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Exomic Sequencing of Immune-Related Genes Reveals Novel Candidate Variants Associated with Alopecia Universalis

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Exomic Sequencing of Immune-Related Genes Reveals Novel Candidate Variants Associated with Alopecia Universalis Exomic Sequencing of Immune-Related Genes Reveals Novel Candidate Variants Associated with Alopecia Universalis Seungbok Lee1,2., Seung Hwan Paik3., Hyun-Jin Kim1,2, Hyeong Ho Ryu3, Soeun Cha1, Seong Jin Jo3, Hee Chul Eun3,4,5, Jeong-Sun Seo1,2,6,7,8, Jong-Il Kim1,2,6,7*, Oh Sang Kwon3,4,5* 1 Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea, 2 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea, 3 Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea, 4 Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea, 5 Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, Korea, 6 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea, 7 Psoma Therapeutics Inc., Seoul, Korea, 8 Macrogen Inc., Seoul, Korea Abstract Alopecia areata (AA) is a common autoimmune disorder mostly presented as round patches of hair loss and subclassified into alopecia totalis/alopecia universalis (AT/AU) based on the area of alopecia. Although AA is relatively common, only 5% of AA patients progress to AT/AU, which affect the whole scalp and whole body respectively. To determine genetic determinants of this orphan disease, we undertook whole-exome sequencing of 6 samples from AU patients, and 26 variants in immune-related genes were selected as candidates. When an additional 14 AU samples were genotyped for these candidates, 6 of them remained at the level of significance in comparison with 155 Asian controls (p,1.9261023). Linkage disequilibrium was observed between some of the most significant SNPs, including rs41559420 of HLA-DRB5 (p,0.001, OR 44.57) and rs28362679 of BTNL2 (p,0.001, OR 30.21). While BTNL2 was reported as a general susceptibility gene of AA previously, HLA-DRB5 has not been implicated in AA. In addition, we found several genetic variants in novel genes (HLA-DMB, TLR1, and PMS2) and discovered an additional locus on HLA-A, a known susceptibility gene of AA. This study provides further evidence for the association of previously reported genes with AA and novel findings such as HLA- DRB5, which might represent a hidden culprit gene for AU. Citation: Lee S, Paik SH, Kim H-J, Ryu HH, Cha S, et al. (2013) Exomic Sequencing of Immune-Related Genes Reveals Novel Candidate Variants Associated with Alopecia Universalis. PLoS ONE 8(1): e53613. doi:10.1371/journal.pone.0053613 Editor: Amanda Ewart Toland, Ohio State University Medical Center, United States of America Received August 16, 2012; Accepted November 30, 2012; Published January 11, 2013 Copyright: ß 2013 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was partly supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (Green Cosmetic Research Center, A092055) and conducted under a research agreement with AmorePacific Corporation, Republic of Korea. This work was partly supported by the National Research Foundation of Korea [NRF] grant funded by the Korea government [MESF] [No. 2011-0030738]. The funders had norole in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: JS is a PLOS ONE Editorial Board member. JS is a consultant for Macrogen and Psoma Therapeutics, and JK is a consultant for Psoma Therapeutics. This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials. * E-mail: [email protected] (JK); [email protected] (OSK) . These authors contributed equally to this work. Introduction therapies, further supporting an autoimmune basis for the disease [6]. In addition, several genetic studies on AA have shown that Alopecia areata (AA) is characterized by autoimmune-mediated immune factors are key genetic components of AA. Early patchy hair loss. The alopetic patches can be multiple and coalesce association studies with selected candidate genes revealed that to diffuse hair loss over the scalp, even the whole body. Severe AA or AT/AU is associated with several immune-related genes forms of AA are named based on the body area affected by including HLA-DQB1, MICA, PTPN22, IL1RN, AIRE, and alopecia and include alopecia totalis (AT; affecting the whole TRAF1/C5 [7–14]. Furthermore, HLA-DQB1, MICA, PTPN22, scalp) and alopecia universalis (AU; affecting the entire body). IL1RN, and TRAF1/C5 were found to influence disease severity Although AA is fairly common, with the life-time risk being 1.7% [7,9–11,13,14]. Genetic susceptibility loci harboring murine [1], progression to AT/AU is rare and only reported in 5% of AA homologues of HLA have also been discovered in a C3H/HeJ patients [2]. Clinically, the extent of hair loss is the most important mouse model of AA [15]. In addition, recent genome-wide linkage prognostic factor in AA [3]. Although more than 50% of classic and association studies have identified several susceptibility loci AA patients recover without treatment [4], less than 10% of near, or within, genes related to autoimmunity, such as MICA and patients with AT/AU recover fully [5]. BTNL2 [16–18]. The underlying etiopathogenesis of AA has been revealed as an Although previous studies have identified AA as an immune- autoimmune mechanism from multiple lines of studies. Histolog- related disorder and have shown several genetic loci throughout ically, AA is characterized by immune infiltrates surrounding the the genome, association studies for the most severe type of AA hair follicle. Moreover, AA is responsive to immunosuppressive (AU) have rarely been performed, especially using next-generation PLOS ONE | www.plosone.org 1 January 2013 | Volume 8 | Issue 1 | e53613 Novel Candidate Variants of Alopecia Universalis sequencing technology. Most rare missense genetic variations are Whole-exome sequencing of 6 individuals with alopecia predicted to be deleterious and, thus, association studies with these universalis variants may be helpful in this regard [19]. Recent studies have Exomic regions of DNA were captured by SureSelect Human also suggested that the majority of variants seem to be rare, and All Exon v.2 Kits (Agilent Technologies, California, USA) and these rare variants are likely to be key determinants for the health sequenced through HiSeq 2000 (Illumina, California, USA) in 6 status of individuals [20,21]. Given that AU patients are rare and samples among study subjects. All procedures followed the have the most severe AA phenotype, identification of rare variants manufacturer’s instructions. The generated reads were aligned to with large effect sizes would be a good strategy to further elucidate the NCBI human reference genome build 37 (hg19) using the the genetic basis for this disease. Genomic Short-read Nucleotide Alignment Program alignment In this study, on the basis of the immune-related mechanism of tool [22]. Only positions having $8 uniquely aligned reads and the disease, we conducted an exomic sequence analysis of $20 mean quality score (Q score) were carried forward for further immune-related genes in AU patients with the aim of identifying analyses. Variant calling was performed according to the criteria genetic determinants of AU by focusing on rare and pathogenic of our previous study [23], and all the variants called were candidates. annotated by the RefSeq gene set and compared with dbSNP build 132. Materials and Methods Ethics statement Filtration into functional candidate variants In this study, we focused on the variants found in immune- Ethical approval for the study was obtained from the relevant related genes. Candidate genes were categorized by gene ontology Ethics Committees (The Institutional Review Board of the Seoul by using DAVID [24] and only variants in immune-related genes National University Hospital). This study was conducted accord- were collected. Among them, we selected nonsynonymous single ing to Declaration of Helsinki principles. Written informed nucleotide polymorphisms (SNPs), coding sequence insertions/ consent was obtained before blood was taken from patients with deletions (indels), and canonical splice-site variants as pathogenic AU. candidates. For further filtration, genotype frequencies of pathogenic Study sample selection and DNA extraction candidates were compared between patient and control groups For this study, 20 patients with AU were recruited from the in both dominant and recessive models. The control samples used outpatient clinic of Seoul National University Hospital. Overall for this study were as follows: (1) 59 Korean samples (8 from demographic data and clinical features are summarized in Table 1, whole-genome sequencing (WGS), 41 from whole-exome sequenc- and detailed individual data are presented in Table S1. A ing (WES)), (2) 56 Asian HapMap samples (10 from WGS, 46 from diagnosis of AU was based on any experience of whole body hair WES), and (3) 40 Mongolian samples from WES. These controls loss in the participant’s lifetime, and involved areas other than the were selected from the Asian Genome Project of our group, and scalp were eyebrow, axillary hair, and pubic hair (eyebrow only in 58 of them were published in our previous studies [25,26]. child). Genomic DNA was extracted from peripheral blood by Statistical comparisons were drawn using a non-parametric using QuickGene DNA whole blood kit with QuickGene-610L method of Fisher’s exact test, and a p-value less than 0.05 was equipment (Fujifilm, Tokyo, Japan). DNA concentrations were used as a standard for the candidate selection. To reduce the measured by Nanodrop ND-1000 spectrophotometer (Nano-drop number of variants selected by chance, we further narrowed our Technologies, Delaware, USA). candidates into those shown in at least 2 patient samples.
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