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1 Biomedical Science Letters 2018, 24(2): 94~101 eissn : Original Article Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis Case 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 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. Key Words: IL2RA, Tuberculosis, Genetic association, Mycobacterium tuberculosis, SNP, Polymorphism 서론결핵은결핵균감염에의해발병하는질병으로전세계 1/3이감염되어있고국내에서아직까지높은발병률과사망률을보이고있는질병이다 (Corbett et al., 2003). 결핵균에감염된사람중약 10% 는결핵으로발병한다. 결핵발병은결핵균이가지고있는균의특성뿐만아니라결핵균감염환자의유전적감수성이조절한다고알려져있다 (Comstock, 1978). 현재결핵발병과유전적감수성에 대한상관성을보는연구가많이진행되고있다. Interleukin 2 (IL-2) 는 CD4+ helper T cell 중 type 1 T helper (Th1) activity 가분비하는 cytokine 으로결핵균에대한면역반응에필요하다. 그리고 Th1 그룹 cytokine 들의상호작용에관여하여 T cell의면역반응에중요한역할을한다고알려져있다 (Caccamo et al., 2010). 또한 IL-2 는 chain α, β, γ로이루어진 receptor 와결합하여세포내부로생화학적신호를전달한다 (Gaffen and Liu, 2004). IL-2 가 T cell 에서 Major histocompatibility complex (MHC)- peptide 복합체를인식한후 T cell의항원수용체인 T-cell * Received: May 3, 2018 / Accepted: May 17, 2018 Corresponding author: Sangjung Park. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea. Tel: , Fax: , sangjung@hoseo.edu C The Korean Society for Biomedical Laboratory Sciences. All rights reserved. CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

2 receptor 를통해세포내부로신호를전달한다. 이렇게세포내부로전달된신호는세포변화를일으켜초기 T cell 이 effector T cell과 memory T cell로분화하도록촉진한다. 또한세균이나바이러스에감염된세포가정상 T cell을공격하는것을억제한다 (Liao et al., 2011). 결핵균에감염되면 T cell이활성화되어 IL-2 를분비하고 IL-2 receptor 를세포표면에발현한다. 이때 IL-2는 T cell의증식을촉진하고육아종형성에관여하며결핵감염에대한통제및면역에핵심적인역할을수행한다 (Kaufmann, 2001; Wang et al., 2012; Sharma et al., 2014). IL-2 receptor 중 α chain 은 β, γ chain 과는다르게 soluble 한형태로혈중으로유리되고혈중 IL-2 receptor α (IL-2Rα) 의농도는유전자의발현정도에따라달라진다. 따라서혈중 IL-2Rα 의농도는 T cell 활성의지표가되기도한다 (Rubin et al., 1985; Wang et al., 2012). 또한결핵균이잠복감염된환자에서 IL-2 와 IFN-γ 를모두발현하는 T cell의비율이현성감염환자에비하여높은것으로나타났다는결과를보고한연구도진행되었다 (Casey et al., 2010; Sester et al., 2011). 따라서본연구에서는한국인유전체역학조사사업의일환으로구성되어있는코호트자료를활용하여결핵환자와정상인간 IL-2 receptor 유전자의유전적다형성이결핵발병에영향을주었는지확인하고자유전적변이에대한상관성분석연구를시행하였다. 재료및방법연구대상자본연구를위한한국인연구대상자는한국인유전체역학조사사업 (Korean Genome and Epidemiology Study; KoGES) 의일환인 Korean Association Resource (KARE) 를기반으로하였다 (Cho et al., 2009). 이때사용한자료는질병관리본부인체자원은행에서분양을받아사용하였다 ( ). 연구에서사용한연구대상자의선별은이전연구와동일하게설정하였다 (Jin and Park, 2017). 요약하면환자군으로는과거에결핵진단을받은적이있는 443명을선정하였고건강대조군은특별한질환이없는 3,228 명을선정하였다. 결핵환자군과건강대조군의평균나이는각각 51.0세와 51.6세로유사하였다. 본연구에활용한유전정보는질병관리본부 (KNIH) 와호서대학교에서연구윤리승인을받은후분석을수행하였다 ( HR ). 유전형분석과 Single Nucleotide Polymorphism (SNP) 선별본연구에서는 KARE 유전형자료를기반으로 SNP 을선별하였다. DNA 시료는연구참여자의말초혈액에서분리추출하였고, 유전형판독을위해서는 Affymetrix Genome-Wide Human SNP array 5.0 (Affymetrix, Inc., Santa Clara, CA, USA) 를사용하였다. 유전형판독정확도가 98% 이하이거나, 4% 이상의높은 missing genotype call rate을보이거나, 30% 초과의 heterozygosity 를가지거나, 성별불일치가존재하는대상자들은제외되었다. 본연구에서분석한 IL2RA, IL2RB, IL2RG 유전자영역은전사체양말단에서 5 kb씩확장하여이범위에존재하는각각 16개, 4개, 2개의 SNP들을대상으로하였다. 이 SNP들의염색체상의위치는 UCSC Genome Browser on Human Mar (NCBI36/hg18) 를기준으로하였다. 또한, 실제실험적으로 SNP의유전형을확인한것이외에도 IL2RA 유전자영역에서는 MACH (Li et al., 2010) 를사용하여추가적으로 37개의 imputation SNP을발굴하여분석에사용하였다. Imputation 은 HapMap database (release 24) (International HapMap Consortium 2003) 에서중국인 (Han Chinese form Beijing) 과일본인 (Japanese in Tokyo) 의것을참고로진행하였다. Imputed SNP들중에서 Minor Allele Frequency (MAF) 가 1% 미만이거나상관계수 (r 2 ) 가 0.5 미만인것은분석에서제외하였다. 상관성분석과통계분석대부분의통계분석에는 PLINK version 1.07 ( pngu.mgh.harvard.edu/~purcell/plink) 과 PASW Statistics version 18.0 (SPSS Inc. Chicago, IL, USA) 을사용하였다. 결핵환자군과건강대조군에대한유전적변이의상관성분석은 Logistic 회귀분석을사용하였으며 additive genetic model 을기반으로하였다. 분석값에대한유의수준은 0.05 이하를기준으로하였다. KARE 유전형정보를바탕으로 Haploview version 4.2 (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) 프로그램을사용하여연관불균형 (linkage disequilibrium) 블록구조를확인하였다. 결과 IL2RA, IL2RB, IL2RG 유전자영역의 SNP 선별과상관성분석결과 IL-2 receptor 유전자들은 UCSC Genome Browser on

3 Human Mar (NCBI36/hg18) 를기준으로각각염색체에서유전자의영역을설정 ( 전사체기준으로하여양방향으로 5 kb씩영역확장 ) 한후 KARE 유전형자료에서 SNP을확인하였다. 그결과 IL2RA 는 10번염색체에서 16 개의 SNP이확인되었다. 마찬가지로 IL2RB는 22번염색체에서 4개의 SNP이 IL2RG 는 X 염색체에서 2개의 SNP 을확인할수있었다. 선별된 IL-2 receptor 유전자의 SNP 을대상으로결핵환자군과건강대조군에대한 Logistic 회귀분석을시행한결과 IL2RA 유전자의 16개의 SNP 중 6개의 SNP에서통계적으로유의한상관관계 (P<0.05) 를확인할수있었다. 그러나 IL2RB 유전자에서는분석결과통계적으로유의한 SNP이존재하지않았으며, IL2RG 유전자는 X 염색체의특이성으로분석결과에의미를부여 하기가어려웠다 (Table 1). IL2RA 유전자의 SNP 중가장높은유의수준 (P= ) 을보이는 rs 은상대적위험도 (OR) 는 0.78 으로나타났고신뢰구간 (95% CI) 은 0.68~0.91 으로나타났다. rs 의 minor allele는 T, major allele는 C이다. MAF를살펴보면결핵환자군은 36.4% 이고, 건강대조군은 42.2% 로약 6% 의빈도차이가있어서 T 염기를보유할경우에결핵발생을감소시키는방향으로상관성이있는것을알수있었다. 그러나 rs 는상대적위험도가 1.3으로확인되어 minor allele 를보유하고있을수록결핵발생을증가시키는방향으로의상관성이있다는것을알수있었다. 유의성이높은 6개의 SNP 중 rs 를제외한 5개의 SNP은상대적위험도가낮게확인되었 Table 1. Results of the case-control association analysis between SNPs in the IL2RA, IL2RB, IL2RG genes and tuberculosis in the KARE subjects Gene No. SNP BP Function A1 A2 IL2RA IL2RB IL2RG Cases (n=443) MAF Controls (n=3,228) OR (95% CI) Additive P value 1 rs Intronic G A (0.48~1.68) rs Intronic C T (0.68~0.92) 2.77E-03 3 rs Intronic T C (0.87~1.27) rs Intronic C A (0.96~1.32) rs Intronic G A (0.92~1.26) rs Intronic T C (0.68~0.91) 1.10E-03 7 rs Intronic A G (0.69~0.92) 2.56E-03 8 rs Intronic C A (0.99~1.33) rs Intronic A C (0.94~1.29) rs Intronic A G (0.66~0.91) 1.65E rs Intronic A G (0.97~1.29) rs Intronic A G (0.97~1.30) rs Intronic C T (1.03~1.65) 3.00E rs Intronic C T (0.84~1.33) rs Intronic T A (0.82~1.25) rs Upstream T C (0.72~0.97) 1.72E-02 1 rs Downstream G A (0.81~1.11) rs Intronic A G (0.84~1.22) rs Intronic G C (0.82~1.17) rs Intronic G A (0.93~1.26) rs Intronic G A N/A N/A 2 rs Downstream G A N/A N/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.

4 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. SNP BP Function A1 A2 Cases (n=443) MAF Controls (n=3,228) OR (95% CI) * Additive P value I1 rs Downstream A G (1.07~1.53) 6.92.E-03 I2 rs Downstream T C (1.07~1.53) 6.92.E-03 I3 rs Downstream A G (1.07~1.53) 6.92.E-03 I4 rs Downstream T C (1.07~1.53) 6.92.E-03 I5 rs Downstream T A (1.07~1.53) 6.92.E-03 I6 rs Downstream G C (1.07~1.53) 6.92.E-03 I7 rs Downstream A G (1.07~1.53) 6.92.E-03 I8 rs Downstream G A (1.11~2.60) I9 rs Intronic A G (0.62~0.86) 1.53.E-04 I10 rs Intronic C T (1.15~2.70) 9.88.E-03 I11 rs Intronic G T (0.65~0.89) 5.90.E-04 I12 rs Intronic T G (1.08~1.44) 2.71.E-03 I13 rs Intronic C G (1.01~1.49) I14 rs Intronic T C (1.03~1.44) I15 rs Intronic C T (0.71~0.95) 8.79.E-03 I16 rs Intronic A T (0.69~0.92) 2.75.E-03 G1 rs Intronic G A (0.69~0.93) 2.87.E-03 I17 rs Intronic C T (0.65~0.89) 7.63.E-04 I18 rs Intronic A G (0.65~0.89) 6.35.E-04 I19 rs Intronic G A (1.03~1.37) I20 rs Intronic C A (1.01~1.40) I21 rs Intronic G T (1.02~1.36) I22 rs Intronic G A (0.24~0.94) I23 rs Intronic G A (1.01~1.35) I24 rs Intronic C T (1.00~1.35) I25 rs Intronic G C (0.65~0.88) 4.87.E-04 I26 rs Intronic A C (0.65~0.88) 4.87.E-04 I27 rs Intronic T C (1.04~1.38) G2 rs Intronic A G (0.66~0.89) 5.37.E-04 I28 rs Intronic G C (0.68~0.92) 2.39.E-03 I29 rs Intronic C T (1.01~1.36) I30 rs Intronic G A (1.02~1.36) G3 rs Intronic A G (0.68~0.92) 2.45.E-03 G4 rs Intronic A G (0.67~0.91) 2.01.E-03 I31 rs Intronic G T (0.70~0.94) 5.60.E-03 I32 rs Intronic G A (0.69~0.93) 3.83.E-03 I33 rs Intronic C A (0.67~0.92) 2.55.E-03 I34 rs Intronic C T (0.73~0.98) I35 rs Upstream T C (0.73~0.97) I36 rs Upstream T C (0.73~0.97)

5 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) (Continued) No. SNP BP Function A1 A2 Cases (n=443) MAF Controls (n=3,228) OR (95% CI) * Additive P value I37 rs Upstream C T (0.73~0.97) G5 rs Upstream A G (0.73~0.97) *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. Table 3. Results of the Regulome DB of imputed SNP in the IL2RA gene on chromosome 10 SNP BP A1 A2 Regulome DB Score TFBS DNase Proteins bound Motifs rs A G 3a + + GTAT1, POLR2A ZNF740, NERF1a rs C T 2a + + CTCF, RAD21, SMC3 RFX, BRCA1:USF2 rs C T 2b + + E2F6 PPARG::RXRA rs C A 3a + + SPI1, CHD1, IKZF1 HNF4, 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. 고이중 rs 은 5' 방향의 upstream 영역에서나타났다. IL2RA 유전자 SNP의 Linkage disequilibrium (LD) 구조 IL2RA 유전자에서확인한유의성이높은 6개의 SNP 간의연관불균형현상이나타나는지 Haploview 프로그램을활용하여확인해보고자하였다. 상대적위험도가낮았던 5개의 SNP 중 5kb 확장지역에존재하는 SNP을제외한 4개의 SNP는하나의 LD block을형성하고있었다. 다른 LD block에는상대적위험도가높은 SNP이포함되어있었다 (Fig. 1). IL2RA 유전자 SNP imputation 후상관성분석결과 KARE 유전형자료를기반으로하여 IL2RA 유전자 SNP imputation 을수행하여더많은 SNP과결핵과의상관성여부를확인해보았다. 그결과 182개의 SNP이확인되었고그중 42개의 SNP이통계적으로유의하였다. Imputation 수행전분석결과는결핵발병과상대적위험도가낮은 SNP이대부분이었던반면 imputation 수행후에는상대적위험도가높은 SNP의수와낮은 SNP의수가비슷하게나타났다. Imputation 수행후결핵발생과유의한 상관관계를보이는 SNP들의수가증가한것은 IL2RA 유전자의유전적다형성이결핵발병에영향을줄가능성이높다는것을의미한다 (Table 2). IL2RA 유전자의 SNP이유전자와단백질발현에미치는영향 Imputation 후유의성이높은 IL2RA 유전자가어떻게유전자혹은단백질발현에서영향을미칠것인지 Regulome- DB ( 에서확인해보았다. 확인결과 rs , rs , rs764850, rs 의 4개의 SNP에서의미있는 score를확인할수있었다. 그중 rs 는전사인자결합반응에영향을줄수있을뿐만아니라 DNase peak 차이가있다는것을확인할수있었다. 뿐만아니라이곳은본래 RFX와 BRCA1: USF2 의 motif 로작용하기때문에 IL2RA 유전자발현에영향을줄수있다는것을확인할수있었다. 또한 rs 는 IL2RA 유전자의 3' 말단쪽 5kb 확장범위에존재하는 SNP임에도불구하고통계적유의성과높은 RegulomeDB score가의미있게나타난것은유전자에인접한지역이유전적다양성의조절에있어서중요한역할을할가능성이있음을보여준다 (Table 3)

6 Fig. 1. Linkage disequilibrium of IL2RA SNP on chromosome 10. The 16 SNPs and LD structure were shown by a Haploview of LD (r 2 ) 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. 고찰본연구에서는 IL-2 receptor를발현하는유전자에서 SNP의결핵환자군과건강대조군간 MAF 차이에따른통계적유의성을분석하여유전적변이에따른결핵발병과의상관성에대하여알아보고자하였다. 그결과 IL2RB 와 IL2RG 는결핵환자군과건강대조군간유전변이의 MAF 차이가일정수준이하로나타났다. 이것은 IL-2 receptor β와 γ chain 유전자의유전변이가결핵발병과상관성이낮다는것으로생각할수있었다. 그러나 IL2RA 유전자는 6개의 SNP에서결핵발병과높은유의성이확인되었다. 이 SNP 중 MAF가건강대조군에비하여결핵환자군에서낮은 SNP과높은 SNP 모두확인할수있었 다. 이것은 IL2RA 유전자의유전변이는결핵발병에있어서다양한방향으로영향을미칠수있다는것을의미한다. 또한위의 SNP의 LD 구조를확인해보았을때상대적위험도의방향성이반대인두 SNP이서로다른 LD block 에속해있는것을확인할수있었으며같은방향성을갖는 SNP은같은 LD blcok에속해있는것을볼수있었다 (Fig. 1). 위의결과들을통하여 IL-2 receptor 를발현하는유전자중 α chain을발현하는유전자에존재하는 SNP들이결핵발병과통계적으로유의한상관성이있다는것을확인할수있었다. 기존의 KARE 자료에서 imputation 후의 SNP을기준으로 IL2RA 유전자의통계적유의성을분석해보았을때기존의결과보다많은 SNP을선별할수있었으며높은유의성을갖는 SNP도확인할수있었다. 또한 RegulomeDB

7 결과가높은 score를갖는것도확인할수있었다. 결국 imputation 후의결과는 IL2RA 유전자의유전변이가어떻게결핵발병에영향을주는지자세하게확인해볼수있었고유전변이와결핵발병의상관성이있다는사실을뒷받침해주었다. 인체면역에관여하는여러유전자의유전적차이는면역체계를이루는요소들의차이를만들어결국결핵균의인체침입과이에대한방어와관련된감수성변화를가져올수있다. 결핵균에대한면역학적관점에서보게되면결핵균이감염되었을때인체내에서는다양한면역반응이일어나며이에관여하는세포들은다양하다 (Kleinnijenhuis et al., 2011; Dey and Bishai, 2014). 결핵감염초기에결핵균이완전하게제거되지않으면 T cell 이결핵균에대한면역에관여하게된다. T cell 은결핵균을포함한육아종을형성하여그안에서균의사멸을유도한다 (Gideon et al., 2015). 하지만환자의면역학적상태에따라결핵균의사멸은조절되며이환자의상태는환자에감염된결핵균의특성뿐만아니라환자의임상증상과면역력등이관여한다. T cell과 macrophage 는결핵균을사멸하고병변을형성한다. 이때 CD4+ T cell은 IL-2, IFN-γ 와같은 cytokine 을분비하여항원발현을증강시키고세포매개면역반응을촉진시키는역할을한다 (Edwards and Kirkpatrick, 1986). 또한활성화된 T cell은 IL-2 receptor 가세포표면에발현되어 IL-2 와결합한다 (Morgan et al., 1976; Rubin et al., 1985). 결합된 IL-2는휴지기 T cell을 effector T cell, memory T cell로분화하도록촉진하고 Th1 cytokine 의발현조절에관여한다. T cell의표면에발현하는 IL-2 receptor 중 α chain은 soluble 한상태 (sil-2rα) 로유리되어남게된다. 앞선연구에서는정상인의혈청에존재하는 sil-2rα 보다세포매개면역반응이진행될때의 sil-2rα 가증가한것을관찰하였다 (Rubin et al., 1985). sil-2rα 의정상혈청농도보다증가한상태는 T cell의활성화정도와세포면역기능의증감을예측할수있는지표로활용되는연구는활발하게진행되고있다. 따라서 IL-2Rα 를발현하는유전자에유전적변이가생긴다면 IL-2Rα 가발현되는양에조절이생길것이고그렇게되면 IL-2Rα 가관여하는면역체계에는변화가있을것이다. 결국결핵균의특성과환자의임상증상이결핵의감수성과관련하여중요하지만면역에관련된유전적다형성또한결핵에대한감수성에영향을줄수있다. 그동안국내의많은연구에서결핵의발병과관련하여결핵균의특성을고려하는연구들이진행되어왔다 (Oh et al., 2009; Park et al., 2012; Cho et al., 2014). 그러나본연구에서는결핵발병에영향을줄수있는면역에관여하는숙주의유전적다형성이결핵발병과관한환자의감수성이조절될수있는가능성을제시해주고있으며이결과를통하여결핵에유전적인감수성이있는환자에대한연구와관리가가능할것이라고생각한다. 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 (2017R1C1B ). 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. REFERENCES Caccamo N, Guggino G, Joosten SA, Gelsomino G, Di Carlo P, Titone L, Galati D, Bocchino M, Matarese A, Salerno A, Sanduzzi A, Franken WP, Ottenhoff TH, Dieli F. Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection. Eur J Immunol : Casey R, Blumenkrantz D, Millington K, Montamat-Sicotte D, Kon OM, Wickremasinghe M, Bremang S, Magtoto M, Sridhar S, Connell D, Lalvani A. Enumeration of functional T-cell subsets by fluorescence-immunospot defines signatures of pathogen burden in tuberculosis. PLoS One : e Cho JE, Cho SN, Cho S. RpoB Peptide Derived from Mycobacterium tuberculosis is Processed and Presented to HLA- A*0201 Restricted CD8+ T Cells via an Alternate HLA-I Processing Pathway : Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Lee JK, Oh B, Kim HL. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet :

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untitled Korean J Clin Lab Sci. 2019;51(3):323-328 https://doi.org/10.15324/kjcls.2019.51.3.323 Korean Society for Clinical Laboratory Science ORIGINAL ARTICLE Association between Tuberculosis Case and CD44 Gene