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Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis Case
Biomed Sci Letters 2018;24:94-101
Published online June 30, 2018;  https://doi.org/10.15616/BSL.2018.24.2.94
© 2018 The Korean Society For Biomedical Laboratory Sciences.

Sang-In Lee, Hyun-Seok Jin, and Sangjung Park

Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea
Correspondence to: Sangjung Park. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea. Tel: +82-41-540-9967, Fax: +82-41-540-9997, e-mail: sangjung@hoseo.edu
Received May 3, 2018; Accepted May 17, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract

Tuberculosis (TB) is infectious disease caused by Mycobacterium tuberculosis (MTB) infection. It is known that not only the property of microorganism but also the genetic susceptibility of infected patients is controlled. Interleukin 2 (IL-2) is a cytokine belonging to type 1 T helper (Th1) activity. In addition, IL-2, when infected with MTB, binds IL-2 receptor and promotes T cell replication and is involved in granuloma formation. The aim of this study was to investigate the genetic polymorphisms of the IL-2 receptor gene in tuberculosis patients and normal individuals. We analyzed 22 SNPs in three genes using the genotype data of 443 tuberculosis cases and 3,228 healthy controls from the Korea Association Resource for their correlation with tuberculosis case. IL2RA, IL2RB, and IL2RG genes were genotyped of 16, 4, and 2 SNPs, respectively. Among three genes, only IL2RA gene polymorphisms showed statistically significant association with tuberculosis case. 6 SNPs with high significance were identified in the IL2RA gene. In addition, the linkage disequilibrium (LD) structure of IL2RA gene was confirmed. SNP imputation of IL2RA gene was performed, it was confirmed that more SNPs were significant between case and control. If we look at the results of IL2RA gene analysis above, we can see that genetic polymorphism in the gene expressing IL-2Rα will regulate the expression level of IL-2Rα, and the change in the immune system involved in IL-2Rα. In this study, genetic polymorphism that may affect host immunity suggests that susceptibility to tuberculosis may be controlled.

Keywords : IL2RA, Tuberculosis, Genetic association, Mycobacterium tuberculosis, SNP, Polymorphism
꽌濡

寃고빑 寃고빑洹 媛먯뿼뿉 쓽빐 諛쒕퀝븯뒗 吏덈퀝쑝濡 쟾 꽭怨 1/3씠 媛먯뿼릺뼱 엳怨 援궡뿉꽌 븘吏곴퉴吏 넂 諛쒕퀝瑜좉낵 궗留앸쪧쓣 蹂댁씠怨 엳뒗 吏덈퀝씠떎(Corbett et al., 2003). 寃고빑洹좎뿉 媛먯뿼맂 궗엺 以 빟 10%뒗 寃고빑쑝濡 諛쒕퀝븳떎. 寃고빑 諛쒕퀝 寃고빑洹좎씠 媛吏怨 엳뒗 洹좎쓽 듅꽦 肉먮쭔 븘땲씪 寃고빑洹 媛먯뿼 솚옄쓽 쑀쟾쟻 媛먯닔꽦씠 議곗젅븳떎怨 븣젮졇 엳떎(Comstock, 1978). 쁽옱 寃고빑 諛쒕퀝怨 쑀쟾쟻 媛먯닔꽦뿉 븳 긽愿꽦쓣 蹂대뒗 뿰援ш 留롮씠 吏꾪뻾릺怨 엳떎.

Interleukin 2 (IL-2)뒗 CD4+ helper T cell 以 type 1 T helper (Th1) activity媛 遺꾨퉬븯뒗 cytokine쑝濡 寃고빑洹좎뿉 븳 硫댁뿭諛섏쓳뿉 븘슂븯떎. 洹몃━怨 Th1 洹몃9 cytokine뱾쓽 긽샇옉슜뿉 愿뿬븯뿬 T cell쓽 硫댁뿭諛섏쓳뿉 以묒슂븳 뿭븷쓣 븳떎怨 븣젮졇 엳떎(Caccamo et al., 2010). 삉븳 IL-2뒗 chain α, β, γ濡 씠猷⑥뼱吏 receptor 寃고빀븯뿬 꽭룷 궡遺濡 깮솕븰쟻 떊샇瑜 쟾떖븳떎(Gaffen and Liu, 2004).

IL-2媛 T cell뿉꽌 Major histocompatibility complex (MHC)-peptide 蹂듯빀泥대 씤떇븳 썑 T cell쓽 빆썝 닔슜泥댁씤 T-cell receptor瑜 넻빐 꽭룷 궡遺濡 떊샇瑜 쟾떖븳떎. 씠젃寃 꽭룷 궡遺濡 쟾떖맂 떊샇뒗 꽭룷 蹂솕瑜 씪쑝耳 珥덇린 T cell씠 effector T cell怨 memory T cell濡 遺꾪솕븯룄濡 珥됱쭊븳떎. 삉븳 꽭洹좎씠굹 諛붿씠윭뒪뿉 媛먯뿼맂 꽭룷媛 젙긽 T cell쓣 怨듦꺽븯뒗 寃껋쓣 뼲젣븳떎(Liao et al., 2011). 寃고빑洹좎뿉 媛먯뿼릺硫 T cell씠 솢꽦솕릺뼱 IL-2瑜 遺꾨퉬븯怨 IL-2 receptor瑜 꽭룷 몴硫댁뿉 諛쒗쁽븳떎. 씠븣 IL-2뒗 T cell쓽 利앹떇쓣 珥됱쭊븯怨 쑁븘醫 삎꽦뿉 愿뿬븯硫 寃고빑 媛먯뿼뿉 븳 넻젣 諛 硫댁뿭뿉 빑떖쟻씤 뿭븷쓣 닔뻾븳떎(Kaufmann, 2001; Wang et al., 2012; Sharma et al., 2014). IL-2 receptor 以 α chain β, γ chain怨쇰뒗 떎瑜닿쾶 soluble븳 삎깭濡 삁以묒쑝濡 쑀由щ릺怨 삁以 IL-2 receptor α (IL-2Rα)쓽 냽룄뒗 쑀쟾옄쓽 諛쒗쁽 젙룄뿉 뵲씪 떖씪吏꾨떎. 뵲씪꽌 삁以 IL-2Rα쓽 냽룄뒗 T cell 솢꽦쓽 吏몴媛 릺湲곕룄 븳떎(Rubin et al., 1985; Wang et al., 2012). 삉븳 寃고빑洹좎씠 옞蹂 媛먯뿼맂 솚옄뿉꽌 IL-2 IFN-γ瑜 紐⑤몢 諛쒗쁽븯뒗 T cell쓽 鍮꾩쑉씠 쁽꽦 媛먯뿼 솚옄뿉 鍮꾪븯뿬 넂 寃껋쑝濡 굹궗떎뒗 寃곌낵瑜 蹂닿퀬븳 뿰援щ룄 吏꾪뻾릺뿀떎(Casey et al., 2010; Sester et al., 2011).

뵲씪꽌 蹂 뿰援ъ뿉꽌뒗 븳援씤 쑀쟾泥 뿭븰 議곗궗 궗뾽쓽 씪솚쑝濡 援ъ꽦릺뼱 엳뒗 肄뷀샇듃 옄猷뚮 솢슜븯뿬 寃고빑 솚옄 젙긽씤 媛 IL-2 receptor 쑀쟾옄쓽 쑀쟾쟻 떎삎꽦씠 寃고빑 諛쒕퀝뿉 쁺뼢쓣 二쇱뿀뒗吏 솗씤븯怨좎옄 쑀쟾쟻 蹂씠뿉 븳 긽愿꽦 遺꾩꽍 뿰援щ 떆뻾븯떎.

옱猷 諛 諛⑸쾿

뿰援щ긽옄

蹂 뿰援щ 쐞븳 븳援씤 뿰援щ긽옄뒗 븳援씤 쑀쟾泥 뿭븰 議곗궗 궗뾽(Korean Genome and Epidemiology Study; KoGES)쓽 씪솚씤 Korean Association Resource (KARE)瑜 湲곕컲쑝濡 븯떎(Cho et al., 2009). 씠븣 궗슜븳 옄猷뚮뒗 吏덈퀝愿由щ낯遺 씤泥댁옄썝뻾뿉꽌 遺꾩뼇쓣 諛쏆븘 궗슜븯떎(17070301-01-01). 뿰援ъ뿉꽌 궗슜븳 뿰援щ긽옄쓽 꽑蹂꾩 씠쟾 뿰援ъ 룞씪븯寃 꽕젙븯떎(Jin and Park, 2017). 슂빟븯硫 솚옄援곗쑝濡쒕뒗 怨쇨굅뿉 寃고빑吏꾨떒쓣 諛쏆 쟻씠 엳뒗 443紐낆쓣 꽑젙븯怨 嫄닿컯 議곌뎔 듅蹂꾪븳 吏덊솚씠 뾾뒗 3,228紐낆쓣 꽑젙븯떎. 寃고빑 솚옄援곌낵 嫄닿컯 議곌뎔쓽 룊洹 굹씠뒗 媛곴컖 51.0꽭 51.6꽭濡 쑀궗븯떎. 蹂 뿰援ъ뿉 솢슜븳 쑀쟾 젙蹂대뒗 吏덈퀝愿由щ낯遺(KNIH) 샇꽌븰援먯뿉꽌 뿰援ъ쑄由 듅씤쓣 諛쏆 썑 遺꾩꽍쓣 닔뻾븯떎(1041231-170418-HR-056-02).

쑀쟾삎 遺꾩꽍怨 Single Nucleotide Polymorphism (SNP) 꽑蹂

蹂 뿰援ъ뿉꽌뒗 KARE 쑀쟾삎 옄猷뚮 湲곕컲쑝濡 SNP쓣 꽑蹂꾪븯떎. DNA 떆猷뚮뒗 뿰援 李몄뿬옄쓽 留먯큹삁븸뿉꽌 遺꾨━ 異붿텧븯怨, 쑀쟾삎 뙋룆쓣 쐞빐꽌뒗 Affymetrix Genome-Wide Human SNP array 5.0 (Affymetrix, Inc., Santa Clara, CA, USA)瑜 궗슜븯떎. 쑀쟾삎 뙋룆 젙솗룄媛 98% 씠븯씠嫄곕굹, 4% 씠긽쓽 넂 missing genotype call rate쓣 蹂댁씠嫄곕굹, 30% 珥덇낵쓽 heterozygosity瑜 媛吏嫄곕굹, 꽦蹂 遺덉씪移섍 議댁옱븯뒗 긽옄뱾 젣쇅릺뿀떎. 蹂 뿰援ъ뿉꽌 遺꾩꽍븳 IL2RA, IL2RB, IL2RG 쑀쟾옄 쁺뿭 쟾궗泥 뼇 留먮떒뿉꽌 5 kb뵫 솗옣븯뿬 씠 踰붿쐞뿉 議댁옱븯뒗 媛곴컖 16媛, 4媛, 2媛쒖쓽 SNP뱾쓣 긽쑝濡 븯떎. 씠 SNP뱾쓽 뿼깋泥 긽쓽 쐞移섎뒗 UCSC Genome Browser on Human Mar. 2006 (NCBI36/hg18)瑜 湲곗쑝濡 븯떎. 삉븳, 떎젣 떎뿕쟻쑝濡 SNP쓽 쑀쟾삎쓣 솗씤븳 寃 씠쇅뿉룄 IL2RA 쑀쟾옄 쁺뿭뿉꽌뒗 MACH 1.0.16 (Li et al., 2010)瑜 궗슜븯뿬 異붽쟻쑝濡 37媛쒖쓽 imputation SNP쓣 諛쒓뎬븯뿬 遺꾩꽍뿉 궗슜븯떎. Imputation HapMap database (release 24) (International HapMap Consortium 2003)뿉꽌 以묎뎅씤(Han Chinese form Beijing)怨 씪蹂몄씤(Japanese in Tokyo)쓽 寃껋쓣 李멸퀬濡 吏꾪뻾븯떎. Imputed SNP뱾 以묒뿉꽌 Minor Allele Frequency (MAF)媛 1% 誘몃쭔씠嫄곕굹 긽愿怨꾩닔(r2)媛 0.5 誘몃쭔씤 寃껋 遺꾩꽍뿉꽌 젣쇅븯떎.

긽愿꽦 遺꾩꽍怨 넻怨 遺꾩꽍

遺遺꾩쓽 넻怨 遺꾩꽍뿉뒗 PLINK version 1.07 ( http://pngu.mgh.harvard.edu/~purcell/plink)怨 PASW Statistics version 18.0 (SPSS Inc. Chicago, IL, USA)쓣 궗슜븯떎. 寃고빑 솚옄援곌낵 嫄닿컯 議곌뎔뿉 븳 쑀쟾쟻 蹂씠쓽 긽愿꽦 遺꾩꽍 Logistic 쉶洹 遺꾩꽍쓣 궗슜븯쑝硫 additive genetic model쓣 湲곕컲쑝濡 븯떎. 遺꾩꽍 媛믪뿉 븳 쑀쓽 닔以 0.05 씠븯瑜 湲곗쑝濡 븯떎. KARE 쑀쟾삎 젙蹂대 諛뷀깢쑝濡 Haploview version 4.2 (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) 봽濡쒓렇옩쓣 궗슜븯뿬 뿰愿 遺덇퇏삎(linkage disequilibrium) 釉붾줉 援ъ“瑜 솗씤븯떎.

寃곌낵

IL2RA, IL2RB, IL2RG 쑀쟾옄 쁺뿭쓽 SNP 꽑蹂꾧낵 긽愿꽦 遺꾩꽍 寃곌낵

IL-2 receptor 쑀쟾옄뱾 UCSC Genome Browser on Human Mar. 2006 (NCBI36/hg18)瑜 湲곗쑝濡 媛곴컖 뿼깋泥댁뿉꽌 쑀쟾옄쓽 쁺뿭쓣 꽕젙(쟾궗泥 湲곗쑝濡 븯뿬 뼇諛⑺뼢쑝濡 5 kb뵫 쁺뿭 솗옣)븳 썑 KARE 쑀쟾삎 옄猷뚯뿉꽌 SNP쓣 솗씤븯떎. 洹 寃곌낵 IL2RA뒗 10踰 뿼깋泥댁뿉꽌 16媛쒖쓽 SNP씠 솗씤릺뿀떎. 留덉갔媛吏濡 IL2RB뒗 22踰 뿼깋泥댁뿉꽌 4媛쒖쓽 SNP씠 IL2RG뒗 X 뿼깋泥댁뿉꽌 2媛쒖쓽 SNP쓣 솗씤븷 닔 엳뿀떎. 꽑蹂꾨맂 IL-2 receptor 쑀쟾옄쓽 SNP쓣 긽쑝濡 寃고빑 솚옄援곌낵 嫄닿컯 議곌뎔뿉 븳 Logistic 쉶洹 遺꾩꽍쓣 떆뻾븳 寃곌낵 IL2RA 쑀쟾옄쓽 16媛쒖쓽 SNP 以 6媛쒖쓽 SNP뿉꽌 넻怨꾩쟻쑝濡 쑀쓽븳 긽愿愿怨(P<0.05)瑜 솗씤븷 닔 엳뿀떎. 洹몃윭굹 IL2RB 쑀쟾옄뿉꽌뒗 遺꾩꽍 寃곌낵 넻怨꾩쟻쑝濡 쑀쓽븳 SNP씠 議댁옱븯吏 븡븯쑝硫, IL2RG 쑀쟾옄뒗 X 뿼깋泥댁쓽 듅씠꽦쑝濡 遺꾩꽍 寃곌낵뿉 쓽誘몃 遺뿬븯湲곌 뼱젮썱떎(Table 1).

Results of the case-control association analysis between SNPs in the IL2RA, IL2RB, IL2RG genes and tuberculosis in the KARE subjects

GeneNo. SNPBP FunctionA1A2MAFOR (95% CI)Additive P value

Cases (n=443)Controls (n=3,228)
IL2RA1rs115963556104187IntronicGA0.0120.0150.90 (0.48~1.68)0.730
2rs20253456107694IntronicCT0.3770.4310.79 (0.68~0.92)2.77E-03
3rs127225276117334IntronicTC0.1730.1671.05 (0.87~1.27)0.624
4rs112564336117851IntronicCA0.2850.2601.13 (0.96~1.32)0.137
5rs112564486119485IntronicGA0.3030.2861.08 (0.92~1.26)0.343
6rs70723986119852IntronicTC0.3640.4220.78 (0.68~0.91)1.10E-03
7rs47499266125318IntronicAG0.3570.4080.80 (0.69~0.92)2.56E-03
8rs109056566126099IntronicCA0.3920.3591.15 (0.99~1.33)0.066
9rs9422016126298IntronicAC0.2760.2551.10 (0.94~1.29)0.233
10rs7915876128705IntronicAG0.2700.3220.78 (0.66~0.91)1.65E-03
11rs109056686132061IntronicAG0.3730.3451.12 (0.97~1.29)0.134
12rs109056696132099IntronicAG0.3740.3451.12 (0.97~1.30)0.118
13rs22567746137171IntronicCT0.1010.0791.30 (1.03~1.65)3.00E-02
14rs21042866139051IntronicCT0.1050.1001.05 (0.84~1.33)0.656
15rs171494586141866IntronicTA0.1320.1321.01 (0.82~1.25)0.931
16rs107957916148346UpstreamTC0.3680.4090.84 (0.72~0.97)1.72E-02

IL2RB1rs599538535849810DownstreamGA0.2950.3030.95 (0.81~1.11)0.491
2rs321829535863014IntronicAG0.1740.1731.02 (0.84~1.22)0.878
3rs321829435863232IntronicGC0.2020.2050.98 (0.82~1.17)0.800
4rs228403335863980IntronicGA0.3610.3451.08 (0.93~1.26)0.307

IL2RG1rs598106570208925IntronicGA0.3530.350N/AN/A
2rs1717415270319869DownstreamGA0.1010.093N/AN/A

P-values <0.05 are indicated in bold. Abbreviations: A1, minor allele; A2, major allele; BP, base pair; CI, confidence interval; MAF, minor allele frequency; OR, odds ratio; SNP, single nucleotide polymorphism; N/A, Not Applicable. The SNP positions are based on the NCBI Build 36 human genome assembly.


IL2RA 쑀쟾옄쓽 SNP 以 媛옣 넂 쑀쓽 닔以(P=1.10 × 10-3)쓣 蹂댁씠뒗 rs7072398 긽쟻 쐞뿕룄(OR)뒗 0.78쑝濡 굹궗怨 떊猶곌뎄媛(95% CI) 0.68~0.91쑝濡 굹궗떎. rs7072398쓽 minor allele뒗 T, major allele뒗 C씠떎. MAF瑜 궡렣蹂대㈃ 寃고빑 솚옄援곗 36.4%씠怨, 嫄닿컯 議곌뎔 42.2%濡 빟 6%쓽 鍮덈룄 李⑥씠媛 엳뼱꽌 T 뿼湲곕 蹂댁쑀븷 寃쎌슦뿉 寃고빑 諛쒖깮쓣 媛먯냼떆궎뒗 諛⑺뼢쑝濡 긽愿꽦씠 엳뒗 寃껋쓣 븣 닔 엳뿀떎. 洹몃윭굹 rs2256774뒗 긽쟻 쐞뿕룄媛 1.3쑝濡 솗씤릺뼱 minor allele瑜 蹂댁쑀븯怨 엳쓣닔濡 寃고빑 諛쒖깮쓣 利앷떆궎뒗 諛⑺뼢쑝濡쒖쓽 긽愿꽦씠 엳떎뒗 寃껋쓣 븣 닔 엳뿀떎. 쑀쓽꽦씠 넂 6媛쒖쓽 SNP 以 rs2256774瑜 젣쇅븳 5媛쒖쓽 SNP 긽쟻 쐞뿕룄媛 궙寃 솗씤릺뿀怨 씠 以 rs10795791 5’ 諛⑺뼢쓽 upstream 쁺뿭뿉꽌 굹궗떎.

IL2RA 쑀쟾옄 SNP쓽 Linkage disequilibrium (LD) 援ъ“

IL2RA 쑀쟾옄뿉꽌 솗씤븳 쑀쓽꽦씠 넂 6媛쒖쓽 SNP 媛꾩쓽 뿰愿 遺덇퇏삎 쁽긽씠 굹굹뒗吏 Haploview 봽濡쒓렇옩쓣 솢슜븯뿬 솗씤빐 蹂닿퀬옄 븯떎. 긽쟻 쐞뿕룄媛 궙븯뜕 5媛쒖쓽 SNP 以 5kb 솗옣 吏뿭뿉 議댁옱븯뒗 SNP쓣 젣쇅븳 4媛쒖쓽 SNP뒗 븯굹쓽 LD block쓣 삎꽦븯怨 엳뿀떎. 떎瑜 LD block뿉뒗 긽쟻 쐞뿕룄媛 넂 SNP씠 룷븿릺뼱 엳뿀떎(Fig. 1).

Fig. 1.

Linkage disequilibrium of IL2RA SNP on chromosome 10. The 16 SNPs and LD structure were shown by a Haploview of LD (r2) based on genotyping data from 8,842 KARE subjects and are generated by using the Haploview program. Of the 6 SNPs with significance, 4 SNPs belong to Block 1, and 2 SNPs belong to Block 2. Since there are significant differences in different blocks, it is expected that each SNP will affect the outbreak of tuberculosis.


IL2RA 쑀쟾옄 SNP imputation 썑 긽愿꽦 遺꾩꽍 寃곌낵

KARE 쑀쟾삎 옄猷뚮 湲곕컲쑝濡 븯뿬 IL2RA 쑀쟾옄 SNP imputation쓣 닔뻾븯뿬 뜑 留롮 SNP怨 寃고빑怨쇱쓽 긽愿꽦 뿬遺瑜 솗씤빐 蹂댁븯떎. 洹 寃곌낵 182媛쒖쓽 SNP씠 솗씤릺뿀怨 洹 以 42媛쒖쓽 SNP씠 넻怨꾩쟻쑝濡 쑀쓽븯떎. Imputation 닔뻾 쟾 遺꾩꽍 寃곌낵뒗 寃고빑 諛쒕퀝怨 긽쟻 쐞뿕룄媛 궙 SNP씠 遺遺꾩씠뿀뜕 諛섎㈃ imputation 닔뻾 썑뿉뒗 긽쟻 쐞뿕룄媛 넂 SNP쓽 닔 궙 SNP쓽 닔媛 鍮꾩듂븯寃 굹궗떎. Imputation 닔뻾 썑 寃고빑 諛쒖깮怨 쑀쓽븳 긽愿愿怨꾨 蹂댁씠뒗 SNP뱾쓽 닔媛 利앷븳 寃껋 IL2RA 쑀쟾옄쓽 쑀쟾쟻 떎삎꽦씠 寃고빑 諛쒕퀝뿉 쁺뼢쓣 以 媛뒫꽦씠 넂떎뒗 寃껋쓣 쓽誘명븳떎(Table 2).

Results of the case-control association analysis between imputed SNP in the IL2RA gene on chromosome 10 and tuberculosis case in the KARE subjects (Result P<0.05).

No.SNPBPFunctionA1A2MAFOR (95% CI)*Additive P value

Cases (n=443)Controls (n=3,228)
I1rs7648506048357DownstreamAG0.2120.1771.28 (1.07~1.53)6.92.E-03
I2rs800066716048408DownstreamTC0.2120.1771.28 (1.07~1.53)6.92.E-03
I3rs594541456048914DownstreamAG0.2120.1771.28 (1.07~1.53)6.92.E-03
I4rs1170406966050159DownstreamTC0.2120.1771.28 (1.07~1.53)6.92.E-03
I5rs1385741896050267DownstreamTA0.2120.1771.28 (1.07~1.53)6.92.E-03
I6rs1176323756050306DownstreamGC0.2120.1771.28 (1.07~1.53)6.92.E-03
I7rs125722576050630DownstreamAG0.2120.1771.28 (1.07~1.53)6.92.E-03
I8rs127226106052172DownstreamGA0.0320.0191.70 (1.11~2.60)0.015
I9rs127226046053286IntronicAG0.2540.3170.73 (0.62~0.86)1.53.E-04
I10rs127225966056294IntronicCT0.0320.0181.76 (1.15~2.70)9.88.E-03
I11rs112563426057231IntronicGT0.2980.3570.76 (0.65~0.89)5.90.E-04
I12rs23868416057732IntronicTG0.4900.4361.25 (1.08~1.44)2.71.E-03
I13rs125728596058040IntronicCG0.1640.1391.23 (1.01~1.49)0.038
I14rs107521756061781IntronicTC0.2450.2141.21 (1.03~1.44)0.023
I15rs66023686062915IntronicCT0.3700.4160.82 (0.71~0.95)8.79.E-03
I16rs123589616066195IntronicAT0.3750.4270.80 (0.69~0.92)2.75.E-03
G1rs20253456067688IntronicGA0.3760.4280.80 (0.69~0.93)2.87.E-03
I17rs125720546069853IntronicCT0.2810.3380.76 (0.65~0.89)7.63.E-04
I18rs20253466070675IntronicAG0.2790.3360.76 (0.65~0.89)6.35.E-04
I19rs20253476070831IntronicGA0.4410.4011.19 (1.03~1.37)0.018
I20rs109056416072293IntronicCA0.2550.2261.19 (1.01~1.40)0.043
I21rs70682766073388IntronicGT0.4350.3971.17 (1.02~1.36)0.028
I22rs122640616073487IntronicGA0.0100.0200.47 (0.24~0.94)0.032
I23rs47478446074201IntronicGA0.4400.4041.17 (1.01~1.35)0.034
I24rs79209466074634IntronicCT0.3540.3231.16 (1.00~1.35)0.050
I25rs125721366077191IntronicGC0.2740.3330.76 (0.65~0.88)4.87.E-04
I26rs66023926078079IntronicAC0.2740.3330.76 (0.65~0.88)4.87.E-04
I27rs112564426079344IntronicTC0.4700.4271.20 (1.04~1.38)0.013
G2rs70723986079846IntronicAG0.3620.4230.77 (0.66~0.89)5.37.E-04
I28rs112564576080794IntronicGC0.3570.4090.79 (0.68~0.92)2.39.E-03
I29rs127225176081040IntronicCT0.3570.3231.18 (1.01~1.36)0.033
I30rs7915936083292IntronicGA0.3580.3241.18 (1.02~1.36)0.031
G3rs47499266085312IntronicAG0.3570.4090.79 (0.68~0.92)2.45.E-03
G4rs7915876088699IntronicAG0.2700.3210.78 (0.67~0.91)2.01.E-03
I31rs7915886089342IntronicGT0.3420.3890.81 (0.70~0.94)5.60.E-03
I32rs7915896089571IntronicGA0.3260.3760.80 (0.69~0.93)3.83.E-03
I33rs13236586094354IntronicCA0.2550.3050.78 (0.67~0.92)2.55.E-03
I34rs7067786098949IntronicCT0.3680.4060.85 (0.73~0.98)0.027
I35rs70727936106266UpstreamTC0.3690.4090.84 (0.73~0.97)0.020
I36rs70732366106552UpstreamTC0.3680.4080.84 (0.73~0.97)0.020
I37rs70963846106638UpstreamCT0.3680.4080.84 (0.73~0.97)0.020
G5rs107957916108340UpstreamAG0.3690.4090.84 (0.73~0.97)0.020

*All data were selected with P-values <0.05. Abbreviations: G of no., genotyped number of SNP; I of no., imputed number of SNP; A1, minor allele; A2, major allele; BP, base pair; CI, confidence interval; MAF, minor allele frequency; OR, odds ratio; SNP, single nucleotide polymorphism. The SNP positions are based on the NCBI Build 37 human genome assembly.


IL2RA 쑀쟾옄쓽 SNP씠 쑀쟾옄 떒諛깆쭏 諛쒗쁽뿉 誘몄튂뒗 쁺뼢

Imputation 썑 쑀쓽꽦씠 넂 IL2RA 쑀쟾옄媛 뼱뼸寃 쑀쟾옄 샊 떒諛깆쭏 諛쒗쁽뿉꽌 쁺뼢쓣 誘몄튌 寃껋씤吏 RegulomeDB ( http://www.regulomedb.org/index)뿉꽌 솗씤빐 蹂댁븯떎. 솗씤 寃곌낵 rs12722596, rs10752175, rs764850, rs1323658쓽 4媛쒖쓽 SNP뿉꽌 쓽誘 엳뒗 score瑜 솗씤븷 닔 엳뿀떎. 洹몄쨷 rs12722596뒗 쟾궗 씤옄 寃고빀 諛섏쓳뿉 쁺뼢쓣 以 닔 엳쓣 肉먮쭔 븘땲씪 DNase peak 李⑥씠媛 엳떎뒗 寃껋쓣 솗씤븷 닔 엳뿀떎. 肉먮쭔 븘땲씪 씠怨녹 蹂몃옒 RFX BRCA1: USF2쓽 motif濡 옉슜븯湲 븣臾몄뿉 IL2RA 쑀쟾옄 諛쒗쁽뿉 쁺뼢쓣 以 닔 엳떎뒗 寃껋쓣 솗씤븷 닔 엳뿀떎. 삉븳 rs764850뒗 IL2RA 쑀쟾옄쓽 3’ 留먮떒 履 5kb 솗옣 踰붿쐞뿉 議댁옱븯뒗 SNP엫뿉룄 遺덇뎄븯怨 넻怨꾩쟻 쑀쓽꽦怨 넂 RegulomeDB score媛 쓽誘 엳寃 굹궃 寃껋 쑀쟾옄뿉 씤젒븳 吏뿭씠 쑀쟾쟻 떎뼇꽦쓽 議곗젅뿉 엳뼱꽌 以묒슂븳 뿭븷쓣 븷 媛뒫꽦씠 엳쓬쓣 蹂댁뿬以떎(Table 3).

Results of the Regulome DB of imputed SNP in the IL2RA gene on chromosome 10

 SNPBPA1A2Regulome DB

ScoreTFBSDNaseProteins boundMotifs
rs7648506048357AG3a++GTAT1, POLR2AZNF740, NERF1a
rs127225966056294CT2a++CTCF, RAD21, SMC3RFX, BRCA1:USF2
rs107521756061781CT2b++E2F6PPARG::RXRA
rs13236586094354CA3a++SPI1, CHD1, IKZF1HNF4, Esrra

Abbreviations: SNP, single nucleotide polymorphism; BP, base pair; A1, minor allele; A2, major allele; TFBS, transcription binding factor site; +, affect. The SNP positions are based on the NCBI Build 37 human genome assembly.


怨좎같

蹂 뿰援ъ뿉꽌뒗 IL-2 receptor瑜 諛쒗쁽븯뒗 쑀쟾옄뿉꽌 SNP쓽 寃고빑 솚옄援곌낵 嫄닿컯 議곌뎔媛 MAF 李⑥씠뿉 뵲瑜 넻怨꾩쟻 쑀쓽꽦쓣 遺꾩꽍븯뿬 쑀쟾쟻 蹂씠뿉 뵲瑜 寃고빑 諛쒕퀝怨쇱쓽 긽愿꽦뿉 븯뿬 븣븘蹂닿퀬옄 븯떎. 洹 寃곌낵 IL2RB IL2RG뒗 寃고빑 솚옄援곌낵 嫄닿컯 議곌뎔媛 쑀쟾 蹂씠쓽 MAF 李⑥씠媛 씪젙 닔以 씠븯濡 굹궗떎. 씠寃껋 IL-2 receptor β γ chain 쑀쟾옄쓽 쑀쟾 蹂씠媛 寃고빑 諛쒕퀝怨 긽愿꽦씠 궙떎뒗 寃껋쑝濡 깮媛곹븷 닔 엳뿀떎. 洹몃윭굹 IL2RA 쑀쟾옄뒗 6媛쒖쓽 SNP뿉꽌 寃고빑 諛쒕퀝怨 넂 쑀쓽꽦씠 솗씤릺뿀떎. 씠 SNP 以 MAF媛 嫄닿컯 議곌뎔뿉 鍮꾪븯뿬 寃고빑 솚옄援곗뿉꽌 궙 SNP怨 넂 SNP 紐⑤몢 솗씤븷 닔 엳뿀떎. 씠寃껋 IL2RA 쑀쟾옄쓽 쑀쟾 蹂씠뒗 寃고빑 諛쒕퀝뿉 엳뼱꽌 떎뼇븳 諛⑺뼢쑝濡 쁺뼢쓣 誘몄튌 닔 엳떎뒗 寃껋쓣 쓽誘명븳떎. 삉븳 쐞쓽 SNP쓽 LD 援ъ“瑜 솗씤빐 蹂댁븯쓣 븣 긽쟻 쐞뿕룄쓽 諛⑺뼢꽦씠 諛섎씤 몢 SNP씠 꽌濡 떎瑜 LD block뿉 냽빐 엳뒗 寃껋쓣 솗씤븷 닔 엳뿀쑝硫 媛숈 諛⑺뼢꽦쓣 媛뽯뒗 SNP 媛숈 LD blcok뿉 냽빐 엳뒗 寃껋쓣 蹂 닔 엳뿀떎(Fig. 1). 쐞쓽 寃곌낵뱾쓣 넻븯뿬 IL-2 receptor瑜 諛쒗쁽븯뒗 쑀쟾옄 以 α chain쓣 諛쒗쁽븯뒗 쑀쟾옄뿉 議댁옱븯뒗 SNP뱾씠 寃고빑 諛쒕퀝怨 넻怨꾩쟻쑝濡 쑀쓽븳 긽愿꽦씠 엳떎뒗 寃껋쓣 솗씤븷 닔 엳뿀떎.

湲곗〈쓽 KARE 옄猷뚯뿉꽌 imputation 썑쓽 SNP쓣 湲곗쑝濡 IL2RA 쑀쟾옄쓽 넻怨꾩쟻 쑀쓽꽦쓣 遺꾩꽍빐 蹂댁븯쓣 븣 湲곗〈쓽 寃곌낵蹂대떎 留롮 SNP쓣 꽑蹂꾪븷 닔 엳뿀쑝硫 넂 쑀쓽꽦쓣 媛뽯뒗 SNP룄 솗씤븷 닔 엳뿀떎. 삉븳 RegulomeDB 寃곌낵媛 넂 score瑜 媛뽯뒗 寃껊룄 솗씤븷 닔 엳뿀떎. 寃곌뎅 imputation 썑쓽 寃곌낵뒗 IL2RA 쑀쟾옄쓽 쑀쟾 蹂씠媛 뼱뼸寃 寃고빑 諛쒕퀝뿉 쁺뼢쓣 二쇰뒗吏 옄꽭븯寃 솗씤빐 蹂 닔 엳뿀怨 쑀쟾 蹂씠 寃고빑 諛쒕퀝쓽 긽愿꽦씠 엳떎뒗 궗떎쓣 뮮諛쏆묠 빐二쇱뿀떎.

씤泥 硫댁뿭뿉 愿뿬븯뒗 뿬윭 쑀쟾옄쓽 쑀쟾쟻 李⑥씠뒗 硫댁뿭泥닿퀎瑜 씠猷⑤뒗 슂냼뱾쓽 李⑥씠瑜 留뚮뱾뼱 寃곌뎅 寃고빑洹좎쓽 씤泥 移⑥엯怨 씠뿉 븳 諛⑹뼱 愿젴맂 媛먯닔꽦 蹂솕瑜 媛졇삱 닔 엳떎. 寃고빑洹좎뿉 븳 硫댁뿭븰쟻 愿젏뿉꽌 蹂닿쾶 릺硫 寃고빑洹좎씠 媛먯뿼릺뿀쓣 븣 씤泥 궡뿉꽌뒗 떎뼇븳 硫댁뿭諛섏쓳씠 씪뼱굹硫 씠뿉 愿뿬븯뒗 꽭룷뱾 떎뼇븯떎(Kleinnijenhuis et al., 2011; Dey and Bishai, 2014). 寃고빑 媛먯뿼 珥덇린뿉 寃고빑洹좎씠 셿쟾븯寃 젣嫄곕릺吏 븡쑝硫 T cell씠 寃고빑洹좎뿉 븳 硫댁뿭뿉 愿뿬븯寃 맂떎. T cell 寃고빑洹좎쓣 룷븿븳 쑁븘醫낆쓣 삎꽦븯뿬 洹 븞뿉꽌 洹좎쓽 궗硫몄쓣 쑀룄븳떎(Gideon et al., 2015). 븯吏留 솚옄쓽 硫댁뿭븰쟻 긽깭뿉 뵲씪 寃고빑洹좎쓽 궗硫몄 議곗젅릺硫 씠 솚옄쓽 긽깭뒗 솚옄뿉 媛먯뿼맂 寃고빑洹좎쓽 듅꽦 肉먮쭔 븘땲씪 솚옄쓽 엫긽利앹긽怨 硫댁뿭젰 벑씠 愿뿬븳떎. T cell怨 macrophage뒗 寃고빑洹좎쓣 궗硫명븯怨 蹂묐쓣 삎꽦븳떎. 씠 븣 CD4+ T cell IL-2, IFN-γ 媛숈 cytokine쓣 遺꾨퉬븯뿬 빆썝 諛쒗쁽쓣 利앷컯떆궎怨 꽭룷 留ㅺ컻 硫댁뿭諛섏쓳쓣 珥됱쭊떆궎뒗 뿭븷쓣 븳떎(Edwards and Kirkpatrick, 1986). 삉븳 솢꽦솕맂 T cell IL-2 receptor媛 꽭룷 몴硫댁뿉 諛쒗쁽릺뼱 IL-2 寃고빀븳떎(Morgan et al., 1976; Rubin et al., 1985). 寃고빀맂 IL-2뒗 쑕吏湲 T cell쓣 effector T cell, memory T cell濡 遺꾪솕븯룄濡 珥됱쭊븯怨 Th1 cytokine쓽 諛쒗쁽 議곗젅뿉 愿뿬븳떎. T cell쓽 몴硫댁뿉 諛쒗쁽븯뒗 IL-2 receptor 以 α chain soluble븳 긽깭(sIL-2Rα)濡 쑀由щ릺뼱 궓寃 맂떎. 븵꽑 뿰援ъ뿉꽌뒗 젙긽씤쓽 삁泥뿉 議댁옱븯뒗 sIL-2Rα 蹂대떎 꽭룷 留ㅺ컻 硫댁뿭諛섏쓳씠 吏꾪뻾맆 븣쓽 sIL-2Rα媛 利앷븳 寃껋쓣 愿李고븯떎(Rubin et al., 1985). sIL-2Rα쓽 젙긽 삁泥 냽룄蹂대떎 利앷븳 긽깭뒗 T cell쓽 솢꽦솕 젙룄 꽭룷 硫댁뿭 湲곕뒫쓽 利앷컧쓣 삁痢≫븷 닔 엳뒗 吏몴濡 솢슜릺뒗 뿰援щ뒗 솢諛쒗븯寃 吏꾪뻾릺怨 엳떎. 뵲씪꽌 IL-2Rα瑜 諛쒗쁽븯뒗 쑀쟾옄뿉 쑀쟾쟻 蹂씠媛 깮湲대떎硫 IL-2Rα媛 諛쒗쁽릺뒗 뼇뿉 議곗젅씠 깮湲 寃껋씠怨 洹몃젃寃 릺硫 IL-2Rα媛 愿뿬븯뒗 硫댁뿭泥닿퀎뿉뒗 蹂솕媛 엳쓣 寃껋씠떎. 寃곌뎅 寃고빑洹좎쓽 듅꽦怨 솚옄쓽 엫긽利앹긽씠 寃고빑쓽 媛먯닔꽦怨 愿젴븯뿬 以묒슂븯吏留 硫댁뿭뿉 愿젴맂 쑀쟾쟻 떎삎꽦 삉븳 寃고빑뿉 븳 媛먯닔꽦뿉 쁺뼢쓣 以 닔 엳떎.

洹몃룞븞 援궡쓽 留롮 뿰援ъ뿉꽌 寃고빑쓽 諛쒕퀝怨 愿젴븯뿬 寃고빑洹좎쓽 듅꽦쓣 怨좊젮븯뒗 뿰援щ뱾씠 吏꾪뻾릺뼱 솕떎(Oh et al., 2009; Park et al., 2012; Cho et al., 2014). 洹몃윭굹 蹂 뿰援ъ뿉꽌뒗 寃고빑 諛쒕퀝뿉 쁺뼢쓣 以 닔 엳뒗 硫댁뿭뿉 愿뿬븯뒗 닕二쇱쓽 쑀쟾쟻 떎삎꽦씠 寃고빑 諛쒕퀝怨 愿븳 솚옄쓽 媛먯닔꽦씠 議곗젅맆 닔 엳뒗 媛뒫꽦쓣 젣떆빐 二쇨퀬 엳쑝硫 씠 寃곌낵瑜 넻븯뿬 寃고빑뿉 쑀쟾쟻씤 媛먯닔꽦씠 엳뒗 솚옄뿉 븳 뿰援ъ 愿由ш 媛뒫븷 寃껋씠씪怨 깮媛곹븳떎.

ACKNOWLEDGEMENTS

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by Ministry of Sciences, ICT & Future Planning(2017R1C1B5016589). Epidemiologic data used in this study were from the Korean Genome and Epidemiology Study(KoGES) of the Korea Centers for Disease Control & Prevention, Republic of Korea.

CONFLICT OF INTEREST

The authors have no conflicts of interest to disclose.

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