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Fine Mapping of the GWAS Loci Identifies SLC35D1 and IL23R As Journal of Dermatological Science 84 (2016) 322–329 Contents lists available at ScienceDirect Journal of Dermatological Science journal homepage: www.jdsjournal.com Fine mapping of the GWAS loci identifies SLC35D1 and IL23R as potential risk genes for leprosy a,d,1 a,1 a a,d a,b Guo-Dong Li , Dong Wang , Deng-Feng Zhang , Qun Xiang , Jia-Qi Feng , c b a,d, Xiao-An Li , Yu-Ye Li , Yong-Gang Yao * a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China b Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China c Yuxi City Center for Disease Control and Prevention, Yuxi, Yunnan 653100, China d Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China A R T I C L E I N F O A B S T R A C T Article history: Background: Previous genome-wide association study (GWAS) identified two new leprosy associated loci Received 26 July 2016 (1p31.3 [rs3762318] and 6q24.3 [rs2275606]). However, there were insufficient validations in Received in revised form 23 September 2016 independent populations. Accepted 28 September 2016 Objective: To validate the association and to map the potentially causal variants/genes underlying the association between the confirmed GWAS hit and leprosy. Keywords: Methods: We genotyped 10 variants in the regions encompassing the two loci in 1110 Han Chinese Leprosy subjects with and without leprosy, followed by expression quantitative trait loci (eQTL), mRNA SLC35D1 expression profiling, and network analysis. We further sequenced the exon region of four genes that were IL23R fi GWAS located in the con rmed GWAS hit region in 80 leprosy patients and 99 individuals without leprosy. À4 Susceptibility Results: We validated the positive association of rs3762318 with multibacillary leprosy (P = 7.5 Â10 ), eQTL whereas the association of rs2275606 could not be validated. eQTL analysis showed that both the GWAS À3 locus rs3762318 and one surrounding positively associated SNP rs2144658 (P = 1.8 Â 10 ) significantly affected the mRNA expression of a nearby gene SLC35D1, which might be involved in metabolism. Moreover, SLC35D1 was differentially expressed in skin tissues of leprosy patients, and the differential expression pattern was consistent among leprosy subtypes. Rare damaging missense variants in IL23R were significantly enriched in leprosy patients. Conclusion: Our results supported the positive association between the GWAS reported rs3762318 and leprosy, and SLC35D1 and IL23R might be the causal genes. ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. 1. Introduction Population-based studies had suggested a positive association between leprosy and host genetic background [3–5]. Many Leprosy (also called Hansen’s disease) is a chronic infectious susceptible genes of leprosy have been identified in the past disease caused by Mycobacterium leprae (M. leprae). This patho- years, such as TLR1, TLR2 [6], IFNG [7], CFH [8], and NOD2 [9]. In a genic bacterium mainly affects the skin, peripheral nerves and recent genome-wide association study (GWAS), Zhang et al. [10] other areas including eyes, nose and testicles [1]. Although the reported two genome-wide significant leprosy susceptible loci, epidemic of leprosy is now under effective control, new cases of with index single nucleotide polymorphisms (SNPs) of rs3762318 leprosy are detected every year, with more than 20,000 cases (chromosome 1p31.3) and rs2275606 (chromosome 6q24.3). worldwide in the past 8 years [2]. Evidently, leprosy remains an However, there was no validation of this result in other Han important public health problem. Chinese populations. In this study, we aimed to validate the association and to fine- map the potential causal variants/genes. We genotyped 10 SNPs * Corresponding author at: Kunming Institute of Zoology, Chinese Academy of covering the two GWAS loci in 1110 subjects, followed by Sciences, Kunming, Yunnan, 650223, China. expression quantitative trait loci (eQTL) and differential expression E-mail addresses: [email protected], [email protected] (Y.-G. Yao). – 1 analyses [11 13]. We validated the association of rs3762318 with These authors contributed equally to this study. http://dx.doi.org/10.1016/j.jdermsci.2016.09.018 0923-1811/ ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. G.-D. Li et al. / Journal of Dermatological Science 84 (2016) 322–329 323 leprosy, and identified SLC35D1 as the potentially causal gene. 2.2. SNP selection, genotyping and sequencing Exome sequencing of four genes that were located in the validated GWAS hit region showed that IL23R had an enrichment of missense Genomic DNA samples from the patients and controls were TM variants with potential pathogenicity in leprosy patients. extracted from whole blood by using the AxyPrep Blood Genomic DNA Miniprep Kit (Axygen, USA). The two SNPs (rs3762318 and rs2275606) identified by the previous GWAS 2. Materials and methods [10] were selected. To fine-map the potential causal variants/genes, another eight SNPs (rs2144658, rs17129664, rs6670134, 2.1. Subjects rs10789224, rs1321157, rs7539625, rs11465817, rs10889677) were selected according to the SNP information in public database (NCBI A total of 527 leprosy patients (279 multibacillary leprosy [MB] dbSNP, http://www.ncbi.nlm.nih.gov/projects/SNP/; HapMap, and 248 paucibacillary leprosy [PB]) and 583 healthy controls were http://hapmap.ncbi.nlm.nih.gov/, phase 3, CHB dataset [19]) under collected from the Yuxi Prefecture, Yunnan Province, Southwest a rational of minor allele frequency (MAF) >5%. Among these China. These subjects had been described in our previous studies selected SNPs, seven (rs2144658, rs6670134, rs17129664, – [8,14 18]. Leprosy was diagnosed on the basis of clinical and rs1321157, rs7539625, rs11465817 and rs10889677) were tag histopathological features and/or bacteriological index (if avail- SNPs, one (rs10789224) was previously reported to be associated able). The healthy controls had no history of leprosy, HIV and with Crohn’s disease [20]. The detailed information of each SNP tuberculosis. Eighty leprosy patients were collected from the was included in Table S1. All these 10 SNPs were genotyped by 1 Wenshan Prefecture, Yunnan Province, and were sequenced for the using the SNaPshot assay (SNaPshot Multiplex System, Life exons of four genes that were located in the GWAS hit region, Technologies, California, USA) following the same procedure together with 99 individuals without leprosy. Informed consents described in our previous studies [14–16,18]. Primers for genotyp- conforming to the tenets of the Declaration of Helsinki were ing were listed in Table S2. The genotyping data were read by two obtained from all participants. This study was approved by the researchers (G.-D.L. and Q.X.) independently by using the institutional review board of the Kunming Institute of Zoology. GeneMarker software [21]. Table 1 The allele and genotype frequencies of 10 SNPs in 527 leprosy patients and 583 healthy controls. SNP Allele/Genotype No. of controls Leprosy vs. CN PB vs. CN MB vs. CN * * * No. P No. P No. P OR (95%CI) rs2144658 Allelic A/G 253/913 194/852 0.07 110/386 0.83 84/466 1.8EÀ03 0.65 (0.50–0.85) Genotype AA/AG/GG 23/207/353 21/152/350 0.07 12/86/150 0.83 9/66/200 2.1EÀ03 – Dominant AA + AG/GG 230/353 173/350 0.03 98/150 0.99 75/200 5.1EÀ04 0.58 (0.42–0.79) Recessive AA/AG + GG 23/560 21/502 0.95 12/236 0.56 9/266 0.628 NS rs17129664 Allelic T/C 136/1030 117/937 0.68 64/432 0.48 53/505 0.178 NS Genotype TT/TC/CC 3/130/450 8/101/418 0.12 5/54/189 0.13 3/47/229 0.125 – Dominant TT + TC/CC 133/450 109/418 0.39 59/189 0.76 50/229 0.100 NS Recessive TT/TC + CC 3/580 8/519 0.09 5/243 0.04 3/276 0.354 NS rs6670134 Allelic T/C 376/790 316/738 0.25 144/352 0.20 172/386 0.553 NS Genotype TT/TC/CC 53/270/260 57/202/268 0.03 26/92/130 0.05 31/110/138 0.151 – Dominant TT + TC/CC 323/260 259/268 0.04 118/130 0.04 141/138 0.180 NS Recessive TT/TC + CC 53/530 57/470 0.34 26/222 0.53 31/248 0.349 NS rs3762318 Allelic C/T 104/1062 65/983 0.02 41/455 0.67 24/528 7.5EÀ04 0.46 (0.29–0.73) Genotype CC/CT/TT 4/96/483 4/57/463 0.03 2/37/209 0.84 2/20/254 1.1EÀ03 – Dominant CC + CT/TT 100/483 61/463 0.01 39/209 0.61 22/254 3.2EÀ04 0.42 (0.26–0.68) Recessive CC/CT + TT 4/579 4/520 0.88 2/246 0.85 2/274 0.950 NS rs10789224 Allelic C/T 385/781 319/735 0.16 148/348 0.20 171/387 0.324 NS Genotype CC/CT/TT 59/267/257 48/223/256 0.32 23/102/123 0.34 25/121/133 0.593 – Dominant CC + CT/TT 326/257 271/256 0.13 125/123 0.14 146/133 0.322 NS Recessive CC/CT + TT 59/524 48/479 0.57 23/225 0.71 25/254 0.591 NS rs1321157 Allelic A/G 438/728 383/671 0.55 187/309 0.96 196/362 0.326 NS Genotype AA/AG/GG 84/270/229 69/245/213 0.80 39/109/100 0.79 30/136/113 0.330 – Dominant AA + AG/GG 354/229 314/213 0.70 148/100 0.78 166/113 0.732 NS Recessive AA/AG + GG 84/499 69/458 0.53 39/209 0.62 30/249 0.138 NS rs7539625 Allelic G/A 534/632 487/567 0.85 245/251 0.18 242/316 0.343 NS Genotype GG/GA/AA 120/294/169 115/257/155 0.83 60/125/63 0.40 55/132/92 0.489 – Dominant GG + GA/AA 414/169 372/155 0.88 185/63 0.29 187/92 0.233 NS Recessive GG/GA + AA 120/463 115/412 0.61 60/188 0.25 55/224 0.766 NS rs11465817 Allelic C/A 492/674 472/582 0.22 231/265 0.10 241/317 0.696 NS Genotype CC/CA/AA 103/286/194 105/262/160 0.47 52/127/69
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