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The Genetic Variations of NOD2 Are Associated With White Blood Cell Counts
Biomed Sci Letters 2018;24:334-340
Published online December 31, 2018;  https://doi.org/10.15616/BSL.2018.24.4.334
© 2018 The Korean Society For Biomedical Laboratory Sciences.

Hyun-Seok Jin1,2,*, and Sangwook Park3,†,*

1Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea,
2The Research Institute for Basic Science, Hoseo University, Asan, Chungnam 31499, Korea,
3Department of Biomedical Laboratory Science, College of Health and Nurse, Kyungwoon University, Gumi 39160, Korea
Correspondence to: Sangwook Park. Department of Biomedical Laboratory Science, College of Health and Nurse, Kyungwoon University, Gumi 39160, Korea. Tel: +82-54-479-1282, Fax: +82-54-479-1280, e-mail: spark367@ikw.ac.kr
Received August 17, 2018; Revised September 19, 2018; Accepted October 8, 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

The cytoplasmic elicitor, nucleotide-binding domain and leucine-rich repeat containing domain receptors (NLRs) is well established molecules in its role in inflammatory response. Among 22 NLR receptors, NOD2 is one of the intensively studied genes of elucidating for the inflammatory bowel disease and Crohn’s disease as well. Recent research have accumulated that common genetic mutations in Parkinson’s disease (PD) are increasingly related to the susceptibility to Crohn’s disease. In this study, with the Korean Genome and Epidemiology Study, we aimed to perform the association between NOD2 polymorphisms and blood cell counts [WBC (white blood cell) count, RBC (red blood cell) count, platelet count], which linked supposedly to cytoplasmic inflammatory responses with clinical specialty. Linear regression analyses were performed, controlling for residential area, sex, and age as covariates. As a results, 12 SNPs from NOD2 gene were significantly associated with WBC counts (Bonferroni correction P-value criteria < 0.05/23=0.00218). In this study, we could ensure an association with NOD2 gene and WBC counts. This is the first report to have relationship between SNPs of NOD2 gene and WBC counts.

Keywords : Nucleotide-binding, Oligomerization domain-containing 2 (NOD2), White Blood cell (WBC), Association, Single Nucleotide Polymorphism (SNP)
꽌 濡

蹂묒썝꽦 誘몄깮臾쇱쓣 슚怨쇱쟻쑝濡 젣嫄고븯湲 쐞빐 떎냼 蹂듭옟븯吏留 젙援먰븳 諛⑹뼱떆뒪뀥쓣 삎꽦븯뒗 諛⑺뼢쑝濡 씤媛꾩 吏꾪솕빐 솕떎(Pétrilli et al., 2007; Trinchieri and Sher, 2007). 씤媛꾩쓽 硫댁뿭諛⑹뼱 泥닿퀎씤 珥덇린硫댁뿭 泥닿퀎(innate immunity) 쟻쓳硫댁뿭 泥닿퀎(adaptive immunity)瑜 넻븯뿬 씤泥대뒗 쇅遺쓽 誘몄깮臾쇰뱾쓣 슚怨쇱쟻쑝濡 諛⑹뼱빐 솕떎(Mantovani et al., 2011). 쟻쓳硫댁뿭 B, T 由쇳봽援ъ쓽 겢濡좎꽑깮怨 빆썝듅씠닔슜泥댁쓽 쑀쟾옄 옱議고빀怨 媛숈 遺꾩옄깮臾쇳븰쟻씤 怨쇱젙쓣 嫄곗퀜 듅씠 빆썝쓣 씤吏븷 닔 엳룄濡 꽕怨꾨맂떎(McHeyzer-Williams and McHeyzer-Williams, 2005). 諛섎㈃뿉, 珥덇린硫댁뿭 泥닿퀎뒗 깮떇꽭룷뿉꽌 븫샇솕 맂(germline encoded) 뙣꽩 씤떇닔슜泥(pattern recognition receptors, PRRs)씪怨 遺덈━뒗 珥덇린硫댁뿭닔슜泥닿 蹂묒썝泥댁쑀궗遺꾩옄뙣꽩(pathogen-associated molecular patterns, PAMPs)泥섎읆 吏꾪솕쟻쑝濡 옒 蹂댁〈맂 誘몄깮臾쇱쓽 怨듯넻援ъ“瑜 씤떇븿쑝濡쒖뜥 씤泥대갑뼱湲곗쟾쓣 떆옉븯룄濡 룄솕꽑쓣 젣怨듯븳떎(Medzhitov and Janeway, 1997; Wilkins and Gale, 2010; Zipfel, 2014). 씤媛꾧쾶냸議곗쭅(Human Genome Organization, HUGO)쓽 쑀쟾옄 紐낅챸쐞썝쉶뿉꽌뒗 22媛쒖쓽 돱겢젅삤떚뱶 寃고빀 냼以묓빀泥댄솕 룄硫붿씤 븿쑀 떒諛깆쭏 2 쑀궗 닔슜泥(nucleotide-binding, oligomerization domain-containing 2 like receptor, NOD2-like receptor; NLR)쓽 몴以 紐낆묶쓣 듅씤븯뿬(Ting et al., 2008) 꼸由 궗슜릺怨 엳떎. 씠뱾 NLR 닔슜泥 以묒뿉꽌 珥덇린 硫댁뿭諛섏쓳뿉꽌 넧쑀궗 닔슜泥(Toll-like Receptor; TLR) 븿猿 媛옣 삤옯룞븞 씎誘몃∼寃 뿰援щ맂 쑀쟾옄뒗 Nucleotide-binding, oligomerization domain-containing 2 (NOD2) 留ㅺ컻 닔슜泥댁씠떎. NOD2뒗 쇅遺 珥됱쭊젣(agonist) 씤 muramyldipeptide (MDP)쓽 옉슜뿉 쓽빐 꽭룷吏덈궡뿉꽌 씤뵆씪留덉씤 NODosme 蹂듯빀泥대 삎꽦븳떎(Girardin et al., 2003). 寃곌낵쟻쑝濡 뿼利앸ℓ媛쒖꽦 IL-1β, IL-18怨 媛숈 궗씠넗移댁씤쓣 遺꾨퉬븿쑝濡쒖뜥 쇅遺 臾쇱쭏뿉 븳 옄洹뱀뿉 븳 젙긽쟻씤 닕二쇰갑뼱瑜 쐞븳 諛⑸쾾꽱꽌뿭븷쓣 떞떦븯怨 뿼利앷린쟾쓣 議곗젅븳떎. 엫긽쟻쑝濡 以묒슂븳 뿼利앹꽦 옣吏덈퀝씤 겕濡좊퀝(Crohn’s disease) 븘吏 洹 썝씤쓣 젙솗엳 븣 닔 뾾吏留 쑀쟾븰쟻씤 痢〓㈃뿉꽌 洹 썝씤 NOD2 쑀쟾옄쓽 룎뿰蹂씠泥닿 썝씤쑝濡 븣젮졇 엳떎(Hugot et al., 2001). 씠 쇅뿉룄 NOD2뒗 옄媛룷떇(Autophagy) 쁽긽뿉 愿뿬븯硫 NOD1怨 븿猿 ATG16L1쓣 걣뼱뱾뿬 옄媛룷떇 湲곗쟾뿉 以묒슂븳 뿭븷쓣 븳떎(Travassos et al., 2010). 理쒓렐뿉뒗 룞臾쇱떎뿕뿉꽌 NOD2쓽 寃곗넀씠 옣뿼怨 愿젴엳뒗 옣吏곸옣븫쓣 쑀諛쒗븯뒗 寃껋쑝濡 蹂닿퀬릺뿀떎(Branquinho et al., 2016).

삁븸쓽 二쇱슂 援ъ꽦꽦遺꾩씤 諛깊삁援щ뒗 빑씠 뾾뒗 쟻삁援ъ 삁냼뙋怨 떖由 빑쓣 吏땶떎. 諛깊삁援щ뒗 쇅遺移⑥엯옄 媛먯뿼吏덈퀝쑝濡쒕꽣 씤泥대갑뼱瑜 쐞빐 硫댁뿭怨꾩뿉꽌 以묒슂븳 엫臾대 닔뻾븳떎怨 븣젮졇 엳떎. 諛깊삁援щ뒗 뿼利앸컲쓳뿉 寃곗젙쟻씤 뿭븷쓣 떞떦븯뒗 삁븸떒諛깆쭏씠怨 由쇳봽援ъ 삊뾽븯뿬 궗씠넗移댁씤쓣 諛⑹텧븯뒗 벑 뿼利앸컲쓳쓣 議곗젅, 쑀吏떆궎뒗 뿭븷쓣 떞떦븳떎. 諛깊삁援ъ쓽 닔뒗 湲됱꽦, 留뚯꽦뿼利앹쭏蹂묒쓽 吏몴옄濡쒖뜥 醫낆쥌 궗슜릺怨 엳떎. 씠 뿰援ъ쓽 紐⑹쟻 NOD2쓽 쑀쟾쟻 떎삎꽦怨 삁븸 꽭룷닔뱾怨쇱쓽 긽愿 遺꾩꽍쓣 넻빐꽌, 듅엳 뿼利앸컲쓳怨 愿젴씠 留롮 諛깊삁援 닔移섏쓽 愿젴꽦쓣 솗씤븯怨좎옄 븯떎.

옱猷 諛 諛⑸쾿

뿰援щ긽옄

蹂 뿰援щ뒗 븳援씤 쑀쟾泥 뿭븰 議곗궗 궗뾽(Korean Genome and Epidemiology Study; KoGES)쓽 씪솚씤 Korean Association REsource (KARE) 븳援씤 옄猷뚮 씠슜븯뿬 뿰援щ 긽옄瑜 궗슜븯떎(Cho et al., 2009). 씠븣 씠슜븳 옄猷뚮뒗 吏덈퀝愿由щ낯遺 씤泥댁옄썝뻾뿉꽌 遺꾩뼇쓣 諛쏆븘 궗슜븯떎(17100901-01-01). 吏덈퀝愿由щ낯遺뿉꽌 븳援씤쓣 긽쑝濡 援誘쇰낫嫄댁쬆吏 諛 쑀쟾泥 뿰援ъ쓽 씪솚쑝濡 2001뀈遺꽣 떆옉맂 寃쎄린룄 븞꽦떆 븞궛떆 嫄곗<옄瑜 뿰援щ긽옄濡 궪 洹쒕え 쑀쟾泥 뿭븰 肄뷀샇듃濡쒖뜥, 궓(40~69꽭) 10,038紐낆쓣 옄썝 紐⑥쭛븯쑝硫, 씠뱾 以묒뿉꽌 QC (Qualilty Control) 怨쇱젙쓣 넻怨쇳븳 8,842紐(궓꽦: 4,183紐, 뿬꽦: 4,659紐)쓣 뿰援щ긽옄濡 꽑젙븯떎. 蹂 뿰援ъ뿉 솢슜븳 쑀쟾젙蹂대뒗 吏덈퀝愿由щ낯遺(KNIH) 샇꽌븰援먯뿉꽌 뿰援ъ쑄由ъ떖쓽쐞썝쉶(Institutional Review Board; IRB) 듅씤쓣 諛쏆 썑 遺꾩꽍쓣 닔뻾븯떎(1041231-170822-BR-062-01). 뿰援щ긽옄쓽 닔, 궓 鍮꾩쑉, 굹씠 諛 삁援 닔移섎뱾뿉 븳 젙蹂대뒗 Table 1뿉 굹궡뿀떎.

Basic characteristics of the KARE study cohort and blood cell counts

  Characteristics Mean ± Standard deviation
Number of subjects (n) 8842
Age (years) 55.22±8.92
Male (%) 47.3
WBC count (103/ μL) 6.59±1.83
RBC count (106/ μL) 4.42±0.47
Platelet count (103/ μL) 266.34±65.27

Abbreviations: WBC, white blood cell; RBC, red blood cell.



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. 뿰援 李몄뿬옄뱾쓽 留먯큹삁븸뿉꽌 遺꾨━, 異붿텧븳 DNA 떆猷뚮뒗, 씤媛꾩쟾옣쑀쟾泥 SNP 쑀쟾삎 뙋룆쓣 쐞빐꽌 Affymetrix Genome-Wide Human SNP array v.5.0 (Affymetrix, Santa Clara, CA, USA)쓣 궗슜븯떎. 쑀쟾삎 뙋룆 젙솗룄媛 98% 씠븯씠嫄곕굹 4% 씠긽쓽 넂 missing genotype call rate쓣 蹂댁씠嫄곕굹, 30% 珥덇낵쓽 heterozygosity쓣 媛吏嫄곕굹, 꽦蹂 遺덉씪移섍 議댁옱븯뒗 긽옄뱾 젣쇅릺뿀떎. 蹂 뿰援ъ뿉꽌 遺꾩꽍븳 NOD2 쑀쟾옄 쁺뿭 쟾궗泥 뼇履 걹 留먮떒뿉꽌 5 kb뵫 솗옣븳 踰붿쐞뿉 쐞移섑븳 7媛쒖쓽 SNP뱾쓣 긽쑝濡 븯떎. 씠뱾 SNP뱾쓽 뿼깋泥 긽쓽 쐞移섎뒗 UCSC Genome Browser on Human Mar. 2006 (NCBI36/hg18)쓣 湲곗쑝濡 븯떎. 삉븳, 떎젣 떎뿕쟻쑝濡 SNP쓽 쑀쟾삎쓣 솗씤븳 寃 씠쇅뿉룄 NOD2 쑀쟾옄 쁺뿭뿉꽌 MACH 1.0.16 (Li et al., 2010)瑜 궗슜븯뿬 異붽쟻쑝濡 16媛쒖쓽 imputation SNP쓣 諛쒓뎬븯뿬 遺꾩꽍뿉 궗슜븯떎. Imputation HapMap database (release 24) (PMID: 14685227)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媛 1% 誘몃쭔씠嫄곕굹 긽愿怨꾩닔(r2)媛 0.5 誘몃쭔씤 寃껋 遺꾩꽍뿉꽌 젣쇅븯떎.

삁援 닔移 痢≪젙

쟾泥 8,842紐낆쓽 뿰援щ긽옄쓽 삁븸 떆猷뚭 삁援 닔移 遺꾩꽍뿉 궗슜 媛뒫븯떎(Table 1). 뿰援щ긽옄쓽 젙留ν삁愿뿉꽌 K3-EDTA 빆쓳怨좎젣媛 룷븿맂 4.5 mL 뒠釉뚯뿉 梨꾪삁븳 썑 30遺꾩뿉꽌 4떆媛 궗씠 떆媛꾩뿉 삁援 닔移섎 痢≪젙븯떎. 삁援 닔移 痢≪젙뿉뒗 옄룞삁援щ텇꽍湲곗씤 ADVIA 120 hematology system (Bayer Diagnostics, Tarrytown, NY USA)쓣 궗슜븯떎. 諛깊삁援 닔(WBC count), 쟻삁援 닔(RBC count), 삁냼뙋 닔(Platelet count)뒗 紐⑤뱺 삁븸 떆猷뚮뱾뿉 빐 옄룞쟻쑝濡 怨꾩닔릺뿀떎.

긽愿꽦 遺꾩꽍怨 넻怨 遺꾩꽍

뿼깋泥 16踰덉뿉 쐞移섑븳 NOD2 몴쁽삎 삎吏덉쓽 뿰愿꽦 넻怨 遺꾩꽍쓣 쐞빐 PLINK (http://pngu.mgh.harvard.edu/~purcell/plink; v 1.07) PASW Statistics v.18.0 (SPSS, Chicago, IL, USA)쓣 궗슜븯떎. NOD2쓽 쑀쟾쟻 蹂씠 삁援 닔移섏쓽 긽愿 遺꾩꽍 꽑삎 쉶洹 遺꾩꽍쓣 궗슜븯쑝硫 additive genetic model쓣 湲곕컲쑝濡 븯떎. 쉶洹 遺꾩꽍쓽 떆뻾뿉 엳뼱꽌 굹씠, 吏뿭, 꽦蹂꾩쓣 怨듬닔濡 泥섎━븯뿬 遺꾩꽍븯떎. 遺꾩꽍 媛믪뿉 븳 쑀쓽 닔以 떎以 鍮꾧탳뿉 쓽븳 삤瑜 蹂댁젙(Bonferroni correction) 썑 0.00218 誘몃쭔쓣 湲곗쑝濡 븯떎. Regional association plots쓣 솗씤븯湲 쐞븯뿬 쎒 湲곕컲 봽濡쒓렇옩씤 Locuszoom version 1.1 (http://csg.sph.umich.edu/locuszoom) (Pruim et al., 2010)쓣 궗슜븯떎.

寃 怨

NOD2 쑀쟾옄 쁺뿭쓽 SNP 꽑蹂꾧낵 imputation

KARE 쑀쟾삎 옄猷뚯뿉꽌 遺꾩꽍뿉 궗슜븷 SNP쓣 꽑蹂꾪븯湲 쐞븯뿬 UCSC Genome Browser on Human Mar. 2006(NCBI36/hg18)쓣 湲곗쑝濡 뿼깋泥 16踰덉뿉꽌 NOD2 쑀쟾옄쓽 쁺뿭쓣 꽕젙[쟾궗泥(transcript)瑜 湲곗쑝濡 뼇諛⑺뼢쑝濡 5 Kbp뵫 踰붿쐞 솗옣]븯떎. 洹 寃곌낵 빐떦 踰붿쐞뿉꽌 7媛쒖쓽 SNP씠 솗씤릺뿀떎. 뿬湲곗뿉 뜑븯뿬 KARE 쑀쟾삎 옄猷뚮 湲곕컲쓽 SNP imputation쓣 닔뻾븯뿬 異붽濡 16媛쒖쓽 SNP쓣 솗蹂댄븷 닔 엳뿀떎. 뵲씪꽌, 蹂 뿰援ъ뿉꽌뒗 7媛쒖쓽 genotyped SNPs怨 16媛쒖쓽 imputed SNPs쑝濡 援ъ꽦맂 珥 23媛쒖쓽 SNP쓣 遺꾩꽍 긽쑝濡 븯떎.

NOD2 쑀쟾옄 SNP怨 삁援 닔移섏쓽 긽愿 遺꾩꽍

NOD2 쑀쟾옄쓽 SNP쓣 긽쑝濡 삁援 닔移섎뱾(諛깊삁援ъ닔, 쟻삁援 닔, 삁냼뙋 닔)怨쇱쓽 긽愿 遺꾩꽍 寃곌낵瑜 궡렣蹂대㈃, 諛깊삁援 닔移섏쓽 쑀쓽븳 긽愿 愿怨꾨 굹궡怨 엳떎. 떎以 鍮꾧탳뿉 쓽븳 삤瑜 蹂댁젙쑝濡 媛옣 뾼寃⑺븳 湲곗씤 Bonferroni correction쓣 쟻슜븯쓣 븣쓽 쑀쓽 닔以씤 P < 0.00218쓣 留뚯”븯뒗 SNP씠 諛깊삁援 닔移섏쓽 遺꾩꽍 寃곌낵뿉꽌 12媛 SNP뿉 빐떦븯뒗뜲, 씠寃껋 遺꾩꽍븳 쟾泥 23媛 SNP 以묒뿉꽌 52.2%씪뒗 留ㅼ슦 겙 鍮덈룄瑜 蹂댁뿬 二쇨퀬 엳떎. 洹몃━怨, 씠젃寃 쑀쓽븳 12媛쒖쓽 SNP뱾 紐⑤몢 minor allele瑜 媛吏덉닔濡 諛깊삁援 닔移섍 利앷븯뒗 寃쏀뼢쓣 蹂댁뿬二쇨퀬 엳떎. 12媛쒖쓽 SNP뱾 以묒뿉꽌룄 3’ untranslated region뿉 쐞移섑븳 rs3135500씠 媛옣 넂 쑀쓽 닔以(P=5.75 × 10-4)쓣 蹂댁뿬二쇨퀬 엳떎(Table 2).

Association results of the 23 SNPs in the NOD2 gene with blood cell counts in the KARE subjects

No.  SNP A1 MAF Consequence to transcript WBC count RBC count Platelet count



beta ± se Add P beta ± se Add P beta ± se Add P
I1 rs4785224 A 0.048 Upstream 0.12±0.06 0.069 0.011±0.01 0.398 2.73±2.30 0.236
I2 rs2067085 G 0.049 Upstream 0.11±0.06 0.077 0.009±0.01 0.482 2.21±2.28 0.332
I3 rs6500328 G 0.263 Iintronic 0.11±0.03 6.42×10-4 0.013±0.01 0.048 2.52± 1.11 0.023
G1 rs8057341 G 0.264 Intronic 0.10±0.03 7.69×10-4 0.012±0.01 0.058 2.53± 1.10 0.022
I4 rs13339578 A 0.263 Intronic 0.11±0.03 6.77×10-4 0.013±0.01 0.047 2.52± 1.11 0.023
I5 rs11642646 A 0.223 Intronic 0.11±0.03 1.15×10-3 0.016±0.01 0.019 1.70± 1.18 0.147
I6 rs5743270 A 0.040 Intronic 0.05±0.07 0.497 -0.005±0.01 0.703 5.04±2.49 0.043
I7 rs11647841 A 0.220 Intronic 0.10±0.03 1.99×10-3 0.016±0.01 0.018 1.59± 1.19 0.179
G2 rs1861759 G 0.170 Synonymous 0.08±0.04 0.028 0.015±0.01 0.049 0.78± 1.30 0.549
I8 rs4785225 G 0.26 Intronic 0.10±0.03 1.22×10-3 0.012±0.01 0.056 2.41±1.11 0.030
G3 rs751271 G 0.259 Intronic 0.10±0.03 1.47×10-3 0.013±0.01 0.043 2.34± 1.11 0.035
G4 rs748855 G 0.221 Intronic 0.11±0.03 1.47×10-3 0.017±0.01 0.016 1.74± 1.18 0.141
G5 rs1861758 A 0.219 Intronic 0.10±0.03 1.91×10-3 0.016±0.01 0.023 1.51±1.18 0.202
I9 rs1861757 C 0.170 Intronic 0.08±0.04 0.025 0.015±0.01 0.043 0.97± 1.31 0.459
I10 rs10521209 G 0.219 Intronic 0.10±0.03 2.56×10-3 0.017±0.01 0.014 1.78± 1.19 0.134
G6 rs1077861 T 0.222 Intronic 0.11±0.03 8.11×10-4 0.016±0.01 0.019 1.75± 1.18 0.136
I11 rs7203344 G 0.039 Intronic 0.05±0.07 0.501 -0.005±0.01 0.719 5.59±2.52 0.026
G7 rs3135499 C 0.263 3’ UTR 0.10±0.03 9.89×10-4 0.014±0.01 0.035 2.64± 1.11 0.018
I12 rs3135500 A 0.261 3’ UTR 0.11±0.03 5.75×10-4 0.013±0.01 0.041 2.60± 1.11 0.020
I13 rs12600253 A 0.039 Downstream 0.05±0.07 0.503 -0.003±0.01 0.854 5.33±2.54 0.036
I14 rs12598306 C 0.037 Downstream 0.02±0.07 0.777 -0.001±0.02 0.929 5.48±2.61 0.036
I15 rs7205423 G 0.302 Downstream 0.08±0.03 5.65×10-3 0.015±0.01 0.014 1.88± 1.06 0.076
I16 rs718226 G 0.217 Downstream 0.10±0.03 3.21×10-3 0.016±0.01 0.021 1.37± 1.18 0.247

Age, sex, and residential area were included as covariates in the additive genetic models. The P-values lower than the Bonferroni-corrected significance level (P < 0.00218) are indicated in bold and underlined. Abbreviations: Add P, additive genetic model P value; A1, minor allele; G of No., genotyped SNP’s number; I of No., imputed SNP’s number; KARE, Korean Association Resource; MAF, minor allele frequency; RBC, red blood cell; SNP, single nucleotide polymorphism; WBC, white blood cell.



諛깊삁援 닔移섏뿉꽌 쑀쓽븳 긽愿 愿怨꾨 蹂댁씠뒗 12媛쒖쓽 SNP뱾뿉 빐 쟻삁援 닔移섏 삁냼뙋 닔移섏뿉 빐 궡렣蹂대㈃, 쑀쓽 닔以쓣 0.05瑜 湲곗쑝濡 媛젙븯쓣 븣, 쟻삁援 닔移섎뒗 10媛쒖쓽 SNP (83.3%), 삁냼뙋 닔移섏뿉꽌뒗 7媛쒖쓽 SNP (58.3%)씠 留뚯”븯怨 엳뿀떎(Table 2). 洹몃━怨, 씠뱾 SNP뱾씠 minor allele瑜 媛吏덉닔濡 쟻삁援 닔移섏 삁냼뙋 닔移섎뒗 利앷븯뒗 寃쏀뼢쓣 蹂댁뿬二쇨퀬 엳뿀떎. 듅엳, 5媛쒖쓽 SNP(rs6500328, rs13339578, rs751271, rs3135499, rs3135500)쓽 寃쎌슦뿉뒗 꽭 醫낅쪟쓽 삁援 닔移섍 紐⑤몢 쑀쓽븳 긽愿 愿怨꾨 굹궡怨 엳쑝硫, minor allele뿉 뵲씪 삁援 닔移섍 利앷븯뒗 寃쏀뼢룄 紐⑤몢 씪移섑븯떎.

NOD2 쑀쟾옄 SNP怨 諛깊삁援 닔移섏쓽 긽愿 愿怨 regional association plot

NOD2 쑀쟾옄 SNP怨 媛옣 쑀쓽븳 긽愿 愿怨꾨 蹂댁뿬二쇨퀬 엳뒗 諛깊삁援 닔移섏쓽 寃곌낵瑜 湲곕컲쑝濡 쎒 湲곕컲 봽濡쒓렇옩씤 Locuszoom version 1.1 (http://csg.sph.umich.edu/locuszoom)쓣 궗슜븯뿬 솗씤븯떎(Fig. 1). 洹 寃곌낵 媛옣 넂 쑀쓽 닔以쓣 蹂댁씠뒗 rs3135500씠 옄二쇱깋 떎씠븘紐щ뱶濡 몴떆릺뼱 엳뒗 寃껋쓣 蹂 닔 엳떎. 洹몃━怨, 긽쟻쑝濡 NOD2 쑀쟾옄쓽 븵 遺遺꾩뿉 쐞移섑븯硫댁꽌 rs3135500怨 r2> 0.8 씠긽씤 5媛쒖쓽 SNP뱾씠 넂 쑀쓽 닔以쓣 蹂댁뿬二쇨퀬 엳쓬쓣 븣 닔 엳떎. 洹 쇅쓽 SNP뱾룄 NOD2 쑀쟾옄 쁺뿭뿉 怨④퀬猷 遺꾪룷릺뼱 엳쑝硫댁꽌 쑀쓽븳 긽愿 愿怨꾨 굹궡怨 엳뒗 寃껋쑝濡 蹂 븣, NOD2 쑀쟾옄 諛깊삁援 닔移섏쓽 긽愿 愿怨꾨뒗 긽떦엳 쑀쓽誘명븯떎怨 蹂 닔 엳떎.

Fig. 1.

Plots for the association result of the NOD2 SNPs with WBC count in the KARE subjects. The position of the SNPs is shown at the top, and association results between SNPs in the NOD2 gene and white blood cell count in the KARE study cohort are shown in the middle. The statistical significance (-log10P-value) of the analyzed 23 SNPs is plotted, which are compose of experimentally genotyped 7 SNPs and in silico genotyped (imputed) 16 SNPs. The recombination rate estimated from the HapMap CHB (Han Chinese from Beijing) and JPT (Japanese from Tokyo) population data is shown by a blue line. The purple diamond with a SNP number (rs3135500) and P-value represents the SNPs most strongly associated with WBC count, and its correlated SNPs are shown in the indicated colors according to the levels of linkage disequilibrium (r2). At the bottom, the position (Mb) of the NOD2 gene on chromosome 16 (NCBI build 36) is shown along with the gene structures.


怨 李

蹂 뿰援ъ뿉꽌 NOD2 쑀쟾옄 쁺뿭뿉 議댁옱븯뒗 23媛쒖쓽 SNPs 쑀쟾 蹂씠瑜 긽쑝濡 삁援 닔移섏쓽 긽愿 遺꾩꽍쓣 吏꾪뻾븯뿬 諛깊삁援 닔移섏뿉꽌 12媛쒖쓽 SNP뱾씠 넻怨꾩쟻 쑀쓽꽦(Bonferroni 蹂댁젙 媛, P < 0.00218)쓣 留뚯”븯떎. 씠뱾 12媛쒖쓽 SNP뱾뿉 빐 쑀쓽 닔以 P < 0.05瑜 湲곗쑝濡 쟻삁援 닔移섏 삁냼뙋 닔移섏뿉 븳 뿰愿 遺꾩꽍 寃곌낵瑜 蹂대㈃, 쟻삁援 닔移섎뒗 10媛쒖쓽 SNP (83.3%), 삁냼뙋 닔移섎뒗 7媛쒖쓽 SNP (58.3%)씠 留뚯”븯怨 엳뿀떎(Table 2). 諛깊삁援 닔移섏쓽 遺꾩꽍뿉꽌 媛옣 쑀쓽 닔以씠 넂 rs3135500怨 諛붾줈 쁿뿉 쐞移섑븳 rs3135499쓽 2媛 SNP 3’ 留먮떒쓽 UTR뿉 쐞移섑븯怨, 쑀쓽 닔以쓣 留뚯”븯뒗 떎瑜 10媛쒖쓽 SNP뱾 紐⑤몢 씤듃濡좎뿉 쐞移섑븯怨 엳뿀떎. 쑀쟾옄 諛쒗쁽 쟾궗 썑 닔젙(post-transcriptional modification) 닔以뿉꽌 留ㅼ슦 젙諛븯寃 議곗젅맂떎. mRNA쓽 踰덉뿭怨 쐞移섏꽑젙(localization), 遺꾪빐 벑쓣 쐞빐꽌뒗 5’ 留먮떒쓽 UTR쓽 뿭븷씠 以묒슂븯떎. 寃고빀떒諛깆쭏怨 寃고빀, Hairpin 2李 猷⑦봽援ъ“ 삎꽦, 由щ낫넑 吏꾩엯遺쐞(internal ribosome entry site, IRES) 援ъ“ 벑쓣 삎꽦븯硫 떒諛깆쭏踰덉뿭쓣 룙뒗떎. 븳렪, 3’ 留먮떒쓽 UTR 뿼湲곗꽌뿴 븘뜲땺以묓빀泥댄삎꽦(polyadenylation), 떒諛깆쭏蹂듯빀泥 벑怨 寃고빀븯뿬 mRNA 븞젙솕뿉 湲곗뿬븯뒗 寃껋쑝濡 옒 븣젮졇 엳떎(Mignone et al., 2002). 蹂 뿰援ъ뿉꽌 諛앺궦 rs3135499, rs-3135500뒗 紐⑤몢 3’ 留먮떒 UTR뿉 쐞移섑븳 SNP濡 P 媛믪씠 媛곴컖 9.89 × 10-4, 5.75 × 10-4쑝濡 긽떦엳 넂 쑀쓽븳 긽愿 愿怨꾨 굹궡뿀떎.

씠뱾 쑀쓽꽦씠 넂 3’ 留먮떒 UTR뿉 議댁옱븯뒗 SNP뱾씠 NOD2 쑀쟾옄 洹 떒諛깆쭏뿉 뼱뼚븳 쁺뼢쓣 二쇰뒗吏 솗씤빐 蹂닿린 쐞빐 RegulomeDB (www.regulomedb.org)뿉꽌 솗씤빐 蹂댁븯떎. 삁긽븳濡, rs3135499뒗 떒빑援(monocyte)뿉꽌 NOD2쓽 由쎌쑀쟾옄 C뿼湲곗쓽 諛쒗쁽李⑥씠(eQTL)瑜 굹깉쑝硫, 샇以묎뎄 떒빑援ъ뿉꽌 媛뺥븳 쟾궗씤옄쓽 寃고빀 紐⑦떚봽뿉 쁺뼢쓣 誘몄튂怨 엳쓬쓣 솗씤븷 닔 엳뿀떎. rs3135500 삉븳 샇以묎뎄 떒빑援ъ뿉꽌 쟾궗씤옄 寃고빀뿉 쁺뼢쓣 二쇰ʼn HNF1, NR4A2, RORα1 벑쓽 紐⑦떚봽瑜 삎꽦븯뒗 寃껋쓣 솗씤븯떎. 洹몃윭誘濡, 씠뱾 3’ 留먮떒 UTR뿉 쐞移섑븳 SNP뱾 떒빑援щ굹 샇以묎뎄뿉꽌 NOD2 쑀쟾옄 諛쒗쁽뿉 쁺뼢쓣 以 닔 엳뒗 媛뒫꽦씠 긽떦엳 엳떎怨 蹂댁뿬吏꾨떎.

湲됱꽦 삉뒗 留뚯꽦뿼利앹쓽 媛옣 以묒슂븳 留덉빱뒗 C-reactive protein (CRP) white blood cell (WBC) 닔移섎씪뒗 궗떎 옒븣젮졇 엳떎. 理쒓렐뿉 쟾옣쑀쟾泥대텇꽍(Genome-wide association study)쓣 넻빐 hepatocyte nuclear factor 1 alpha (HNF1A) 쑀쟾옄뿉 쐞移섑븳 rs2393791 SNP씠 CRP 媛옣 쑀쓽븳 긽愿 愿怨꾨 蹂댁씠뒗 쑀쟾 蹂씠怨, 17踰 뿼깋泥댁뿉 쐞移섑븳 proteasome 26S subunits non-ATPase 3 (PSMD3)怨 colony stimulating factor 3 (CSF3) 쑀쟾옄 궗씠뿉 쐞移섑븳 intergenic SNP씤 rs8078723媛 諛깊삁援 닔移섏쓽 긽愿 愿怨 쑀쓽꽦씠 媛옣 넂 쑀쟾 蹂씠엫씠 솗씤릺뿀떎(Kong and Lee, 2012). 蹂 뿰援ъ뿉꽌뒗 NOD2 쑀쟾옄쓽 蹂씠뱾怨 삁援 닔移섏씤 諛깊삁援 닔移, 쟻삁援 닔移, 洹몃━怨, 삁냼뙋 닔移섏쓽 긽愿 愿怨꾨 議곗궗븯떎. 遺꾩꽍 寃곌낵뿉 뵲瑜대㈃, 諛깊삁援 닔移섏 NOD2 쑀쟾옄쓽 intronic SNP뱾씠 쑀쓽꽦 엳뒗 긽愿 愿怨꾨 蹂댁쑝굹(Bonferroni 蹂댁젙 媛, P < 0.00218), 쟻삁援 닔移섏 삁냼뙋 닔移섏뒗 떎以 鍮꾧탳뿉 쓽븳 삤瑜 蹂댁젙 썑뿉뒗 쑀쓽 닔以쓣 留뚯”븯吏뒗 紐 븯떎(Table 2). 湲됱꽦뿼利앹뿉 愿뿬븯뒗 CRP媛 諛깊삁援 닔移섏 媛뺥븳 뿰愿꽦쓣 蹂댁씤 諛섎㈃ NOD2 쑀쟾옄뒗 쟾 뿰愿꽦쓣 굹궡吏 븡븯떎(Data not shown). 씠윭븳 寃곌낵濡 쑀異뷀빐 蹂 븣, NOD2 쑀쟾옄 떎삎꽦 湲됱꽦뿼利 蹂대떎뒗 留뚯꽦쟻씤 뿼利앷낵 뜑 愿젴씠 엳쓣 媛뒫꽦씠 겕떎뒗 寃껋쓣 븣 닔 엳怨, 씠寃껋 삉븳 誘몄깮臾쇱뿉 븳 꽑泥쒕㈃뿭 떆뒪뀥뿉 옉슜븯뒗 꽭 遺瑜섏쓽 湲곕뒫쟻 諛깊삁援ъ뿉 쁺뼢쓣 誘몄튇떎뒗 寃껋쓣 쓽誘명븯怨 엳떎.

씤뵆씪留덉씤 NODosome쓽 뿭븷 꽭룷 궡遺쓽 쐞뿕떊샇瑜 媛먯븯뒗 뿭븷쓣 닔뻾븳떎. 꽭룷궡 誘몄깮臾쇱쓽 移⑥엯怨 媛숈 쐞뿕븳 닚媛꾩뿉 꽭룷媛 寃る뒗 留덉留 怨좏넻쑝濡쒕꽣 꽭룷뒗 꽭룷 諛뽰쑝濡 씤꽣猷⑦궓쓣 諛⑹텧븿쑝濡쒖뜥 뿼利앸컲쓳쓣 쑀룄븳떎. 떇꽭룷(macrophage)媛 궡뒗 IL-6뿉 쓽빐 媛꾩뿉꽌 CRP媛 깮꽦맂떎뒗 젏쓣 怨좊젮븷 븣, 理쒖냼븳 NOD2 떒諛깆쭏씠 愿뿬븳 씤뵆씪留덉씤 NODosome쓽 뿼利앸컲쓳怨쇰뒗 깮꽦寃쎈줈媛 꽌濡 由ш린 븣臾몄뿉 CRP 긽愿 愿怨꾧 뾾뒗 寃껋씠씪怨 깮媛곹븳떎. 諛섎㈃뿉, 씤뵆씪留덉쓣 삎꽦븯뒗 NOD2뒗 caspase-1 슚냼媛 愿뿬븯뒗 꽭룷궗硫(pyroptosis)쓣 넻빐꽌 IL-1α 벑쓽 궗씠넗移댁씤 벑쓣 諛⑹텧븿쑝濡쒖뜥 뿼利앸컲쓳쓣 쑀룄븳떎(Hsu et al., 2008; Bergsbaken et al., 2009).

蹂 뿰援ъ뿉꽌뒗 겕濡좊퀝쓽 썝씤 쑀쟾옄씤 NOD2瑜 뿼利앹쓽 愿젏뿉꽌 젒洹쇳븯뿬 諛깊삁援 닔移섏쓽 긽愿 愿怨꾨 洹쒕챸븯떎. 理쒓렐 끉臾몄뿉 쓽븯硫, 씠윭븳 NOD2 쑀쟾옄뒗 옄媛룷떇(Cooney et al., 2010; Travassos et al., 2010)怨 愿젴븯뿬 LRRK2 諛젒븯寃 愿젴릺뼱 엳쑝硫댁꽌 p62/SQSTM-1쓽 留ㅺ컻濡 吏꾪뻾맂떎뒗 궗떎씠 븣젮졇 엳떎(Park et al., 2016; Kalogeropulou AF 2018). 삉븳 뙆궓뒯蹂묎낵 겕濡좊퀝쓽 뿰愿꽦쓣 蹂닿퀬븳 뿰援щ갑뼢뱾씠 蹂닿퀬릺怨 엳떎(Lin et al., 2016; Fujioka et al., 2017). 듅엳, 떊寃쎌뿼利(neuroinflammation)씠 뙆궓뒯 蹂묒쓽 硫붿빱땲利섏쓣 諛앺엳뒗 以묒슂븳 뿭븷쓣 닔뻾븷 寃껋쑝濡 異붿젙맂떎(Tansey and Goldberg 2010; Kipnis, 2016). 洹몃윭誘濡, 蹂 뿰援ъ쓽 遺꾩꽍 긽씠뿀뜕 SNP뱾怨 떊寃쎌뿼利앷낵쓽 긽愿 愿怨꾩뿉 븳 옄꽭븳 뿰援ш 뼢썑뿉 닔뻾릺뼱 뿰愿꽦씠 諛앺吏꾨떎硫, NOD2쓽 쑀쟾쟻 떎삎꽦씠 떒닚엳 諛깊삁援 닔移 肉먮쭔 븘땲씪, 留뚯꽦뿼利 諛 꽑泥쒕㈃뿭 떆뒪뀥, 洹몃━怨 뙆궎뒯蹂묎낵 媛숈 떊寃쎌뿼利앷낵쓽 愿젴꽦뿉 빐꽌 泥닿퀎쟻쑝濡 씠빐븷 닔 엳뒗 洹쇨굅媛 留덈젴맆 寃껋쑝濡 湲곕븳떎.

ACKNOWLEDGEMENT

This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) grant (http://nrf.re.kr) to H.S.J (NRF-2017R1D1A3B03034752), and to S.P. (NRF-2017R1D1A3B03029902); by a grant from Kyungwoon University (2018) (http://www.ikw.ac.kr) to S.P. 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 declare no conflicts of interest.

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