How To Identify Ankylosing Spondylitis In Chinese People
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1 ARTHRITIS & RHEUMATISM Vol. 65, No. 7, July 2013, pp DOI /art , American College of Rheumatology BRIEF REPORT High-Throughput Sequencing of IL23R Reveals a Low-Frequency, Nonsynonymous Single-Nucleotide Polymorphism That Is Associated With Ankylosing Spondylitis in a Han Chinese Population Stuart I. Davidson, 1 Lei Jiang, 2 Adrian Cortes, 1 Xin Wu, 2 Evgeny A. Glazov, 1 Yi Zheng, 3 Patrick A. Danoy, 1 Yi Liu, 4 Gethin P. Thomas, 1 Matthew A. Brown, 1 and Huji Xu 2 Objective. Ankylosing spondylitis (AS) is a highly heritable common inflammatory arthritis that targets the spine and sacroiliac joints of the pelvis, causing pain and stiffness and leading eventually to joint fusion. Although previous studies have shown a strong association of IL23R with AS in white Europeans, similar studies in East Asian populations have shown no association with common variants of IL23R, suggesting either that IL23R variants have no role or that rare genetic variants contribute. The present study was undertaken to screen IL23R to identify rare variants associated with AS in Han Chinese. Methods. A 170-kb region containing IL23R and Supported by the Australian National Health and Medical Research Council (grant ). Dr. Davidson s work was supported by the Australian National Health and Medical Research Council (Student Fellowship). Dr. Thomas work was supported by the Lions Medical Research Foundation (Senior Fellowship). Dr. Brown s work was supported by the Australian National Health and Medical Research Council (Principal Research Fellowship ). Dr. Xu s work was funded by the National Natural Science Foundation of China (grants , , and ) and the Science and Technology Commission of Shanghai Municipality (grants 08XD , , and 10JC ). 1 Stuart I. Davidson, PhD, Adrian Cortes, MSc, Evgeny A. Glazov, PhD, Patrick A. Danoy, PhD, Gethin P. Thomas, PhD, Matthew A. Brown, MBBS, FRACP, MD, FAA: University of Queensland Diamantina Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia; 2 Lei Jiang, MD, Xin Wu, MD, PhD, Huji Xu, MD, PhD: Shanghai Changzheng Hospital and The Second Military Medical University, Shanghai, China; 3 Yi Zheng, MD: Beijing Chaoyang Hospital and Beijing Capital Medical University, Beijing, China; 4 Yi Liu, MD, PhD: Chengdu Huaxi Hospital and Huaxi Medical University, Chengdu, China. Drs. Davidson and Jiang contributed equally to this work. Address correspondence to Matthew A. Brown, MBBS, FRACP, MD, FAA, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia ( matt.brown@uq.edu.au); or to Huji Xu, MD, PhD, Department of Rheumatology and Immunology, Changzheng Hospital, The Second Military Medical University, Shanghai , China ( xuhuji@smmu.edu.cn). Submitted for publication August 19, 2012; accepted in revised form April 9, its flanking regions was sequenced in 50 patients with AS and 50 ethnically matched healthy control subjects from a Han Chinese population. In addition, the 30-kb region of peak association in white Europeans was sequenced in 650 patients with AS and 1,300 healthy controls. Validation genotyping was undertaken in 846 patients with AS and 1,308 healthy controls. Results. We identified 1,047 variants, of which 729 were not found in the dbsnp genomic build 130. Several potentially functional rare variants in IL23R were identified, including one nonsynonomous single-nucleotide polymorphism (nssnp), Gly 149 Arg (position GA on chromosome 1). Validation genotyping showed that the Gly 149 Arg variant was associated with AS (odds ratio 0.61, P ). Conclusion. This is the first study to implicate rare IL23R variants in the pathogenesis of AS. The results identified a low-frequency nssnp with predicted loss-of-function effects that was protectively associated with AS in Han Chinese, suggesting that decreased function of the interleukin-23 (IL-23) receptor protects against AS. These findings further support the notion that IL-23 signaling has an important role in the pathogenesis of AS. Ankylosing spondylitis (AS) is a common inflammatory arthritis with an overall prevalence in Han Chinese populations of % (1) and with disease susceptibility largely genetically determined. The primary AS-associated gene is the class I major histocompatibility complex (MHC) HLA B27 gene (B27), which is found in 80% of Chinese patients with AS (2). However, only 1 5% of B27 carriers develop AS, suggesting that there are other genetic factors involved in disease modification (3). In white European populations, 13 non-mhc loci have been associated with AS (4), and we recently confirmed a number of these loci, including ERAP1, 1747
2 1748 DAVIDSON ET AL TNFRSF1A, STAT3, and the 2p15 gene desert region, in Han Chinese (5,6). Interestingly, no association was found with the common variants of the interleukin-23 receptor (IL-23R) gene (IL23R), one of the genes most strongly associated with AS in white Europeans. IL23R encodes one subunit of the heterodimeric receptor for the cytokine IL-23, and is critical in the regulation of IL-17 producing T cells, including Th17 cells (7) and / T cells (8). Increased levels of both Th17 cells (9) and IL-23R positive, IL-17 producing / T cells (10) have been demonstrated in patients with AS. It is possible that IL23R plays no role in the susceptibility to AS in Han Chinese, and that the association observed in populations of white European descent is ethnicity specific. Alternatively, it is possible that rare or lowfrequency variants in IL23R that are associated with AS might not have been detected. Using a pooled polymerase chain reaction (PCR) approach that has been previously successful in identifying low-frequency IL23R coding variants conferring protection against inflammatory bowel disease (IBD) (11), we carried out a high-throughput sequencing study to identify novel or rare variants in IL23R that may be associated with AS in a Han Chinese population. A number of single-nucleotide polymorphisms (SNPs) were identified from the sequencing and from genotyping in a larger validation cohort, thus demonstrating a novel association of IL23R with AS in Han Chinese. PATIENTS AND METHODS Subjects. Unrelated patients with AS (n 1,180) were recruited from hospital outpatient clinics in Shanghai, Beijing, and Nanjing, China. The diagnosis of AS was confirmed by rheumatologists. Each patient met the modified New York criteria for AS (12), with sacroiliitis confirmed by radiography. Unrelated, ethnically matched healthy blood donors (n 1,680) were recruited from the Shanghai Blood Bank as controls. The study protocol was approved by the Second Military Medical University research ethics committee, and all patients provided written informed consent. Sequencing of pooled PCR products. Primer sets were designed for overlapping 5-kb and 10-kb PCR amplicons covering a 170-kb region (from positions to on chromosome 1) containing IL23R and its 35-kb flanking regions, including the IL23R AS association region in white Europeans, with flanking boundaries determined on the basis of historic recombination rates obtained in healthy controls to cover the region containing IL23R and the nearby areas bordered by recombination hotspots. The 5-kb amplicons were amplified using Kapa HiFi DNA polymerase (Kapa Biosystems), and 10-kb amplicons were amplified using Takara LA Taq (Takara Bio). PCRs covering the 170-kb region were performed on DNA from 50 patients with AS and 50 healthy controls. PCRs covering the region from positions to on chromosome 1, which represents the 30-kb region of peak association with AS that was previously identified (13), were performed in 650 patients with AS and 1,300 healthy controls. Two pools of PCR products covering the 170-kb region were made from the 50 patients with AS and 50 healthy controls. The PCR amplicons from the 30-kb region were pooled into one pool of 100 patients with AS, one pool of 650 patients with AS, one pool of 100 healthy controls, and two pools of 650 healthy controls, and sequencing was performed using an Illumina GAII sequencer, with 58-bp paired-end sequencing. Genotyping. Genotyping was performed using a Taq- Man OpenArray platform (Applied Biosystems) according to the manufacturer s protocol, and genotype calls were made using Applied Biosystems OpenArray SNP Genotyping Analysis software (version 1.0.3). Thirty custom genotyping assays were designed. These assays targeted all potentially functional SNPs not found in the dbsnp genomic build 130 ( and identified by sequencing, as well as the SNPs identified as showing the strongest association in the 30-kb region. For a number of these SNPs, assays were unable to be designed because the variants lay in regions of repetitive or low-complexity DNA, and therefore additional SNPs showing less association were selected. Statistical analysis. Quality assessment of base calling and sequence reads was performed using Illumina Data Analysis Pipeline software (version 1.6), with alignment to the reference human genome (NCBI 36 assembly) using a Burrows Wheeler alignment tool (14). Read quality scores were recalibrated using the Genome Analysis Toolkit (15). Identification of single-nucleotide variants was performed using the Syzygy package (16), with annotation using Ensembl Perl API and custom scripts. Association analysis for the validation genotyping was performed using the Cochran-Armitage test for trend, with data analyzed using Plink software version 1.03 ( mgh.harvard.edu/ purcell/plink/). SNPs with missingness rates of 0.1 were excluded, and an exact test for Hardy- Weinberg equilibrium was performed in controls, excluding markers with P values less than Analysis of accumulation of rare variants in IL23R was performed using the GRANVIL (Gene- or Region-based Analysis of Variants of Intermediate and Low Frequency) approach (17), which uses a likelihood ratio test based on the proportion of rare variants for which an individual carries minor alleles, and the identified variants with a minor allele frequency (MAF) of less than 0.05 in the verification genotyping were analyzed. RESULTS DNA samples from a total of 50 Han Chinese patients with AS and 50 healthy controls were pooled and sequenced across the 170-kb region containing IL23R and the 35-kb flanking regions. In addition, the 30-kb region of peak association identified in white European patients with AS was sequenced in 650 Han Chinese patients with AS and 1,300 healthy controls. The number of base reads per pool was
3 HIGH-THROUGHPUT SEQUENCING OF IL23R IN HAN CHINESE WITH AS 1749 Table 1. Potentially functional single-nucleotide polymorphisms (SNPs) not found in the dbsnp genome build 130 and identified in the sequencing of IL23R* Minor allele frequency Chromosome position Alleles SNP type Annotation Average sequencing coverage, measured as reads per base per sample, was for the 170-kb region 50-sample pools, while it was for the 30-kb region 100-sample pools and for the 30-kb region 650-sample pools. In total, 1,047 SNPs were identified with a high confidence of call rates, with 729 of these SNPs being novel variants not found in the dbsnp genomic build 130. After all variants present in the dbsnp genomic build 130 were excluded, there remained 10 potentially biologically functional variants that were predicted to affect the translated IL23R sequence or were located in regions of the IL23R gene likely to control IL23R transcription or messenger RNA stability (i.e., the 5 untranslated region [5 -UTR] or 3 -UTR). These variants included the nonsynonymous SNP (nssnp) Gly 149 Arg (position GA on chromosome 1), a splice site variant, a 5 -UTR variant, and 7 3 -UTR variants (Table 1). In the 30-kb region that was sequenced in 650 patients with AS and 1,300 healthy controls, association analysis was performed based on the MAF values obtained in the sequencing. The intronic SNP CT (on chromosome 1) was identified as showing a peak association with AS (P ). In addition, significant associations with AS at a level of P 0.01 were observed for a further 4 rare variants and for 1 common variant, with 11 more variants showing associations at a level of P 0.05 (Table 2). SNPs were selected for validation genotyping on the basis of being potentially biologically functional and absent from the dbsnp genomic build 130, or showing potential association in the sequencing of the 30-kb region. Validation genotyping was performed on DNA AS patients samples from 846 patients with AS and 1,308 healthy controls. Of the 30 SNPs genotyped, 26 passed quality control. Samples with low genotyping rates (genotyping 90% completed) were excluded, leaving sample sizes of 800 patients with AS and 1,228 healthy controls for validation genotyping. Two SNPs were significantly associated with AS at a level of P 0.05 (Table 3). Peak association in the verification genotyping was observed with the Gly 149 Arg nssnp (odds ratio [OR] 0.61, P ). A further 5 rare variants showed an association with AS at a significance of P 0.05, including the intronic SNP TG (on chromosome 1) (OR 0.38, P 0.017) and the 3 -UTR variant TC (on chromosome 1) (P 0.11). An enrichment of rare variants in IL23R was observed in healthy controls, as the likelihood of having a rare variant of IL23R was found to be significantly different when compared to AS patients (P 0.011, by GRANVIL likelihood ratio test). Healthy controls GC 5 -UTR NA GA nssnp Gly 149 Arg CT Splice site NA CT 3 -UTR NA TG 3 -UTR NA GA 3 -UTR NA TA 3 -UTR NA GT 3 -UTR NA GA 3 -UTR NA GD 3 -UTR NA *AS ankylosing spondylitis; 5 -UTR 5 -untranslated region; NA not applicable; nssnp nonsynonomous SNP. DISCUSSION Utilizing a targeted high-throughput sequencing approach, we identified the Gly 149 Arg variant of IL23R as being protective against AS in Han Chinese. This is the first IL23R variant associated with AS in a population of non white European descent. Peak association with AS was observed with an nssnp at on chromosome 1, where a G-to-A polymorphism causes the Gly 149 Arg protein change. This amino acid change has been predicted to be damaging to protein function in studies using the prediction algorithms SIFT (18) and PolyPhen-2 (19). This suggests that the minor allele protects against AS by
4 1750 DAVIDSON ET AL Table 2. Single-nucleotide polymorphisms (SNPs) identified as showing an association with ankylosing spondylitis (AS) in Han Chinese in the resequencing of IL23R* Minor allele frequency Chromosome position Alleles SNP type Annotation diminishing IL-23 signaling. This highly conserved residue is found in the extracellular cytokine receptor domain I of IL-23R, but it is unclear how changes at this Table 3. AS patients Healthy controls CT Intronic NA CT Intronic NA TG Intronic rs GA Intronic NA TC Intronic NA CT Intronic NA CG Intronic rs GA Intronic NA AC Intronic NA CT Intronic NA AC Intronic rs CT 3 -UTR NA AG Intronic NA CT Intronic NA CA Intronic NA GA Intronic rs AG Intronic rs *NA not applicable; 3 -UTR 3 -untranslated region. Validation genotyping association results* residue may affect receptor function. This is in contrast to the effects of rs , the primary AS-associated SNP in white European populations, which causes the Marker Allele 1 Allele 2 Type No. affected/total No. unaffected/total 2 P OR (95% CI) A G nssnp 47/1, /2, ( ) T G Intronic 7/1,589 28/2, ( ) A G Intronic 5/1,589 18/2, ( ) T G Intronic 472/1, /1, ( ) T C 3 -UTR 0/1,592 4/2, C A Intronic 18/1,570 44/2, ( ) G T Intronic 0/1,560 4/2, A G Downstream 12/1,582 10/2, ( ) G A Intronic 470/1, /1, ( ) G A Downstream 412/1, /1, ( ) C A Intronic 466/1, /1, ( ) G A Intronic 1/1,579 6/2, ( ) T C Intronic 20/1,568 22/2, ( ) A C Intronic 50/1,528 93/2, ( ) C G 5 -UTR 3/1,595 9/2, ( ) G C Intronic 50/1,542 91/2, ( ) G C Intronic 5/1,589 4/2, ( ) A G Intronic 429/1, /1, ( ) C A Intronic 53/1,539 95/2, ( ) T C Intronic 50/1,538 89/2, ( ) A G Intronic 0/1,592 1/2, C T Intronic 4/1,592 10/2, ( ) A G Intronic 50/1,544 87/2, ( ) C G Intronic 4/1,588 8/2, ( ) G C Intronic 5/1,587 6/2, ( ) T C Intronic 6/1,588 9/2, ( ) P *OR odds ratio; 95% CI 95% confidence interval; nssnp nonsynonomous single-nucleotide polymorphism; 3 -UTR 3 -untranslated region.
5 HIGH-THROUGHPUT SEQUENCING OF IL23R IN HAN CHINESE WITH AS 1751 Arg 381 Gln change at a highly conserved residue in the intracellular domain of IL-23R, in the region where JAK-2 binds, and is also in contrast to the effects of the secondary associated SNP rs , which is found upstream of IL23R. The Arg 381 Gln variant is also predicted to be damaging to protein function, as assessed by the SIFT and PolyPhen-2 algorithms, and decreases IL-23 signaling, which in turn reduces IL-23 induced CD4 and CD8 T cell responses (20,21). Whether the (chromosome 1) variant will also induce such a functional change remains to be investigated. Although the disease-associated IL23R variants observed in white European and Han Chinese populations are situated in different domains of IL23R, the observed MAF values for the associated variants in each population were very similar (MAFs of and for rs in patients with AS and healthy controls, respectively, among white Europeans, compared to MAFs of 0.03 and 0.05 for GA [chromosome 1] in patients with AS and healthy controls, respectively, among Han Chinese), as were the ORs (OR of 0.53, 95% confidence interval for the SNP in white Europeans, compared to an OR of 0.61, 95% confidence interval for the variant in Han Chinese) and attributable risk fractions (2.61% for rs in white Europeans, compared to 1.86% for [chromosome 1] in Han Chinese) (13). This suggests that the different variants associated in each population are making a similar contribution to disease susceptibility. The identification of the Gly 149 Arg variant of IL23R as being associated with AS in Han Chinese in the present study further implicates the IL-23 signaling pathway in susceptibility to AS in Chinese populations, with IL23R joining the previously identified STAT3 as a novel IL-23 signaling pathway gene (6). The association of IL-23 signaling cascade genes with AS across ethnically distinct populations highlights the importance of this pathway in disease susceptibility and pathogenesis, and further promotes this pathway as a potential therapeutic target. IL23R is strongly associated with IBD in white European populations; however, no association has been observed in East Asian populations (22). This lack of association has been thought to be due to the lack of polymorphism of rs in East Asians, whereas this SNP is the main causal variant for both IBD and AS in white Europeans. Given the close clinical relationship between AS and IBD, the Gly 149 Arg variant may also be associated with IBD in East Asians. Recent studies investigating rare, nonsynonymous IL23R variants in IBD in white European populations have shown an association with the Gly 149 Arg variant (11,23). These studies revealed that the Gly 149 Arg variant has a very low MAF in white European populations (MAF in IBD patients and in healthy controls), and therefore this variant confers a very small attributable risk in this population. The contribution of the Gly 149 Arg variant to AS is, however, much greater in East Asians, owing to the much higher MAF; therefore, investigating this variant in East Asian patients with IBD may reveal further association. The Gly 149 Arg variant of IL23R was previously identified in a study investigating Crohn s disease susceptibility in a Chinese population (24), in which IL23R exons were sequenced in 50 patients and 50 healthy controls. The MAFs were 0.04 and 0.02 in patients and healthy controls, respectively, and no association with Crohn s disease was observed, probably because of the very small sample sizes. The discovery cohort sequenced in the present study also comprised 50 patients and 50 healthy controls; however, we performed validation genotyping in a much larger replication cohort, and the results generated suggest that further investigation of the Gly 149 Arg variant in IBD in a Chinese population may be valuable. In summary, this study identified a low-frequency nssnp in IL23R that is protective against AS. This identified association highlights the importance of the IL-23 signaling pathway in the susceptibility to AS in both East Asian and white Europeans, and suggests that IL-17 producing immune cells have a role in AS susceptibility. This study also demonstrates the value of performing deep-sequencing studies to identify rare or low-frequency variants associated with susceptibility to complex diseases, and suggests that the use of this approach may be informative for pinpointing causal variants in candidate genes. ACKNOWLEDGMENTS We would like to thank all participating patients with AS and healthy individuals who provided the DNA samples and clinical information necessary for this study. The assiduous DNA extraction work provided by our colleagues Drs. Zhongwei Wang, Ting Li, Yiping Lin, and Chao Wu is also greatly appreciated, as is the assistance with DNA preparation for sequencing and genotyping provided by Johanna Hadler, Rebecca Foale, Katherine Cremin, Ran Duan, and Poh-Lynn Low. In addition, we acknowledge the contribution of Marina Donskoi to the design and performance of the sequencing component of the study.
6 1752 DAVIDSON ET AL AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Drs. Brown and Xu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Davidson, Jiang, Glazov, Danoy, Thomas, Brown, Xu. Acquisition of data. Davidson, Jiang, Wu, Glazov, Zheng, Liu, Brown, Xu. Analysis and interpretation of data. Davidson, Jiang, Cortes, Brown, Xu. REFERENCES 1. Zeng Q, Chen R, Darmawan J, Xiao Z, Chen S, Wigley R, et al. Rheumatic diseases in China. Arthritis Res Ther 2008;10:R Liu Y, Jiang L, Cai Q, Danoy P, Barnardo MC, Brown MA, et al. Predominant association of HLA-B*2704 with ankylosing spondylitis in Chinese Han patients. Tissue Antigens 2010;75: Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL, et al. 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Nat Immunol 2007;8: Awasthi A, Riol-Blanco L, Jager A, Korn T, Pot C, Galileos G, et al. IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 2009;182: Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum 2008;58: Kenna TJ, Davidson SI, Duan R, Bradbury LA, McFarlane J, Smith M, et al. Enrichment of circulating interleukin-17 secreting interleukin-23 receptor positive / T cells in patients with active ankylosing spondylitis. Arthritis Rheum 2012;64: Momozawa Y, Mni M, Nakamura K, Coppieters W, Almer S, Amininejad L, et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat Genet 2011;43: Van der Linden S, Valkenburg HA, Cats A. 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