers aged 20 to 42 years on a Cree reservation lumbar flexion and chest expansion were measured and HLA typing was performed on peripheral blood lymphocytes. Of the 14 subjects with HLA-B27, 2 had radiologic evidence of sacroiliitis but none could be said to have definite ankylosing spondylitis on clinical grounds.     

Association of two variants in the interleukin-6 receptor gene and premature coronary heart disease in a Chinese Han population

Two novel single nucleotide polymorphisms (SNPs; rs7529229 and rs2228145) in the interleukin-6 receptor (IL6R) gene have recently been associated with coronary heart disease (CHD) in a European population. We sought to replicate this finding and to investigate associations of these two SNPs with the severity and clinical phenotypes of premature CHD in a Chinese Han population. A total of 418 patients were studied, including 187 cases with coronary stenosis ≥50 % or acute myocardial infarction (males < 55 years and females < 65 years) and 231 controls without documented CHD. A ligase detection reaction was performed to detect rs7529229 and rs2228145. There were no differences between the controls and premature CHD groups in the frequencies for the three genotypes and alleles of rs7529229 and rs2228145 (all P > 0.05), nor did they differ between the two groups when grouped by gender (all P > 0.05). There were also no associations between these two SNPs and the severity of coronary lesions or clinical phenotypes of premature CHD (all P > 0.05). Our results do not support an association between rs7529229 or rs2228145 with premature CHD in the Chinese Han population. Further studies are warranted to elucidate the role of these two SNPs in the development of atherosclerosis and CHD.     

Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis in a Han Chinese population

The aim of this study was to perform an association study between two single nucleotide polymorphisms (SNPs) rs2910164 G>C and rs3746444 T>C in pre-miRNA (hsa-mir-146a and hsa-mir-499) and rheumatoid arthritis (RA) in the Han Chinese population. 208 Han Chinese patients with RA and 240 healthy controls were recruited in this study. The SNPs was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme linked immunosorbent assay and rheumatoid factor (RF) was measured by rate nephelometry. The genotype frequencies between cases and controls were compared by χ(2) analysis. No significant association between the SNPs (rs2910164 and rs3746444) and RA was observed (P = 0.631 and 0.775, respectively), and the SNPs did not show any association with the RF-positive (P = 0.631 and 0.775, respectively). However, there was a significant difference on the level of anti-CCP antibody between different genotypes in rs3746444 (P = 0.007). The heterozygote CT had significantly higher level of anti-CCP antibody compared with homozygote CC and TT (P = 0.054 and 0.003, respectively). We first investigated the association between the SNPs (rs2910164 G>C and rs3746444 T>C) in the pre-miRNA (hsa-mir-146a and hsa-mir-499) and RA in a Han Chinese population. We did not find a significant association between the SNPs and the susceptibility to RA, while the SNP rs3746444 may affect anti-CCP antibody production.     

No significant association between Fc receptor-like 3 gene polymorphisms and human leukocyte antigen-B27 positive ankylosing spondylitis in Han Chinese population

Ankylosing spondylitis (AS) is a rhematoid arthritis, which is a common autoimmune disease with a complex genetic etiology. Although HLA-B27 has been identified to be associated with AS, a number of other genes may also be involved in the disease. Fc receptor-like 3 (FCRL3) gene has been shown to be associated with rheumatoid arthritis in Japanese population. Here we aim to explore the association FCRL3 gene and susceptibility to human leukocyte antigen (HLA)-B27-positive AS in Han Chinese population. Among 169 AS patients, the frequencies of C and T (rs7522061) in FCRL3 gene were 38.7 and 61.3%, respectively; in 184 controls (HLA-B27-positive), the frequencies of C and T were 38.6 and 61.4%, respectively. The frequencies of alleles and genotype are not of statistically significant difference in two groups (χ² = 0.000, P = 0.983; χ² = 0.099, P = 0.952, respectively),but the distribution of HLA-B27 subtypes are statistically significant difference between cases and controls (χ² = 8.214, P = 0.042). Our data reveal that the FCRL3 gene does not appear associated with susceptibility to HLA-B27-positive AS in Han Chinese population.     

Association of TNF-alpha genetic polymorphisms with hepatocellular carcinoma susceptibility: a case-control study in a Han Chinese population

The single nucleotide polymorphisms (SNPs) within the tumor necrosis factor-a (TNF-a) gene promoter region have been reported to be associated with susceptibility to various types of cancers. A case-control study (126 hepatocellular carcinoma [HCC] patients and 126 normal controls) was conducted to elucidate their possible association with the risk of hepatitis B virus (HBV)-related HCC in a Han Chinese population. TNF-alpha polymorphisms -1031T/C, -863C/A, -857C/T, -308G/A, and -238G/A were genotyped by polymerase chain reaction (PCR) and direct DNA sequencing. Disease associations were analyzed by the chi-square test or Fisher's exact test. When analyzed by overall groups, no significant differences in genotype and allele distributions were observed between the control and cases. However, stratified analysis according to sex showed that the frequency of the homozygous C allele of the -857 polymorphism was lower in female cases than in female controls (62.9% vs. 88.9%, p=0.026). In addition, further haplotype analysis revealed that the TCCGA (-1031/-863/-857/-308/-238) was more frequent in controls than cases (p=0.018; odds ratio = 0.266; 95% confidence interval, 0.083-0.857). These results indicated that the TNF-alpha-857C/T polymorphism may modify HBV-related HCC risk among women, and the haplotype TCCGA (-1031/-863/-857/-308/-238) may account for a decreased susceptibility to HCC development in the Han Chinese population. Additional studies in patients with different ethnic backgrounds are needed to validate these finding and to further explore the genetic pathogenesis of HBV-related HCC.     

Association study of ACE polymorphisms and systemic lupus erythematosus in Northern Chinese Han population

Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. Angiotensin converting enzyme (ACE) gene was reported to have important roles in the development and progression of SLE. In this study, a case-control study was carried out to investigate the effects of seven SNPs and I/D in ACE gene in the development of SLE in Northern China. Seven SNPs including A5466C, T3892C, A240T, C1237T, G2215A, A2350G and C3409T were genotyped by PCR-RFLP method, and I/D was examined by agarose gel electrophoresis followed PCR directly. 314 SLE patients were compared to 320 normal controls in the study. Data were analyzed by SPSS 13.0 and HaploView software. The frequency distribution of SNP A2350G and Alu I/D and five haplotypes (AAAACCCI, AGAACCTD, AAAATCTI, TAAATTTI and TAAATCTI) were demonstrated to be different between case and control groups significantly. Whereas other SNPs and haplotypes had no differences in two cohorts. The results revealed that variations of ACE gene had association with SLE, which indicated ACE gene may play an important role in pathogenesis of SLE in Northern Chinese Han population.     

Association of rs4552569 and rs17095830 single-nucleotide polymorphisms with susceptibility to ankylosing spondylitis in east Asian population: a meta-analysis

Several studies have been conducted in east Asian population to evaluate the association between rs4552569 and rs17095830 single-nucleotide polymorphisms (SNPs) with susceptibility to ankylosing spondylitis (AS), but the outcomes are inconsistent. A summary evaluation of the evidence supporting the associations has not been performed. Therefore, we performed this meta-analysis to access whether the two SNPs are related to ankylosing spondylitis. We systematically searched PubMed, EMBASE, Web of Science and Cochrane Library for papers published up until 3 February 2017, to obtain relevant studies using our research strategy. The allele/genotype frequencies were extracted from each study. We calculated the summary odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations between the two SNPs and AS risk. Four papers including five studies were obtained for this meta-analysis. The included studies suggested that there was no significant association between rs4552569 SNP and AS (C vs T, OR = 1.08, 95% CI: 0.96–1.22, P = 0.20). With regard to rs17095830 SNP, significant association was observed (G vs A, OR = 1.19, 95% CI: 1.06–1.33, P = 0.002). Based on a comprehensive analysis of the currently available evidence, rs4552569 SNP is not significantly associated with the predisposition of AS, while rs17095830 SNP is likely a susceptibility variant for AS in east Asian population. Further studies with different population groups are needed to confirm these potential associations.     

吉林人群强直性脊柱炎6号染色体短臂上的HLA区域遗传易感基因定位研究

为了寻找中国人群中与强直性脊柱炎相关的新的易感基因及其所在位置, 在与强直性脊柱炎强连锁的6 号染色体短臂上的HLA基因区域内选取11个SNPs多态位点, 通过对中国吉林地区79名AS患者和132名正常对照者进行case-control分析, 发现TNF-a -850处TT突变基因型在AS组中的分布高于正常对照组（P=0.027）, 突变型T等位基因在AS组和正常对照组中的分布差异更为显著（P=0.002）。通过多位点之间的连锁不平衡分析发现, LTA基因、TNF-a基因、LST1基因和NCR3基因中的 5个SNPs多态位点之间存在连锁不平衡, 范围是15 kb, 在这5个SNPs多态位点组成的单体型中, TCTTC单体型在AS组和正常对照组中的分布有显著差异（c2=7.406, P=0.0065）,并且该单体型中含有具有统计学意义的TNF-a –850的突变型等位基因T。提示在LTA、TNF-a、NCR3和LST1 这4个基因构成的15 kb范围内可能存在增加AS患病易感性的位点, 可能是TNF-a –850 C→T突变, 也可能是在TNF-a –850附近的其他位点。