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PDGFC, MARK3 and BCL2 Polymorphisms are Associated with Left Ventricular Hypertrophy in Korean Population
Biomed Sci Letters 2019;25:237-246
Published online September 30, 2019;  https://doi.org/10.15616/BSL.2019.25.3.237
© 2019 The Korean Society For Biomedical Laboratory Sciences.

Tae-Eun Jeon* and Hyun-Soek Jin†,**

Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea
Correspondence to: Hyun-Seok Jin. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea.
Tel: +82-41-540-9968, Fax: +82-41-540-9997, e-mail: jinhs@hoseo.edu
*Undergraduate student, **Professor.
Received July 24, 2019; Revised September 11, 2019; Accepted September 16, 2019.
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
Left ventricular hypertrophy (LVH) refers to the expansion and the enlarged myocardium due to the increased resistance to ejection from the left ventricle to the aorta and/or the periphery, or the long-term burden imposed by the blood increase. Hypertension is a major risk factor that accounts for more than 50% of the causes of cardiovascular disease. If hypertension endure in the long term, the myocardium responds to abnormal heartbeat in the heart. Therefore, the prevalence of left ventricular hypertrophy also increases. As a result of genome-wide association study (GWAS) analysis for European people, PDGFC, MARK3, and BCL2 were related to blood pressures. In this study, the genetic polymorphisms of PDGFC, MARK3, and BCL2 were extracted and selected based on Korean genomic and epidemiologic data, and then logistic regression analysis was performed on LVH. As a result, one SNP (rs9307953) in PDGFC gene, four SNPs (rs6575983, rs17679475, rs2273703 and rs10141388) in MARK3 gene and two SNPs (rs17756073 and rs17070739) in BCL2 gene were statistically significant. The rs6575983 of the MARK3 gene showed the highest significance level (P=7.2 × 10-3) among the SNPs and the relative risk of 1.08 (95% confidence interval: 1.06 to 1.45). These results suggest that the polymorphisms of PDGFC, MARK3, and BCL2 not only affect European blood pressures but also correlate with LVH in Korean. These results suggest that increased understanding of the genetic correlations of the pathogenesis of LVH.
Keywords : BCL2, Candidate gene association study, Hypertension, Left ventricular hypertrophy, MARK3, PDGFC
꽌 濡

醫뚯떖떎 鍮꾨(Left Ventricular Hypertrophy)뒗 鍮꾩젙긽쟻씤 떖遺븯뿉 븳 떖洹쇱쓽 諛섏쓳 삎깭씠떎. 醫뚯떖떎뿉꽌 룞留 샊 留먯큹濡쒖쓽 諛뺤텧빆씠 넂븘吏嫄곕굹 삁븸웾 利앷濡 씤빐 옣湲곗쟻씤 遺떞씠 媛빐吏硫 떖洹쇱씠 뒛뼱굹怨 솗옣씠 씪뼱굹寃 맂떎(Im, 1995; Chung and Song, 2007). 삉븳 愿긽룞留μ쭏솚, 湲됱궗, 떖遺쟾 벑쓽 떖삁愿怨 吏덊솚뿉꽌 룆由쎌쟻씤 쐞뿕 슂씤쑝濡 옉슜븳떎. 醫뚯떖떎 鍮꾨瑜 吏꾨떒븯뒗 寃궗濡쒕뒗 떖쟾룄 寃궗, 떖옣珥덉쓬뙆寃궗, 떒닚 쓨遺 諛⑹궗꽑寃궗 벑씠 떆뻾릺硫, 씠 以 떖쟾룄 寃궗媛 醫뚯떖떎 鍮꾨쓽 꽑蹂꾧궗뿉꽌 媛옣 留롮씠 궗슜릺怨 엳떎(Reichek and Devereux, 1981).

怨좏삁븬 슦由щ굹씪 씤援 以 30꽭 씠긽뿉꽌 빟 30%쓽 쑀蹂묐쪧쓣 굹궡뒗 몴쟻씤 留뚯꽦吏덊솚쑝濡 닔異뺢린 삁븬(Systolic Blood Pressure, SBP) 삉뒗 씠셿湲 삁븬(Diastolic Blood Pressure, DBP)씠 吏냽쟻쑝濡 넂寃 쑀吏릺뒗 긽깭瑜 留먰븳떎(Ahn, 2007). 理쒓렐뿉뒗 꽌援ы솕맂 떇뒿愿怨 뒪듃젅뒪 벑쑝濡 씤븯뿬 鍮꾨쭔씤 씤援ш 利앷븯怨 엳떎. 씠뿉 뵲씪 삁愿뿉 怨쇰븯媛 吏냽릺硫댁꽌 怨좏삁븬씠 쑀諛쒕릺怨 엳떎. 怨좏삁븬씠 옣湲곗쟻쑝濡 吏냽맆 寃쎌슦 떖옣뿉 鍮꾩젙긽쟻씤 떖遺븯濡 씤빐 떖洹쇱씠 諛섏쓳븯뿬 醫뚯떖떎 鍮꾨쓽 쑀蹂묐쪧 뿭떆 利앷맂떎(Levy et al., 1990; Sullivan et al., 1993; Oh, 1996; Chung and Song, 2007). 怨좏삁븬 떖삁愿怨 吏덊솚쓽 諛쒖깮 썝씤 以 二쇱슂 쐞뿕슂냼濡, 썝씤쓽 빟 50% 씠긽쓣 李⑥븳떎(WHO, 2002). 怨좏삁븬쓽 諛쒖깮 썝씤 삁븬뿉 뵲씪 떊옣뿉꽌 Na+怨 닔遺꾩쓽 옱씉닔瑜 議곗젅븯怨 떖삁愿 湲곕뒫쓽 議곗젅뿉 愿뿬븯뒗 젅땶-븞吏삤뀗吏-븣룄뒪뀒濡 떆뒪뀥(Renin-Angioten-Aldosterone System, RAAS) 諛 援먭컧 떊寃쎄퀎(Sympathetic Nervous System, SNS)쓽 옣븷뿉 쓽븳 寃껊뱾씠 몴쟻쑝濡 븣젮졇 엳떎(Drummond et al., 2019). 뵲씪꽌 씠윭븳 怨좏삁븬 쑀쟾쟻 슂씤怨 떇뒿愿 諛 깮솢솚寃 벑쓽 솚寃쎌쟻 슂씤씠 蹂듯빀쟻쑝濡 옉슜릺뼱 굹궃떎.

븵꽌 蹂닿퀬맂 끉臾(Evangelou et al., 2018)뿉꽌뒗 쑀읇怨 궗엺뱾(UK Biobank data: 502,620紐, ICBP data: 299,024紐)쓣 긽쑝濡 삁븬怨 愿젴맂 듅꽦[SBP, DBP, Pulse Pressure (PP)]뿉 빐 genome-wide association study (GWAS) 遺꾩꽍쓣 븯떎. 洹 寃곌낵 535媛쒖쓽 깉濡쒖슫 쑀쟾醫뚯쐞(gene loci)媛 諛쒓껄릺뿀떎. 蹂 뿰援ъ뿉꽌뒗 諛쒗몴맂 쑀쟾醫뚯쐞 以 SBP, DBP, PP쓽 꽭 媛吏 빆紐⑹뿉꽌 怨듯넻쟻쑝濡 쑀쓽꽦쓣 蹂댁씤 쑀쟾醫뚯쐞(PDGFC, MARK3, BCL2)瑜 븳援씤 쑀쟾泥 뿭븰 뜲씠꽣瑜 湲곕컲쑝濡 媛 쑀쟾옄쓽 떎삎꽦怨 醫뚯떖떎 鍮꾨쓽 긽愿愿怨꾨 遺꾩꽍븯떎.

옱猷 諛 諛⑸쾿

뿰援 긽옄

씠踰 뿰援щ 쐞븳 븳援씤 뿰援 긽옄뒗 븳援씤 쑀쟾泥 뿭븰 議곗궗 궗뾽(Korean genome and epidemiology; KoGES)쓽 씪솚씤 Korean Association Resource (KARE)瑜 湲곕컲쑝濡 븯떎(Cho et al., 2009). 뿰援ъ뿉 궗슜맂 옄猷뚮뒗 吏덈퀝愿由щ낯遺 씤泥댁옄썝뻾뿉꽌 遺꾩뼇쓣 諛쏆븘 궗슜븯떎(KBN-2017-046). 씠뒗 吏덈퀝愿由щ낯遺뿉꽌 븳援씤 뿭븰 諛 쑀쟾泥 뿰援щ 쐞빐 寃쎄린룄 븞꽦 吏뿭怨 븞궛 吏뿭 嫄곗<옄뱾쓣 긽쑝濡 븳 肄뷀샇듃 뿰援ъ씠떎. 긽옄뒗 40꽭뿉꽌 69꽭 궗씠쓽 10,038紐낆쓣 紐⑥쭛븯怨, 씠 以 QC (Quality Control) 怨쇱젙쓣 넻빐 遺꾩꽍 湲곗뿉 쟻빀븯吏 븡 1,198紐낆씠 젣쇅릺뼱 8,840紐(궓꽦: 4,182紐, 뿬꽦: 4,658紐)쓣 遺꾩꽍뿉 媛뒫븳 뿰援 긽옄濡 꽑젙븯떎. 씠踰 뿰援щ뒗 醫뚯떖떎 鍮꾨뿉 븳 쑀쟾 蹂씠쓽 긽愿꽦 뿰援ш 紐⑹쟻씠誘濡 8,840紐낆쓽 긽옄 以묒뿉꽌 떖쟾룄 寃궗瑜 븯吏 븡 긽옄瑜 젣쇅븯뿬 理쒖쥌쟻쑝濡 8,828紐낆쓣 뿰援 긽쑝濡 꽑젙븳 썑, 醫뚯떖떎 鍮꾨 솚옄 嫄닿컯 議곌뎔쓣 꽑蹂꾪븯떎. 醫뚯떖떎 鍮꾨 솚옄援곗쑝濡쒕뒗 떖쟾룄 寃궗뿉꽌 醫뚯떖떎 鍮꾨쓽 吏꾨떒 湲곗뿉 빐떦븯뒗 1,274紐낆쓣 꽑젙븯怨, 嫄닿컯 議곌뎔쑝濡쒕뒗 7,581紐 以 듅蹂꾪븳 吏덊솚씠 뾾뒗 2,772紐낆쓣 꽑젙븯떎. 醫뚯떖떎 鍮꾨 솚옄援곌낵 嫄닿컯 議곌뎔쓽 룊洹 굹씠뒗 媛곴컖 54.41 ± 9.08꽭 50.66 ± 8.70꽭濡 몢 洹몃9 궗씠뿉 쑀쓽븳 李⑥씠媛 엳뿀떎. 씠踰 뿰援ъ뿉 솢슜븳 쑀쟾 젙蹂대뒗 吏덈퀝愿由щ낯遺(KNIH, National Institutes of Health) 샇꽌븰援먯뿉꽌 뿰援 쑄由 듅씤쓣 諛쏆 썑 遺꾩꽍쓣 吏꾪뻾븯떎(1041231-170822-BR-062-01).

醫뚯떖떎 鍮꾨 吏꾨떒 湲곗

醫뚯떖떎 鍮꾨뒗 Minnesota Code Classification 떆뒪뀥뿉 湲곗큹븳 떖쟾룄 寃곌낵瑜 湲곕컲쑝濡 吏꾨떒릺뿀쑝硫, 吏꾨떒 湲곗 R 吏꾪룺씠 V5, V6뿉꽌 26.0 mm瑜 珥덇낵븯嫄곕굹 I, II, III, aVL 쑀룄뿉꽌 20.0 mm瑜 珥덇낵븯嫄곕굹 샊 aVL 쑀룄뿉꽌 12.0 mm瑜 珥덇낵뻽쓣 寃쎌슦뿉 醫뚯떖떎 鍮꾨濡 뙋떒븯떎(Tuinstra et al., 1982). 삉븳 留뚯빟 씠媛 굹굹吏 븡 寃쎌슦뿉뒗 I 쑀룄뿉꽌 R 吏꾪룺씠 쟾泥댁쟻쑝濡 15.0 mm瑜 珥덇낵븯吏留 20.0 mm 씠븯씠嫄곕굹 샊 V5 삉뒗 V6뿉꽌쓽 R 吏꾪룺怨 V1뿉꽌쓽 S 吏꾪룺씠 35.0 mm瑜 珥덇낵븯뒗 긽옄瑜 醫뚯떖떎 鍮꾨濡 吏꾨떒븯떎.

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

씠踰 뿰援ъ뿉꽌뒗 KARE 쑀쟾삎 옄猷뚮 湲곕컲쑝濡 SNP쓣 꽑蹂꾪븯떎. DNA 떆猷뚮뒗 뿰援 李몄뿬옄쓽 留먯큹 삁븸뿉꽌 遺꾨━ 異붿텧븯怨, 쑀쟾삎 뙋룆쓣 쐞빐꽌뒗 Affymetrix Genome-Wide human SNP array 5.0 (Affymetrix, Inc., 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 heterozygosity瑜 媛吏嫄곕굹, 꽦蹂 遺덉씪移섍 議댁옱븯뒗 긽옄뱾 젣쇅릺뿀怨 삉븳 븫쓣 媛뽮퀬 엳뜕 긽옄뱾룄 젣쇅릺뿀떎. 씠踰 뿰援ъ뿉꽌 遺꾩꽍븳 PDGFC, MARK3, BCL2 쑀쟾옄뱾쓽 쁺뿭 媛곴컖쓽 쟾궗泥(209,783 bp, 118,466 bp, 196,035 bp) 뼇 留먮떒뿉꽌 5 kb뵫 솗옣븯뿬 씠 踰붿쐞뿉 議댁옱븯뒗 媛곴컖 15媛, 18媛, 35媛쒖쓽 SNP뱾쓣 긽쑝濡 븯떎. 씠 SNP뱾쓽 뿼깋泥 긽쓽 쐞移섎뒗 UCSC Genome Browser on Human Mar. 2006 (NCBI human genome build 36)쓣 湲곗쑝濡 븯떎.

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. 醫뚯떖떎 鍮꾨 솚옄援곌낵 嫄닿컯 議곌뎔뿉 븳 쑀쟾쟻 蹂씠쓽 긽愿꽦 遺꾩꽍 濡쒖뒪떛 쉶洹 遺꾩꽍쓣 궗슜븯쑝硫 additive genetic model쓣 湲곕컲쑝濡 븯떎. 쉶洹 遺꾩꽍 떆뻾 떆 怨듬닔뿉 굹씠, 吏뿭, 꽦蹂꾩쓣 泥섎━븯뿬 遺꾩꽍븯怨, 遺꾩꽍媛믪뿉 븳 쑀쓽 닔以 0.05 씠븯瑜 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)쓣 궗슜븯떎.

寃 怨

PDGFC, MARK3, BCL2 쑀쟾옄 醫뚯떖떎 鍮꾨쓽 濡쒖뒪떛 쉶洹 遺꾩꽍

뿰援 긽옄뱾뿉 븳 엫긽 몴쁽삎 듅吏뺤 Table 1뿉 젙由ы븯떎. 醫뚯떖떎 鍮꾨 솚옄(n=1,247)쓽 룊洹 굹씠, 꽦蹂 鍮꾩쑉 媛곴컖 50.66 ± 8.70, 궓꽦 63% 뿬꽦 37%濡 굹궗떎. 꽦蹂 鍮꾩쑉 醫뚯떖떎 鍮꾨 솚옄援곗뿉꽌 궓꽦쓽 鍮꾩쑉 63%濡 嫄닿컯 議곌뎔쓽 궓꽦씠 鍮꾩쑉씤 48%뿉 鍮꾪빐꽌 뜑 留롮 鍮꾩쨷쓣 李⑥븯떎.


씠踰 뿰援 긽씤 PDGFC, MARK3, BCL2 쑀쟾옄뱾 UCSC Genome Browser on Human Mar. 2006 (NCBI human genome build 36)쓣 湲곗쑝濡 媛 쑀쟾옄쓽 쟾궗泥 뼇 留먮떒뿉꽌 5 kb뵫 솗옣븯뿬 쑀쟾옄 쁺뿭쓣 꽕젙븳 썑, KARE 쑀쟾삎 젙蹂댁뿉꽌 SNP뱾쓣 꽑蹂꾪븯떎. 洹 寃곌낵 PDGFC 쑀쟾옄쓽 遺꾩꽍 긽 SNP뱾 4踰 뿼깋泥댁뿉꽌 15媛쒖쓽 SNP씠 솗씤릺뿀쑝硫, MARK3 쑀쟾옄뒗 14踰 뿼깋泥댁뿉꽌 18媛쒖쓽 SNP씠 솗씤릺뿀怨, BCL2 쑀쟾옄뒗 18踰 뿼깋泥댁뿉꽌 35媛쒖쓽 SNP씠 솗씤릺뿀떎(Supplementary Table 1). 꽑蹂꾨맂 SNP쓣 긽쑝濡 醫뚯떖떎 鍮꾨 솚옄援곌낵 嫄닿컯 議곌뎔뿉 빐꽌 濡쒖뒪떛 쉶洹 遺꾩꽍쓣 떆뻾븳 寃곌낵 PDGFC 쑀쟾옄뿉꽌뒗 1媛쒖쓽 SNP (rs9307953), MARK3 쑀쟾옄뿉꽌뒗 4媛쒖쓽 SNP (rs6575983, rs17679475, rs2273703, rs10141388), BCL2 쑀쟾옄뿉꽌뒗 2媛쒖쓽 SNP (rs17756073, rs17070739)뿉꽌 넻怨꾩쟻쑝濡 쑀쓽븳 긽愿愿怨(P<0.05)瑜 솗씤븷 닔 엳뿀떎. 씠 以 MARK3 쑀쟾옄쓽 rs6575983뿉꽌 媛옣 넂 쑀쓽 닔以(P=7.2×10-3)씠 굹궗쑝硫, 긽쟻 쐞뿕룄뒗 1.24(95% 떊猶곌뎄媛: 1.06~1.45)濡 굹궗떎. 洹몃윭굹 BCL2 쑀쟾옄 SNP 以 쑀쓽븳 2媛쒖쓽 SNP (rs17756073, rs17070739)뒗 긽쟻 쐞뿕룄媛 몢 SNP 紐⑤몢 0.84濡 솗씤릺뿀쑝硫, 씠뒗 Minor allele (G)瑜 媛吏덉닔濡 醫뚯떖떎 鍮꾨 諛쒖깮쓽 긽쟻 쐞뿕룄瑜 媛먯냼떆궎뒗 諛⑺뼢쑝濡 긽愿꽦씠 엳뿀떎(Table 2).


PDGFC, MARK3, BCL2 쑀쟾옄쓽 쑀쓽븳 SNP뿉 븳 in silico 湲곕뒫 遺꾩꽍

PDGFC, MARK3, BCL2 쑀쟾옄뿉꽌 넻怨꾩쟻쑝濡 쑀쓽꽦쓣 媛吏 珥 7媛쒖쓽 SNP뱾씠 쑀쟾옄 샊 떒諛깆쭏 諛쒗쁽뿉 뼱뼸寃 쁺뼢쓣 誘몄튂뒗吏 솗씤븯湲 쐞빐꽌 Regulome DB (http://www.reguloumdb.org/index) HaploReg (http://archive.broadinstitute.org/mammals/haploreg/haploreg_v3.php)瑜 씠슜븯뿬 in silico 湲곕뒫 遺꾩꽍쓣 븯떎. 洹 寃곌낵 MARK3 쑀쟾옄쓽 SNP 以 2媛쒖쓽 SNP (rs17679475, rs2273703)뿉꽌 1f score쓽 쓽誘 엳뒗 score (score<3a)媛 굹궗떎(Table 3). 1f score뒗 eQTL肉 留 븘땲씪 빐떦 SNP씠 쟾궗 씤옄 寃고빀 諛섏쓳뿉 쁺뼢쓣 誘몄튌 닔 엳嫄곕굹 DNase peak뿉꽌 李⑥씠媛 엳떎뒗 寃껋쓣 쓽誘명븳떎. 삉븳 rs2273703 HaploReg뿉꽌 motif쓽 蹂솕瑜 삁痢≫븯怨 엳쑝誘濡 쑀쟾삎뿉 뵲씪 MARK3 쑀쟾옄 諛쒗쁽뿉 쁺뼢쓣 誘몄튌 媛뒫꽦씠 엳떎뒗 寃껋쓣 蹂댁뿬以떎.


PDGFC, MARK3, BCL2 쑀쟾옄쓽 Regional plot 솗씤

PDGFC, MARK3, BCL2 쑀쟾옄 SNP怨 醫뚯떖떎 鍮꾨 솚옄援 궗씠쓽 긽愿愿怨꾨 湲곕컲쑝濡 LocusZoom Version 1.1 (http://csg.sph.umich.edu/locuszoom), (Pruim et al., 2010) 봽濡쒓렇옩쓣 궗슜븯뿬 regional plot쓣 솗씤븯떎. 遺꾩꽍 떆뿉뒗 湲곗쓣 hg 19 version ASN (Asian population)쑝濡 븯떎. 긽愿 遺꾩꽍 寃곌낵 媛옣 넂 쑀쓽 닔以쓣 굹궦 SNP 옄二쇱깋쓽 떎씠븘紐щ뱶濡 몴떆릺怨, 씠뒗 regional plot쓽 湲곗 SNP씠 맂떎(Fig. 1). MARK3 쑀쟾옄쓽 遺꾩꽍 寃곌낵 rs6575983쓣 湲곗쑝濡 븯쓣 븣 3媛쒖쓽 SNP뿉꽌 r2 > 0.8 씠긽쑝濡 굹궗떎. 뵲씪꽌 rs6575983怨 二쇱쐞뿉 엳뒗 쑀쓽 닔以쓣 媛뽯뒗 MARK3 쑀쟾옄쓽 SNP뱾 꽌濡 뿰愿릺뼱 엳떎뒗 寃껋쓣 솗씤븷 닔 엳뿀떎.

怨 李

꽑뻾맂 끉臾(Evangelou et al., 2018)뿉꽌뒗 UKB (UK Biobank) ICBP (International Consortium of Blood Pressure Genome-wide Association Studies)濡쒕꽣 뼸 쑀읇怨 궗엺뱾쓽 삁븬怨 愿젴맂 듅꽦(SBP, DBP, PP)뿉 빐 GWAS 遺꾩꽍쓣 븯떎. 洹 寃곌낵 535媛쒖쓽 깉濡쒖슫 쑀쟾醫뚯쐞瑜 諛쒓껄븯쑝硫, 씠 以 SBP, DBP, PP쓽 꽭 媛吏 빆紐⑷낵 紐⑤몢 愿젴맂 쑀쟾醫뚯쐞뒗 珥 12媛(BCL2, KLF14, L2HGDH, LRP4, MARK3, PDGFC, RXFP2, TERT, ARMC4, FGFR2, SNRNP70, YTHDF3)떎.

怨좏삁븬씠 삤옒 吏냽릺뒗 寃쎌슦 떖옣뿉 鍮꾩젙긽쟻씤 떖遺븯濡 씤빐 떖洹쇱씠 諛섏쓳븯뿬 醫뚯떖떎 鍮꾨쓽 쑀蹂묐쪧 뿭떆 利앷릺誘濡 怨좏삁븬怨 醫뚯떖떎 鍮꾨뒗 꽌濡 뿰愿꽦씠 엳떎怨 蹂 닔 엳떎(WHO, 2002; Chung and Song, 2007). 洹몃윭誘濡 씠踰 뿰援щ뒗 쑀읇씤뿉꽌 삁븬怨 뿰愿꽦 엳떎怨 깉濡寃 諛쒓껄맂 12媛쒖쓽 쑀쟾醫뚯쐞瑜 媛吏怨 븳援씤쓣 긽쑝濡 쑀쟾옄쓽 蹂씠 醫뚯떖떎 鍮꾨뿉 븳 긽愿 遺꾩꽍쓣 떆뻾븯뿬 媛 쑀쟾옄쓽 쑀쟾쟻 떎삎꽦씠 醫뚯떖떎 鍮꾨뿉 쁺뼢쓣 誘몄튌 媛뒫꽦씠 엳뒗吏 솗씤븯怨좎옄 븯떎. 뵲씪꽌 媛곴컖쓽 쑀쟾옄뿉꽌 濡쒖뒪떛 쉶洹 遺꾩꽍쓣 넻빐 醫뚯떖떎 鍮꾨 솚옄援곌낵 嫄닿컯 議곌뎔 媛꾩쓽 SNP뿉 뵲瑜 넻怨꾩쟻 쑀쓽꽦쓣 遺꾩꽍븯뿬 쑀쟾쟻 蹂씠뿉 뵲瑜 醫뚯떖떎 鍮꾨 諛쒖깮怨쇱쓽 긽愿꽦뿉 븯뿬 솗씤빐 蹂댁븯떎. 洹 寃곌낵 PDGFC 쑀쟾옄뿉꽌 1媛쒖쓽 SNP (rs9307953), MARK3 쑀쟾옄뿉꽌 4媛쒖쓽 SNP (rs6575983, rs17679475, rs2273703, rs10141388), BCL2 쑀쟾옄뿉꽌 2媛쒖쓽 SNP (rs17756073, rs17070739)뱾씠 醫뚯떖떎 鍮꾨 쑀쓽븳 긽愿愿怨(P<0.05)瑜 굹깉떎.

Regulome DB HaploReg瑜 씠슜븯뿬 SNP씠 쑀쟾옄 議곗젅씠굹 떒諛깆쭏 諛쒗쁽뿉 뼱뼸寃 쁺뼢쓣 誘몄튂뒗吏 議곗궗븯떎. 洹 寃곌낵 MARK3 쑀쟾옄쓽 SNP 以 rs17679475 rs2273703 Regulome DB score 1f瑜 굹깉떎. 씠뒗 minor allele瑜 蹂댁쑀븿뿉 뵲씪 MARK3 쑀쟾옄쓽 諛쒗쁽뿉 李⑥씠瑜 굹궡뒗 expression quantitative trait loci (eQTL) 쁺뿭엫쓣 쓽誘명븳떎. rs17679475뿉꽌뒗 뵾븯吏諛, 痍뚯옣, 뇤븯닔泥, 쟾由쎌꽑, 삁愿 벑쓽 17媛 議곗쭅뿉꽌 쑀쟾옄 諛쒗쁽뿉 李⑥씠媛 엳쓬쓣 솗씤븯떎. rs2273703뿉꽌뒗 뵾븯吏諛, 젙媛뺤떊寃, 痍뚯옣, 뇤븯닔泥, 삁븸 벑 16媛 議곗쭅뿉꽌 쑀쟾옄쓽 諛쒗쁽 李⑥씠媛 굹굹뒗 寃껋쓣 솗씤븯떎. 삉븳 rs17679475 rs2273703 DNase peak뿉꽌 李⑥씠媛 엳쓬쓣 솗씤븯떎. DNase뒗 뿼깋吏덉쓽 듅젙 쁺뿭쓣 솢꽦솕떆耳 DNA瑜 끂異쒖떆궓떎. 쟾궗 떒怨꾩뿉 븘슂븳 뿬윭 씤옄뱾 끂異쒕맂 DNA뿉 寃고빀븷 닔 엳寃 릺怨 쟾궗媛 씠猷⑥뼱吏꾨떎. 寃곌뎅 rs17679475, rs2273703 DNase쓽 sensitivity瑜 蹂솕떆耳 MARK3 쑀쟾옄 쟾궗 솢꽦뿉 쁺뼢쓣 誘몄튌 寃껋쑝濡 삁긽븳떎. PDGFC쑀쟾옄쓽 rs9307953 myogenin/NF-1 motif瑜 삎꽦븯怨쟋ARK3 쑀쟾옄쓽 rs10141388 HOXA13 motif瑜, BCL2쑀쟾옄쓽 rs17070739뒗 Sox12 BCL6B motif瑜 삎꽦븳떎. 뵲씪꽌 媛곴컖쓽 SNP뱾 쑀쟾옄 諛쒗쁽뿉 쁺뼢쓣 誘몄튌 媛뒫꽦쓣 蹂댁뿬二쇨퀬 엳떎.

PDGF뒗 삁愿쓽 諛쒕떖怨 룞留 寃쏀솕利앹쓽 諛쒕퀝뿉 愿뿬븳떎(Ross, 1993; Betsholtz and Raines, 1997). PDGFC PDGFDPDGF 쑀쟾옄 援곗뿉 냽븯硫, PDGF-C뒗 誘쇰Т뒳洹 꽭룷뿉꽌 諛쒗쁽릺怨, PDGF-D뒗 꽟쑀紐⑥꽭룷쓽 쇅留됱꽭룷뿉꽌 遺遺 諛쒗쁽릺뼱 吏꾨떎. 몢 쑀쟾옄뒗 諛곗뼇맂 궡뵾꽭룷 諛 떎뼇븳 醫낆뼇 꽭룷二쇱뿉꽌 솢꽦쓣 蹂댁씠뒗 寃껋쑝濡 蹂닿퀬릺뿀떎. PDGF-C PDGF-D뒗 궗엺쓽 愿긽룞留 誘쇰Т뒳洹 꽭룷瑜 옄洹뱁븯硫(Uutela et al., 2001), PDGFC PDGFD媛 떖옣뿉꽌 怨쇰컻쁽 맆 븣, PDGF-C뒗 떖洹쇱쓽 꽟쑀븘꽭룷 利앹떇쓣 利앷떆궎뒗 寃껋쑝濡 굹궗떎(Li et al., 2000).

MARK3쓽 湲곕뒫 븘吏 諛앺吏吏 븡븯쑝굹, MARKs 긽룞愿怨꾧 엳뒗 寃껋쑝濡 諛앺議뚮떎(Ono et al., 1997). MARKs뒗 誘몄꽭냼愿怨 愿젴맂 tau 떒諛깆쭏, MAP2 諛 MAP4쓽 듅씠쟻 씤궛솕뿉 愿뿬븯뒗 깉濡쒖슫 궎굹븘젣씠硫, 寃곌낵쟻쑝濡 in vitro 諛 諛곗뼇맂 꽭룷뿉꽌 誘몄꽭냼愿쑝濡쒕꽣쓽 遺꾨━瑜 珥됰ℓ븳떎(Drewes et al., 1997).

BCL2쓽 諛쒗쁽 誘명넗肄섎뱶由ъ븘뿉꽌 굹삤뒗 궗씠넗겕濡 C쓽 諛⑹텧쓣 뼲젣떆궎怨 Apaf-1 complex쓽 깮꽦쓣 諛⑺빐븯誘濡 꽭룷쓽 二쎌쓬쓣 삁諛⑺븷 닔 엳떎(Yang et al., 1997). 뵲씪꽌 怨좏삁븬怨 媛숈 蹂묓깭깮由ы븰쟻 긽깭뿉꽌 꽭룷옄硫몄궗媛 利앷븯뒗 쁽긽 BCL2 諛쒗쁽씠 뼲젣릺뒗 寃껉낵 愿怨꾧 엳떎怨 븳떎(Yang et al., 1997; Lee et al., 2006). 뵲씪꽌 꽭룷옄硫몄궗瑜 뼲젣떆궎뒗 옉슜쓣 媛吏 떒諛깆쭏쓽 利앷뒗 떖洹쇱쓣 넀긽쑝濡쒕꽣 蹂댄샇븯뒗 슚怨쇰 媛吏怨 엳떎怨 븳떎(Fehrenbach and Northoff, 2001).

씠踰 뿰援щ뒗 洹쒕え 쑀쟾泥 뿭븰 肄뷀샇듃瑜 씠슜븳 뿰援щ줈꽌 PDGFC, MARK3, BCL2 쑀쟾옄쓽 듅젙 SNP뱾씠 醫뚯떖떎 鍮꾨뿉 쁺뼢쓣 誘몄튌 닔 엳쓣 寃껋씠씪뒗 媛뒫꽦쓣 젣떆빐二쇨퀬 엳쑝굹 in silico瑜 넻빐 吏꾪뻾븳 遺꾩꽍씠誘濡 寃곌낵瑜 媛꾩젒쟻쑝濡 솗씤븷 닔 엳뒗 븳怨꾩젏씠 엳떎. 쁽옱源뚯 뿬윭 吏덈퀝뱾쓽 諛쒖깮怨 솚寃쎌쟻 슂씤 諛 쑀쟾쟻 슂씤怨쇱쓽 긽愿愿怨꾩뿉 븳 떎뼇븳 뿰援щ뱾씠 吏꾪뻾릺뿀떎(Jin et al., 2018; Ko and Jin, 2019). 씠踰 뿰援щ뒗 醫뚯떖떎 鍮꾨뿉 빐꽌 븳援씤쓽 쑀쟾泥 뿭븰 옄猷뚮 湲곕컲쑝濡 遺꾩꽍븯쓣 븣 PDGFC, MARK3, BCL2 쑀쟾옄 蹂씠뱾씠 醫뚯떖떎 鍮꾨쓽 긽愿愿怨꾧 꽦由쎈릺뒗吏 솗씤븯怨좎옄 븯떎. 뿰援 寃곌낵瑜 넻빐 PDGFC, MARK3, BCL2 쑀쟾옄뒗 쑀읇씤쓽 삁븬뿉 쁺뼢쓣 誘몄튌 肉 留 븘땲씪 븳援씤뿉꽌 醫뚯떖떎 鍮꾨뿉룄 쁺뼢쓣 誘몄튂뒗 쑀쟾옄엫쓣 쑀異뷀븷 닔 엳떎.

Supplementary
BSL-25-237_Suppl.pdf
ACKNOWLEDGMENT

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) grant (NRF-2017R1D1A3B03034752) funded by the Ministry of Education. This study was conducted with bioresources from National Biobank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (KBN-2017-046).

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

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