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Common Variants at the Promoter Region of the Apomconfer a Risk Of

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Common Variants at the Promoter Region of the Apomconfer a Risk Of EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 11, 613-621, November 2011 Common variants at the promoter region of the APOM confer a risk of rheumatoid arthritis Hae-Jin Hu1,2*, Eun-Heui Jin3*, 711 controls. Through GWAS, we identified a novel Seon-Hee Yim1,4, So-Young Yang1,2, SNP associated with RA at the APOM gene in the MHC Seung-Hyun Jung1,2, Seung-Hun Shin1,2, class III region on 6p21.33 (rs805297, odds ratio (OR) × -7 Wan-Uk Kim5, Seung-Cheol Shim6, = 2.28, P =5.20 10 ). Three more polymorphisms were identified at the promoter region of the APOM by Tai-Gyu Kim2 and Yeun-Jun Chung1,2,7 the re-sequencing. For the replication, we genotyped the four SNP loci in the independent case-control set. 1Integrated Research Center for Genome Polymorphism The association of rs805297 identified by GWAS was 2Department of Microbiology successfully replicated (OR = 1.40, P =6.65× 10-5). The Catholic University of Korea School of Medicine The association became more significant in the com- Seoul 137-701, Korea 3Genome Research Center for Immune Disorders bined analysis of discovery and replication sets (OR = × -10 School of Medicine 1.56, P =2.73 10 ). The individuals with the Wonkwang University rs805297 risk allele (A) at the promoter region showed Iksan 570-749, Korea a significantly lower level of APOM expression com- 4Department of Medical Humanities and Social Sciences pared with those with the protective allele (C) 5Department of Internal Medicine homozygote. In the logistic regressions by the pheno- The Catholic University of Korea School of Medicine type status, the homozygote risk genotype (A/A) con- Seoul 137-701, Korea sistently showed higher ORs than the heterozygote 6Division of Rheumatology one (A/C) for the phenotype-positive RAs. These re- Department of Internal Medicine sults indicate that APOM promoter polymorphisms are Eulji Medi-Bio Research Institute significantly associated with the susceptibility to RA. Eulji University School of Medicine Daejeon 301-746, Korea Keywords: APOM protein, human; autoimmune dis- 7Corresponding author: Tel, 82-2-2258-7343; eases; genome-wide association study; polymorphism, Fax, 82-2-537-0572; E-mail, [email protected] single nucleotide; rheumatoid arthritis *These authors contributed equally to this work. http://dx.doi.org/10.3858/emm.2011.43.11.068 Introduction Accepted 12 August 2011 Available Online 16 August 2011 Rheumatoid arthritis (RA) is a common systemic autoimmune disease that is characterized by Abbreviations: APOM, apolipoprotein M; GWAS, genome-wide chronic inflammation of the synovium, which can association study; RA, rheumatoid arthritis; SNP, single nucleotide lead to progressive joint destruction. It is a complex polymorphism disease that is caused by multiple factors such as genetic, environmental, and hormonal contributions (Firestein, 2003). While the exact pathogenesis of Abstract RA is still unknown, multiple lines of evidence such as a higher concordance rate in monozygotic twins Although the genetic component in the etiology of than in dizygotic twins and the higher risk in rheumatoid arthritis (RA) has been consistently sug- siblings of patients compared with that in a general population (MacGregor et al., 2000; Goronzy and gested, many novel genetic loci remain to uncover. To Weyand, 2009), suggest the genetic component in identify RA risk loci, we performed a genome-wide as- the etiology of this disease. sociation study (GWAS) with 100 RA cases and 600 As for the efforts to understand the genetic controls using Affymetrix SNP array 5.0. The candidate etiology of RA, various genome-wide association risk locus (APOM gene) was re-sequenced to discover studies (GWAS) and meta-analyses have identified novel promoter and coding variants in a group of the a number of risk loci including HLA-DRB1, PTPN22, subjects. Replication was performed with the in- CD40, STAT4, OLIG3, TNFAIP3, TNFRSF14, CTLA4, dependent case-control set comprising of 578 RAs and CCL2, PADI4 and TRAF1/C5 (Plenge et al., 2007a, 614 Exp. Mol. Med. Vol. 43(11), 613-621, 2011 2007b; WTCCC, 2007; Julià et al., 2008; Raychaudhuri et al., 2008; Gregersen et al., 2009; Kochi et al., 2010; Stahl et al., 2010). Some of the significant SNPs in the candidate RA-associated genes have shown consistent significance across diverse ethnic groups, while some other SNPs have not. For example, the significant SNPs in HLA-DRB1, STAT4, OLIG3 and TNFAIP3 identified in Caucasians were consistently replicated in the Japanese population, while PTPN22 and CD40 were not replicated in Asians (Kochi et al., 2010; Stahl et al., 2010). When Lee et al examined whether the known genetic variants at 4q27, 6q23, CCL21, TRAF1/C5 and CD40 identified in Caucasians were also associated with RA in Koreans, those loci did not show any significant associations and some of them were not even polymorphic (Lee et al., 2009). Even within a similar ethnic group, the association of some candidate genetic markers to RA was differently reported. For example, polymorphisms in OLIG3 or TNFAIP3 genes were reported to be significantly associated with RA in Japanese (Kochi et al., 2010) but not in Korean population (Han et al., 2009). Recent meta-analysis of GWAS also suggested that only a small amount of the genetic component can be explained by the known RA risk alleles (Raychaudhuri et al., 2008; Stahl et al., Figure 1. GWAS results and plots in the region around APOM. (A) Manhattan plot displaying the -log10 (P-value) of SNPs in the GWAS for 2010). These data imply that additional risk alleles 100 Korean RA cases and 600 controls. APOM region is marked. (B) The remain to be identified. -log10 (P-value) of SNPs around APOM region. SNPs are represented Based on this inference, we attempted to find with diamond dots and the most strongly associated SNP (rs805297) 2 new risk loci for RA in Korean population. For this was marked with the largest diamond. The strength of LD relationship (r ) between rs805297 and other SNPs is presented with red color intensities purpose, we performed a three step analysis. First, based on the JPT + CHB Hapmap data. The background recombination we identified the risk loci using GWAS analysis rate curve is drawn with the JPT + CHB Hapmap data (light blue curve). with Affymetrix SNP array 5.0 in the discovery set The location and orientation of APOM and neighboring genes are illus- 2 that consisted of 100 RA patients and 600 healthy trated under the -log10 plot. (C) LD map of the APOM region. The r controls. Second, after selecting the candidate risk based LD map is drawn with the genotype data of the RA cases and con- trols using Golden helix SVS software version 7.3.0. loci, we screened the SNPs in the promoter region and in the entire exons, including the exon-intron boundaries of the candidate gene, by PCR-direct check whether the process of SNP quality control sequencing. Third, we performed a replication study effectively removed the false-associations, we with independent Korean samples of 578 RA patients drew the Quantile-Quantile plot (Q-Q plot) based and 711 healthy controls to verify the association. on the P values from a logistic regression analysis Haplotype analysis, qRT-PCT and reporter assay (Supplemental Data Figure S1). Since we did not followed to refine our findings of the candidate observe any notable divergence from the null markers. hypothesis in the plot with the genomic inflation factor (λGC) = 1.03, we performed the GWAS with the 300,909 SNPs (Figure 1A). Eight SNPs were Results found to be significant with P values under 10-5 (unadjusted) (Table 1). Since it is thought that a Genome-wide scan for RA SNP tends to be false positive if it is the solely To identify the RA risk loci, we first performed significant SNP around the region, we examined whole-genome SNP genotyping for 100 RA cases the P-value profiles of the neighboring SNPs and 600 normal controls using Affymetrix Human around the eight significant SNPs to minimize false SNP array 5.0. After filtering the SNPs based on positive results and improve the efficiency of the threshold cutoff as described in the Methods replication (Supplemental Data Figure S2). Based section, we obtained 300,909 reliable SNPs. To on our strategy, we chose the one locus around APOM promoter SNP associated with RA 615 Table 1. Results of genome-wide association study for RA in Korean population Allele Genotype count † Major/ ‡ SNP* Locus Position Gene Case Control MAF values OR (95% CI) P value minor (1/2) 11 12 22 11 12 22 RA Control rs17027492 12q23.1 96741703 - C/A 92 0 8 263 266 46 0.08 0.31 0.19 (0.11-0.32) 1.02 × 10-9 rs6081341 20p11.23 18668419 DTD1 G/A 10 67 14 256 284 54 0.52 0.33 2.59 (1.81-3.70) 1.62 × 10-7 rs805297 6p21.33 31730585 APOM C/A 21 51 28 238 272 60 0.53 0.34 2.28 (1.65-3.14) 5.20 × 10-7 rs12642867 4q35.2 190329271 - T/C 73 0 19 509 63 7 0.21 0.07 2.51 (1.75-3.61) 7.05 × 10-7 rs11228951 11q12.1 56734205 - C/G 57 24 2 227 288 68 0.17 0.36 0.34 (0.22-0.52) 1.15 × 10-6 rs2241520 4q31.22 147218521 - T/C 36 51 13 335 234 20 0.38 0.23 2.28 (0.61-3.22) 3.32 × 10-6 rs1445289 6q27 166437591 - G/A 40 51 1 167 298 130 0.29 0.47 0.44 (0.31-0.63) 5.11 × 10-6 rs7114828 11q21 95357255 MAML2 G/A 55 26 5 489 93 6 0.21 0.09 2.59 (1.71-3.94) 8.03 × 10-6 *Significant SNPs with the smallest P-values were presented.
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