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Association of TNFAIP3 Polymorphism with Rheumatic Heart Disease in Chinese Han Population

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Association of TNFAIP3 Polymorphism with Rheumatic Heart Disease in Chinese Han Population Immunogenetics (2009) 61:739–744 DOI 10.1007/s00251-009-0405-8 ORIGINAL PAPER Association of TNFAIP3 polymorphism with rheumatic heart disease in Chinese Han population Rong Hua & Ji-bin Xu & Jiu-cun Wang & Li Zhu & bing Li & Yang Liu & Sheng-dong Huang & Li Jin & Zhi-yun Xu & Xiao-feng Wang Received: 6 September 2009 /Accepted: 13 October 2009 /Published online: 10 November 2009 # Springer-Verlag 2009 Abstract In a pair-matched case–control study (239 versus (p=0.000). Under a dominant model, CC/CT carriers had 478) conducted in Chinese Han population, we investigated a 0.54-fold reduced risk of RHD (95% confidence interval the association between tumor necrosis factor-α-induced 0.38–0.75, p=0.000) than TT carriers. Therefore, we report protein 3 (TNFAIP3) gene, tumor necrosis factor receptor- a new genetic variant (rs582757) in the TNFAIP3 gene that associated factor 1 (TRAF1) gene, complement component associated with the prevalence of RHD in Chinese Han 5 (C5) gene, and rheumatic heart disease (RHD). We population. Further genetic and functional studies are observed no association with RHD for the five tagging required to identify the etiological variants in linkage single nucleotide polymorphisms (tSNP) in the C5 gene, disequilibrium with this polymorphism. the three tSNPs in the TNFAIP3 gene, or the two tSNPs in the TRAF1 gene. However, we determined that the tSNP, Keywords Rheumatic heart disease . Polymorphism . rs582757, located at intron_5 of the TNFAIP3 gene, Genetics . Association associated with RHD in Chinese Han population. Both the distribution of genotype and allele frequencies differed significantly between case and control subjects (p=0.001 Introduction and p=0.0004, respectively). The minor C allele reduced the risk of RHD with a per-allele odds ratio of 0.57 (0.42– Rheumatic heart disease (RHD) is due to host susceptibility 0.78) for the additive model in univariate analysis following streptococcal infection. In an autoimmune process, epitopes located on human tissue are thought to cross-react Rong Hua and Ji-bin Xu contributed equally to this work. with those present in streptococcus (Kaplan and Meyeserian 1962). The pathogenesis of RHD is complex, and many R. Hua : J.-b. Xu : L. Zhu : b. Li : Y. Liu : S.-d. Huang : Z.-y. Xu (*) molecules (e.g., mannose-binding lectin, VCAM-1) contrib- Department of cardiothoracic surgery, Changhai Hospital, ute to its etiology (Schafranski et al. 2004; Roberts et al. Second Military Medical University, 2001). Only certain individuals can develop this abnormal Shanghai 200433, China immune response triggered by streptococcal infection e-mail: [email protected] (Carapetis et al. 1996), as the host response to streptococcal J.-c. Wang : L. Jin : X.-f. Wang (*) antigens is under genetic control (Guilherme et al. 2005). State Key Laboratory of Genetic Engineering and MOE Key Previous studies have linked several specific genetic variants Laboratory of Contemporary Anthropology, (e.g., HLA class II alleles, TGF-β1 869T allele, MBL2 School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, promoter YA/YA genotype) to the prevalence of rheumatic 220 Handan Rd, fever or RHD (Stanevicha et al. 2003;Chouetal.2004; Shanghai 200433, China Messias Reason et al. 2006; Schafranski et al. 2008). e-mail: [email protected] Tumor necrosis factor-α-induced protein 3 (TNFAIP3) is J.-c. Wang : L. Jin : X.-f. Wang a cytoplasmic zinc finger protein that inhibits nuclear factor CMC Institute of Health Sciences, kappa-B activity and tumor necrosis factor (TNF)-mediated Taizhou 225300 Jiangsu Province, China programmed cell death (Opipari et al. 1990). Mice lacking 740 Immunogenetics (2009) 61:739–744 TNFAIP3 show chronic inflammation (Lee et al. 2000), disease was diagnosed by echocardiography for characteristic consistent with loss of function of this gene playing a role changes. All cases underwent valve replacement. A final in autoimmunity. Tumor necrosis factor receptor–associated pathologic diagnosis was made on all subjects after surgery. factor 1 (TRAF1) and complement component 5 (C5) are For every case subject, two matched control subjects both immune-related genes that are closely involved in the without a history of RHD were recruited among individuals onset and/or perpetuation of the inflammatory process. hospitalized for traumatic diseases in the department of TRAF1 mediates the signal transduction through tumor traumatic surgery and department of general surgery. The necrosis factor-alpha (TNF-α) signaling and activates and control subjects were individually matched with case proliferates T cells (Sabbagh et al. 2006), while C5 plays a subjects according to the following criteria: ethnicity, significant role in vital immunological pathways. Upon gender, age (±5 years), residence area (coming from the activation, C5 is converted into C5a, which acts as a same province), and time of hospitalization (±1 month). chemoattractant for cells including neutrophils (Höpken et Exclusion criteria included inflammation, tumor, genop- al. 1996). Recently, single nucleotide polymorphisms athy, and immune diseases. Informed consent was obtained (SNP) near TNFAIP3 and TRAF1/C5 locus were associated from all subjects enrolled in this study. The study was with rheumatoid arthritis in genome-wide association approved by the human ethics committee of Changhai (GWA) studies in Caucasians (Thomson et al. 2007; Plenge hospital. et al. 2007a, b). Since common autoimmune disorders may have biochemically related pathogenesis in the apparently Selection of tSNPs and genotyping disparate autoimmune disorders (Goodnow 2001), we hypothesized that genetic variants associated with rheuma- Haplotype-tagging SNPs of the TNFAIP3, TRAF1, and C5 toid arthritis discovered in GWA studies may also confer genes were selected using the Chinese Han sample in risk of rheumatic disease. To test this hypothesis, we Beijing, China, available at International HapMap databank conducted a large pair-matched case–control design and a (public data release 21 a/phase II, Jan. 2007; http://www. gene-wide tagging single nucleotide polymorphism (tSNP) hapmap.org/cgi-perl/gbrowse/hapmap_B35/). To identify strategy to investigate the relationship of TNFAIP3, common haplotype tSNPs, eligible SNPs were entered into TRAF1, and C5 with RHD in Chinese Hans. the tagger program that has been implemented in Haplo- view version 3.32 (Barrett et al. 2005). We defined the common variants as those with a heterozygosity of >5% Methods and set a threshold of 0.8 for the linkage disequilibrium (LD) measure r2. We selected five tSNPs in the C5 gene Subjects capturing 45 genotyped alleles, three tSNPs in the TNFAIP3 gene capturing seven genotyped alleles, and Two hundred thirty-nine consecutive Han patients (86 men two tSNPs in the TRAF1 gene capturing 17 genotyped and 153 women, mean age 51.6±11.1 years, range 22–78) alleles. The genomic characteristics of the tSNPs in C5, in the Department of Cardiothoracic Surgery, Changhai TRAF1, and TNFAIP3 are shown in Table 1. Hospital, Second Military Medical University were DNA samples were extracted by standard protocols. recruited between April 2008 and December 2008. Cases Genotyping was conducted by Orchid BioSciences using were recognized according to the Jones’ modified criteria the GenomeLab SNPstream genotyping platform (Beckman (AHA Medical/Scientific Statement 1993). Rheumatic heart Coulter, Fullerton, CA) and its accompanying SNPstream Table 1 Genomic characteristic of selected tSNPs Gene SNP number Chr position Gene position Major/minor Function TNFAIP3 rs719149 42297174 Intron_2 G/A – rs5029935 42299470 Intron_2 A/G – rs582757 42302253 Intron_5 T/C – TRAF1 rs10435843 30989238 Intron_7 G/A rs2239657 30992725 Exon_7 A/G Syn C5 rs12237774 31047176 Exon_34 C/T Syn rs4837805 31067460 Intron_25 A/G rs17611 31090405 Exon_19 T/C Ile/Val rs1017119 31128743 Intron_2 T/C rs10818500 31132088 Intron_1 T/C Immunogenetics (2009) 61:739–744 741 software suite (Bell et al. 2002). The method combines a We did not observe an association between the other two solution-phase multiplex single nucleotide extension (SNE) tSNPs (rs719149 and rs5029935) of the TNFAIP3 gene and with a solid-phase sorting of labeled SNE primers by RHD in Chinese Han subjects (Table 2). We also did not hybridization to a chip that contains 384 4×4 arrays of observe an association between the five tSNPs in the C5 multiplex oligonucleotide tags and four oligonucleotides for gene, or the two tSNPs in the TRAF1 gene, with RHD positive and negative controls. Separation of the 4×4 arrays (Table 2). The overall pair-wise LDs constructed by the during hybridization was achieved with a patented gasket. three tSNPs in the TNFAIP3 gene (r2 ranged from 0 to 0.17, Fig. 1), the five tSNPs of the C5 gene (r2 ranged from Statistical analysis 0 to 0.03), and the two tSNPs in the TRAF1 gene are weak (r2=0.01). There was no haplotype that significantly Deviation from Hardy–Weinberg equilibrium for the genetic increased the risk of RHD in our sample set (data not variants was determined by the chi-square test. Allelic and shown). genotypic frequencies between the RHD subjects and controls were compared using a chi-square test. Comparison of mean ages between case and control group was evaluated by Discussion Student's t test. Logistic regression analysis was performed to estimate odds ratios (ORs) and their corresponding In the present study, we observed the effects of tSNPs in the 95% confidence intervals (CIs), adjusting for the cova- TRAF1, C5, and TNFAIP3 on the development of RHD in riates of gender and age, under the assumption of different a pair-matched case control study. We observed that the genetic models (dominant, additive, and recessive). For derived C allele of the TNFAIP3-rs582757 variant reduced haplotype construction, the genotype data were used to the risk of RHD in Chinese Han population. To the best of estimate intermarker LD by measuring pair-wise D′ and r2 our knowledge, this is the first study correlate TNFAIP3 and by defining LD blocks.
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