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1 118 Hyun-Seok Jin, et al. ITGB2 Gene Polymorphism affects Tuberculosis Case ORIGINAL ARTICLE Korean J Clin Lab Sci. 2018;50(2): pissn eissn Association between ITGB2 Genetic Polymorphisms and Tuberculosis Hyun-Seok Jin, Sang-In Lee, Sangjung Park Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Korea ITGB2 유전자다형성과결핵사이의연관성연구 진현석, 이상인, 박상정 호서대학교생명보건대학임상병리학과 Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB), but the genes associated with the host immune system can be attributed to the development of TB. The ITGB2 gene encodes the integrin beta 2 chain CD18 protein and is present on chromosome 21. The integrin beta 2 chain is an integrin expressed in leukocytes and plays a very important role in leukocyte maturation and attachment. ITGB2 plays an important role in the phagocytosis of MTB and the aggregation of leukocytes in MTB infections. This study examined the genetic polymorphisms of the ITGB2 gene between the TB case and normal control using Korean genomic and epidemiologic data. As a result, a statistically significant correlation was confirmed in 10 SNPs. The most significant SNP was rs (OR=0.69, CI: , P= ). In addition, rs173098, one of the significant 10 SNPs, is possibly located in a binding motif with the transcription factor cofactor p300, and can affect ITGB2 gene expression. These findings suggest that the pathogenesis of TB may be influenced by a range of genetic factors related to the immune function of the host, e.g., the reactions associated with the recruitment and attachment of leukocytes. The results of this study could be used to predict the infection control for tuberculosis in a patient-tailored manner. Key words: CD18, Genetic association study, ITGB2, Mycobacterium tuberculosis, SNP Corresponding author: Sangjung Park Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, 20 Hoseo-ro 79 Beon-gil, Asan 31499, Korea Tel: Fax: sangjung@hoseo.edu 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. Copyright 2018 The Korean Society for Clinical Laboratory Science. All rights reserved. Received: May 1, 2018 Revised: May 15, 2018 Accepted: May 22, 2018 서론결핵은결핵균 (Mycobacterium tuberculosis, MTB) 감염으로발병하는감염성질환이다. 이러한결핵의발병은특정인종및민족, 가족력간의다른비율로결핵이발생하게되는데이러한발병의요인에는숙주의유전적인차이에따른원인이작용하게된다. MTB가생존할수있는환경과숙주사이의유전적인자는복잡한상호작용을통하여결핵발병에중요한역할을하게된다 [1]. 숙주의유전적요인은적어도 MTB에대한감염 의위험성을나타낼수있다. 이전에수행한쌍둥이를이용한연구와 Genome-Wide Association Study (GWAS) 등을통하여숙주의유전적차이가 MTB에대한감수성에영향을줄수있음을시사하고있다 [2-6]. ITGB2 유전자는 integrin beta 2 chain인 CD18 단백을암호화하고있고, 염색체 21q22.3 에위치하고있다 [7]. Beta 2 인테그린은백혈구에서발현하는중요한결합단백이자신호전달을담당하고있는단백질이다. 4 가지 2 인테그린은면역세포기능의세가지주요측면을조절하는데중요한역할을한다.

2 Korean J Clin Lab Sci. Vol. 50, No. 2, June CD18 단백질은 2 인테그린중 beta subunit 을담당하고있으며이는 4가지의 alpha subunit 과결합하여 receptor 를형성하고, 면역반응에관여하는리간드와결합한다. 또한 beta 2 integrin은수지상세포와단핵구, 대식세포의기능을조절하는역할을수행한다고알려져있다 [8]. 그중 CD11b와 CD18로이루어진 Complement receptor 3 (CR3) 는 MTB 감염시사람의대식세포와단핵구에서발현하며, CR1과 CR4와함께 MTB의탐식작용하는데 C3를통한옵소닌화를담당하는것으로알려져있다 [9]. 뿐만아니라 MTB에감염된수지상세포는내피세포에 CD18 발현이감소하여내피세포에대한결합력이감소된다고보고하고있다 [10]. 따라서본연구에서는한국인유전체역학조사사업의일환으로조사를실시한코호트자료를활용하여과거결핵발병이있었던환자군과질병이없는건강대조군을설정하고, 환자군과건강대조군사이에서 ITGB2 유전자의유전적다형성이결핵발병에영향을주었는지확인하고자유전적변이에대한상관성분석을시행하였다. 재료및방법 1. 연구대상자본연구를위한한국인연구대상자는한국인유전체역학조사사업 (Korean Genome and Epidemiology Study, KoGES) 의일환인 Korean Association REsource (KARE) 를기반으로하였다 [11]. 이때사용한유전체자료는질병관리본부인체자원은행에서분양을받아분석을하는데사용하였다 ( ). 본연구에서사용한연구대상자의선별은이전연구와동일하게설정하였다 [12]. 요약하자면환자군은과거에결핵진단을받았던 443명을대상으로하였고, 그외의특별한질환이없는 3,228 명을건강대조군으로선정하여본연구에활용하였다. 본연구에활용한유전정보는질병관리본부 (KNIH) 와호서대학교에서연구윤리승인을받은후수행하였다 ( HR ). 2. 유전형분석과 Single Nucleotide Polymorphism (SNP) 선별자세한유전형판독과 QC 과정은앞서발표된논문 [11] 에잘기술되어있다. 본연구에서분석한 ITGB2 유전자전사체영역에존재하는 9개의 SNP은 KARE 유전형자료에서선별하였다. 유전자전사체영역의양말단에서 5 kb씩확장하여이범위에존재하는 SNP을분석에대상으로사용하였다. 선별된 SNP의 염색체상의위치는 NCBI human genome build 36를기준으로하였다. 뿐만아니라 77개의 imputed SNP를 MACH 을활용하여선별하였다 (Table 1). 3. 상관성분석과통계분석대부분의통계분석에는 PLINK version 1.07 ( mgh.harvard.edu/ purcell/plink) 과 PASW Statistics version 18.0 (SPSS Inc. Chicago, IL, USA) 을사용하였다. 로지스틱회기분석이결핵환자군과건강대조군에대한유전적변이와의상관성분석에사용되었다. 상관성분석은 additive genetic model을기반으로하였고, 유의수준은 0.05 이하를기준으로하였다. Haploview version 4.2 (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) 프로그램을사용하여 KARE 유전형정보를바탕으로연관불균형 (linkage disequilibrium) 블록구조를확인하였다. 또한인터넷을기반으로한 LocusZoom Version 1.1 ( edu/locuszoom) 의 ASN(Asian) population panel 을활용하여 SNP간의 regional association plot을확인하였다. 또한, ITGB2의결핵발병과관련된생물학적 pathway를검색하기위해서 KEGG (Kyoto Encyclopedia of Genes and Genomes, database를활용하여 ITGB2가결핵에미치는영향을알아보고자하였다. 결과 1. 연구대상자정보 KARE 코호트기반의결핵환자군 443명과건강대조군 3,288 명에대한기본적인정보는지난연구결과에서확인할수있다. 간략히언급하자면, 결핵환자군의평균연령은 51.0세이고, 건강대조군은 51.6세로유의한차이가없었다. 그러나, 두그룹에서남성의비율이건강대조군에서는여성의비율과유사하였으나, 결핵환자군에서는남성이 61.2% 로높은비율을보이고있었다. 2. ITGB2 유전자영역의 SNP 선별과상관성분석결과 ITGB2 유전자전사체영역에서양방향으로각각 5kb씩확장한영역에서 9개의 genotyped SNPs 와 77개의 imputated SNPs 을확인할수있었다 (Table 1). 이렇게선별된 ITGB2 유전자의총 86개 SNPs 을대상으로결핵환자군과건강대조군에대한로지스틱회귀분석을시행한결과 10개의 SNP에서통계적으로유의한상관관계를보이고있었다. 그중 genotyped SNP

3 120 Hyun-Seok Jin, et al. ITGB2 Gene Polymorphism affects Tuberculosis Case Table 1. Associations between the 86 SNPs in the ITGB2 gene and tuberculosis in KARE subjects No. SNP Consequence to transcript BP A1 A2 Cases (N=443) MAF Control (N=3,228) OR (95% CI) Additive P value I1 rs intergenic C A ( ) I2 rs intergenic G A ( ) I3 rs intergenic A G ( ) I4 rs intergenic A T ( ) I5 rs intergenic T G ( ) I6 rs intergenic A G ( ) I7 rs intergenic A G ( ) I8 rs intergenic C T ( ) I9 rs intergenic A G ( ) I10 rs intergenic A G ( ) I11 rs intergenic A G ( ) I12 rs intergenic A G ( ) I13 rs intergenic G T ( ) I14 rs downstream C T ( ) I15 rs downstream T C ( ) I16 rs downstream C T ( ) I17 rs ' UTR T G ( ) G1 rs684 3' UTR T C ( ) I18 rs intronic G C ( ) I19 rs intronic A G ( ) I20 rs intronic T C ( ) I21 rs intronic A G ( ) I22 rs intronic G A ( ) I23 rs intronic A C ( ) I24 rs intronic A G ( ) I25 rs intronic T C ( ) I26 rs intronic A G ( ) I27 rs intronic T G ( ) I28 rs intronic T A ( ) I29 rs intronic T G ( ) I30 rs intronic C G ( ) I31 rs intronic T C ( ) G2 rs intronic T C ( ) I32 rs intronic T C ( ) I33 rs intronic T C ( ) I34 rs intronic T C ( ) I35 rs intronic A G ( ) I36 rs intronic A C ( ) I37 rs intronic A G ( ) I38 rs intronic A C ( ) I39 rs intronic A G ( ) G3 rs intronic C T ( ) I40 rs intronic T C ( ) I41 rs intronic A G ( ) I42 rs intronic T C ( ) I43 rs intronic C G ( ) I44 rs intronic A T ( ) I45 rs intronic A G ( ) I46 rs intronic A T ( ) I47 rs intronic T C ( ) I48 rs intronic T C ( ) I49 rs intronic G C ( ) I50 rs intronic G A ( ) 0.293

4 Korean J Clin Lab Sci. Vol. 50, No. 2, June Table 1. Continued No. SNP Consequence to transcript BP A1 A2 Cases (N=443) MAF Control (N=3,228) OR (95% CI) Additive P value G4 rs intronic C T ( ) I51 rs intronic C T ( ) I52 rs intronic A G ( ) I53 rs intronic G A ( ) I54 rs intronic G C ( ) I55 rs intronic G A ( ) I56 rs intronic T G ( ) I57 rs intronic T C ( ) I58 rs intronic T C ( ) I59 rs intronic T C ( ) G5 rs intronic T C ( ) I60 rs intronic C A ( ) I61 rs intronic C G ( ) G6 rs intronic C T ( ) G7 rs intronic T C ( ) I62 rs intronic G A ( ) I63 rs intronic T C ( ) I64 rs intronic G A ( ) I65 rs intronic T G ( ) I66 rs intronic G A ( ) I67 rs intronic G A ( ) I68 rs intronic C T ( ) I69 rs intronic T C ( ) I70 rs intronic G A ( ) I71 rs intronic C T ( ) I72 rs intronic A G ( ) I73 rs intronic A G ( ) I74 rs intronic C T ( ) G8 rs intronic G A ( ) I75 rs intronic T C ( ) G9 rs intronic G A ( ) I76 rs intronic G A ( ) I77 rs intronic C T ( ) P-values of <0.05 are indicated in bold. Abbreviations: A1, minor allele; A2, major allele; BP, base pair; CI, confidence interval; G of no., genotyped number of SNP; I of no., imputed number of SNP; KARE, Korean Association Resource; MAF, minor allele frequency; OR, odds ratio; SNP, single nucelotide polymorphism. The SNP positions are based on NCBI Build 36 human genome assembly. 는하나의 SNP에서유의한결과를보였고, 다른 9개는 imputed SNP에서유의한결과를보였다. 가장높은유의수준 (P= ) 을보이는 SNP은 rs 으로상대적위험도는 0.69에신뢰구간은 을보이고있었다. rs 의 minor allele frequency (MAF) 를살펴보면, 결핵환자군에서는 T 염기의빈도가 7.3% 이고, 대조군에서는 10.3% 로빈도의차이가있어서 rs 의 T 염기를보유할경우에결핵발생을감소시키는방향으로의상관성이존재하였다. 또다른유의한결과를보여주는 9개의 SNPs도역시 minor allele 가질경우에상대적위험도가낮아지는경향을보여주고있었다 (Table 1). 3. ITGB2 유전자 SNP의 Linkage disequilibrium (LD) 구조 Haploview 프로그램을사용하여상관분석에사용한 ITGB2 유전자영역중 3 쪽의 36개 SNP에대해 LD 구조를확인하였다 (Figure 1). 그결과 27개의 SNP 들이하나의 LD 블록을형성하고있었다. 다른 9개의 SNP가또다른 LD 블록을형성하는것을확인할수있었다. 이중상관분석에서가장유의성이높았던 rs 는또다른 4개의 SNP (rs684, rs235375, rs173098, rs ) 와함께 Block 1을형성하는것을확인할수있었고, 또다른 3개의유의성이있는 SNP (rs , rs , rs ) 가 Block2를형성하는것을확인하였다. 이를통해연관성있는 SNPs들이각각의 Block에서존재하

5 122 Hyun-Seok Jin, et al. ITGB2 Gene Polymorphism affects Tuberculosis Case Figure 1. Linkage disequilibrium of ITGB2 SNP on chromosome 21. The LD structure was confirmed for 36 SNPs at the 3 terminus of ITGB2 gene. The 36 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 eight SNPs with significance, five SNPs belong to Block 1, and three SNPs belong to Block 2. Figure 2. Associations between ITGB2 SNPs and tuberculosis case in Korean. The positions of the SNPs are shown at the top of the figure, and associations between SNPs in the ITGB2 gene and tuberculosis in Korean subjects are shown in the middle. The statistical significances ( log 10 P-value) of associations with the genotyped and imputed SNPs are plotted. The recombination rates estimated using HapMap ASN population data is shown by a blue line. The purple diamond with a SNP number represents the SNP most strongly associated with tuberculosis, and its correlations with other SNPs are shown by colors indicating the levels of linkage disequilibrium (r 2 ). At the bottom of the figure, the nucleotide position of the ITGB2 gene on chromosome 21 (NCBI build 36) is shown. 는것을알수있었다. 또한 regional plot 결과에서도크게세개의영역으로나뉘어 SNP들이서로연관성이있다는것을알수있었고, 가장높은유의성이있는 rs 와 ITGB2 유전자의 3 말단에있는 SNP들과연관성이매우높은것을확인할수있었다. 이는 ITGB2 유전자와결핵발생사이에연관성이있다는사실을뒷받침해준다 (Figure 2). 4. ITGB2 유전자의 KEGG pathway 검색결과 ITGB2 유전자의결핵발생과의관련성에대해생물학적 pathway 관점에서살펴보고자 KEGG database에서검색해보았다. 결과는이전연구에서확인했던 cell adhesion molecule 신호전달경로에서항원제시세포 (antigen presenting cells;apc) 와 T 세포의결합이나 Cytotoxic T세포와감염세포가결합하는데있어서 ITGB2가 T 세포 receptor signaling pathway 의결합에중요한역할을하고있는것을확

6 Korean J Clin Lab Sci. Vol. 50, No. 2, June 인할수있었다. 뿐만아니라대식세포나수지상세포가 MTB 탐식작용에있어서 CD11c/CD18과 CD11b/CD18을활용한다는것을알수있었다. 고찰본연구에서는 ITGB2 유전자의연관성연구를통하여 86개의 SNPs에서결핵이발병했던환자군과건강대조군사이에유전변이의빈도차이를확인해보았다. 그결과 10 개의 SNP에서통계적으로유의한수준의빈도차이가있는것을확인할수있었다. 특히가장유의성이있는 SNP는 rs 인것을확인할수있었다. 이 SNP는 Figure 2에서확인할수있듯이 ITGB2 유전자의 3 말단의다른 SNP과 0.6 이상의높은 r 2 값을가지는것을확인할수있었다. 또한이번연구결과에서유의성이있다고나타난 SNP들은모두 minor allele를가질경우상대적위험도가감소하는방향으로나타나는것을확인할수있었다. 뿐만아니라 Figure 1의 LD plot 결과에서도서로다른 2개의 block에유의성을갖는 SNP 들이각각분포하고있는것을확인할수있었고이를통하여 ITGB2 내에존재하는 SNP 들이결핵발병과통계적으로유의한상관관계가있다는것을확인할수있었다. 이러한 intronic SNP들이어떻게 ITGB2 유전자나단백질발현에영향을줄수있는지에대해서 RegulomeDB ( regulomedb.org/index) 로확인해보았다. 그결과 T 세포혹은단핵구에서 rs173098, rs , rs 의세개의 SNP들에서전사인자가결합하고, DNase peak 차이가나타나는것을확인할수있었다. 또한 rs173098는전사보조인자인 p300에대한 motif로작용하는영역에서나타나는것을알수있었다. 따라서이러한 SNP의유전적다형성은 ITGB2의단백질의발현혹은단백질의 2차구조에영향을줄수있는가능성을보여주고있었다. 면역반응에서인테그린은다른세포와의상호작용을하는데있어서중요한신호전달단백질이다. 이러한상호작용은세포외기질단백및세포표면리간드를통하여일어나게된다 [13]. 특히 beta 2 인테그린은백혈구에서만발견되기때문에면역계에서매우중요하다. Beta 2 인테그린은림프조직과염증조직으로백혈구의모집와, 백혈구구르기후혈관외로백혈구가유출하는것을매개한다 [14]. 또한면역학적시냅스형성을포함한백혈구사이의세포상호작용을수행하며 [15], Toll like receptor (TLR) 에의한세포내신호전달체계에따른세포반응에관여하는것으로알려져있다 [16]. 특히 MTB에감염된수지상세포는 ITGB2의발현을억제하고이를통하여백혈구사이의신호전달체계를억제하여, 감염된세포의항원제시능력을억제하며, cytokine 의분비를억제하고, 결국 MTB에대한초기면역반응을억제한다고알려져있다 [17]. 수지상세포뿐만아니라대식세포에서는 beta 2 인테그린 subunit인 CD18과결합하는 4가지의 alpha subunit ( L CD11a, M CD11b, X CD11c, and D CD11d) 들이 4가지의 receptor를형성한다. 그 receptor들은 Leukocyte function associated antigen-1 (LFA-1), Macrophage-1 antigen (MAC-1)/Complement receptor 3 (CR3), Complement receptor 4 (CR4) 그리고 CD18/CD11d등으로형성된다. 이 receptor들을공통적으로 Intercellular Adhesion Molecule 1 (ICAM-1) 을리간드로인지하여결합하는것으로알려져있다. ICAM-1은 MTB 감염에있어서육아종을형성하는데중요한역할을수행하는단백질로 ICAM-1 을 knock out 한마우스에서대식세포의세포집합현상이일어나지않아마우스가쉽게사멸하는것을확인한바있다 [18]. 또다른연구에서는 MTB에감염된대식세포에서 MAC-1 과 ICAM-1 의발현이증가하는현상을확인하기도하였다 [19]. 뿐만아니라 CR3 와 CR4 또한 MTB의 LAM과반응하여대식세포에탐식작용을수행하여 MTB 사멸을유도한다는보고도있다 [20, 21]. 이는우리가 KEGG pathway 에서볼수있었던 MTB 감염시 ITGB2 의역할과동일하다는것을확인할수있었다. 이러한보고를통하여 ITGB2의유전적다형성은결핵발병에있어서수지상세포및대식세포의세포집합과정및 MTB의탐식작용에영향을줄수있고, 이를통하여결핵발병에대한차이를유도할수있을것이라고생각한다. 또한이번연구에서결핵발병과유의성이있다고알려진 SNP 중 rs684의경우 ITGB2 유전자의 3 말단쪽비해독영역에존재하고있는 SNP인데이는 NCBI에서제공하는 ClinVar 에의하면 Leukocyte adhesion deficiency (LAD) 의질병과 Likely benign 으로연관되어있다고알려져있다 ( preview.ncbi.nlm.nih.gov/clinvar/variation/340134/). 이는이 SNP에 C염기에서 T염기로치환되었을경우 LAD를유발하는데이 SNP가영향을줄수있다는것을의미한다. 이질병은백혈구의부착단백이발현되지않는유전적질병으로이병이발현하게되면감염에있어서백혈구들이감염된곳으로이동할수없기때문에감염에쉽게노출될수있는것으로알려져있다 [22]. 본연구에서는결핵이발병했던환자군과건강대조군사이의 rs684의유전형빈도차이가있음을확인할수있었다. 이는이러한유전적양상의차이가 MTB 감염에대항할수

7 124 Hyun-Seok Jin, et al. ITGB2 Gene Polymorphism affects Tuberculosis Case 있는백혈구들의신호전달이나부착등에영향을줄수있을것이라고생각한다. 유전적다형성과질병과의상관관계를분석하여특정질병발병에영향을주는유전적다형성에대한연구는국내에서활발하게진행되고있다 [23]. 그중결핵은감염성질환이지만현재결핵의발병에는숙주세포의다양한유전적차이가결핵발병에영향을미친다고예상하고있는연구가많이진행되고있다 [1, 24-26]. 본연구팀은이전연구에서 CD226 유전자가결핵발병에미치는영향에대해서언급한바있다. 특이이유전자는 NK cell과 T 세포가항원을인지하고제거하는데있어서중요한역할을한다고언급한바있다 [12]. 본연구에서는이와관련하여 CD226과결합하는인자중하나인 ITGB2 의유전적다형성역시결핵발병과연관이있는것을확인하였다. 이를통하여결핵발병은어떤하나의원인이아니라다양한숙주의면역체계의유전적다형성이영향을미칠수있다고생각한다. 본연구결과를활용하여결핵발병에영향을줄수있는사람의유전적인자에대해알아보고, 이를통해 MTB에대한각개인의감염의과정및결과의차이를이해하는데중요한기반이될수있을것으로기대한다. 요약결핵은본질적으로 MTB에의해발생하는감염성질환이지만발병의과정에는숙주의면역계와연관성있는하는유전자가관여한다. ITGB2 유전자는인테그린 beta 2 chain인 CD18 단백질을암호화하고있는유전자로염색체 21번에존재하고있다. 인테그린 beat 2 chain은백혈구에서발현하는인테그린으로백혈구의성숙및부착에매우중요한역할을수행하는단백질이다. ITGB2는결핵발병에서 MTB의탐식과백혈구의집합에도중요한역할을수행한다고알려졌다. 따라서이번연구는한국인의유전체데이터를활용하여결핵발생환자들과정상대조군사이에서 ITGB2의유전적다형성의빈도에통계적으로유의한차이가존재하는지를알아보고자하였다. 그결과 10개의 SNP에서유의한상관관계를확인할수있었다. 가장유의성있는 SNP는 rs 였다 (OR=0.69, CI: , P= ). 또한 rs173098의경우는전사보조인자인 p300이결합할가능성이있는염기서열이존재하여유전적다형성에따라 ITGB2 유전자발현에영향을미칠수있음을확인할수있었다. 이러한결과는결핵의발병기전이백혈구집합이나부착과같은숙주의면역기능과관련된다양한유전적요인에의해영향을받을수있음을시사한다. 이연구결과는결핵 의발병에숙주면역계의유전자들이영향을줄수있다고볼수있다. 이러한결과들을통해 MTB 감염에대해각사람들별로감염의진행과정과결과에차이를가져다주는유전적배경에대한이해에기반을제공할것으로기대한다. 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: None REFERENCES 1. Moller M, Hoal EG. Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis (Edinb). 2010;90: j.tube Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis. 1978;117: van der Eijk EA, van de Vosse E, Vandenbroucke JP, van Dissel JT. Heredity versus environment in tuberculosis in twins: the 1950s United Kingdom Prophit Survey Simonds and Comstock revisited. Am J Respir Crit Care Med. 2007;176: Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, et al. Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun. 2004;5: Mahasirimongkol S, Yanai H, Nishida N, Ridruechai C, Matsushita I, Ohashi J, et al. Genome-wide SNP-based linkage analysis of tuberculosis in Thais. Genes Immun. 2009;10: Mahasirimongkol S, Yanai H, Mushiroda T, Promphittayarat W, Wattanapokayakit S, Phromjai J, et al. Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis. J Hum Genet. 2012;57: Arnaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood. 1990;75: Schittenhelm L, Hilkens CM, Morrison VL. beta2 integrins as regulators of dendritic cell, monocyte, and macrophage function. Front Immunol. 2017;8: fimmu Schlesinger LS, Azad AK, Torrelles JB, Esteban R, Isabelle V, Vojo D. Determinants of phagocytosis, phagosome biogenesis and autophagy for Mycobacterium tuberculosis: Kaufmann HE,

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Microsoft Word - 05-Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis Case

Microsoft Word - 05-Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis Case Biomedical Science Letters 2018, 24(2): 94~101 https://doi.org/10.15616/bsl.2018.24.2.94 eissn : 2288-7415 Original Article Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis