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Replication Study of Genome-Wide Association Study of Platelet Count in Korean Health Examinees (HEXA) Cohort
Biomed Sci Letters 2021;27:187-194
Published online September 30, 2021;  https://doi.org/10.15616/BSL.2021.27.3.187
© 2021 The Korean Society For Biomedical Laboratory Sciences.

Min-Ji Jeoung1,§,* , Yoon-Ji Kong1,§,* , Sangjung Park1,†,* * and Hyun-Seok Jin1,2,†,* *

1Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea
2The Research Institute for Basic Sciences, Hoseo University, Asan, Chungnam 31499, Korea
Correspondence to: Sangjung Park. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, 20 Hoseo-ro 79 Beon-gil, Asan-si, Chungcheongnam-do 31499, Korea.
Tel: +82-41-540-9967, Fax: +82-41-540-9997, e-mail: sangjung@hoseo.edu
Hyun-Seok Jin. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, 20, Hoseo-ro 79 beon-gil, Baebang-eup, Asan-si, Chungnam 31499, Korea.
Tel: +82-41-540-9968, Fax: +82-41-540-9997, e-mail: jinhs@hoseo.edu
*Undergraduate student, **Professor.
§Min-Ji Jeong and Yoonji Kong are equal contributors.
Received August 18, 2021; Revised September 14, 2021; Accepted September 14, 2021.
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
Platelets are derived from fragments formed in the cytoplasm of bone marrow megakaryocytes. Platelet count (PLT) can be altered by factors such as platelet production, destruction, and inflammation. In a previous study, the significant single nucleotide polymorphisms (SNP) were reported by the genome-wide association study (GWAS) for PLT in Koreans. In this study, it was confirmed whether significant SNPs were replicated in the HEXA (The Health Examinees) cohort. As a result, the SNPs of the THPO (rs6141), BAK1 (rs210314, rs9296095), GGNBP1 (rs75080135), ACAD10 (rs6490294), and ABCC4 (rs4148441) were significantly correlated with PLT (P < 10-8). At the same time, it was confirmed that the direction of influence was the same according to the genotype. In conclusion, it can be seen that common SNPs are associated with the platelet count regardless of the cohort for Koreans.
Keywords : GWAS, Platelet, HEXA cohort, SNP
Body

삁냼뙋 삁븸 쓳怨좉낵젙뿉꽌 以묒슂븳 뿭븷쓣 븯뒗 꽦遺 以 븯굹濡, 怨⑥닔怨 嫄고빑꽭룷濡 遺꽣 쑀옒븳떎. 삁냼뙋 젒李, 쓳吏 벑쓽 뿭븷쓣 媛吏 肉먮쭔 븘땲씪 二쎌긽 寃쏀솕利 諛 룞留κ꼍솕쓽 썝씤씠 릺湲곕룄 븳떎(Soranzo et al., 2009). 삁냼뙋 닔移섎뒗 吏삁怨 洹 쇅 엫긽 利앹긽뿉 愿뿬븯뒗 吏몴씠硫 삁쟾씠굹 異쒗삁꽦 吏덊솚쓣 吏꾨떒븯뒗뜲 궗슜븷 닔 엳떎(Oh et al., 2014). 쇅긽씠굹 媛먯뿼怨 媛숈 옄洹뱀씠 엳쓣 寃쎌슦 삁냼뙋 닔媛 쟻쑝硫 異쒗삁꽦 吏덊솚쓣 씪쑝궗 닔 엳쑝硫, 諛섎濡 삁냼뙋 닔媛 넂쑝硫 怨⑥닔 吏덊솚쓣 빞湲고븷 닔 엳떎(Wang et al., 2017). 삁냼뙋씠 깮꽦릺湲 쐞븯뿬 怨⑥닔 궡 嫄고빑꽭룷쓽 꽦닕씠 븘슂븳뜲, 씠븣 TPO (Thrombopoietin)쓽 옄洹뱀씠 븘슂븯떎. TPO뒗 嫄고빑꽭룷 몴硫댁쓽 닔슜泥댁뿉 寃고빀븯뿬 嫄고빑꽭룷쓽 꽦닕怨 遺꾪솕瑜 쑀룄븷 닔 엳떎. 씠윭븳 TPO쓽 깮꽦怨 TPO 닔슜泥댁뿉 꽑泥쒖쟻쑝濡 쑀쟾쟻씤 臾몄젣媛 엳쓣 寃쎌슦, 삁냼뙋 깮꽦뿉 쁺뼢쓣 以 닔 엳떎.

씠윭븳 삁냼뙋 닔移(Platelet count, PLT)뒗 씤醫낆씠굹 꽦蹂꾩뿉 뵲씪 李⑥씠媛 굹吏留, 媛쒖씤쓽 쑀쟾쟻 諛곌꼍뿉룄 쁺뼢쓣 諛쏄퀬 엳떎(Bain, 1996; Buckley et al., 2000; Eicher et al., 2018). 삉븳, 씠쟾 뿰援ъ뿉꽌 삁냼뙋 닔移섎뒗 뿼利 諛 삁냼뙋 諛섏쓳꽦(reactivity)怨 뿰愿꽦씠 엳뒗 寃껋쑝濡 굹궗떎(Bessman et al., 1981; Järemo et al., 2000). 뵲씪꽌 삁냼뙋 닔 뿰愿맂 쑀쟾쟻 슂씤쓣 뿰援ы븿쑝濡쒖뜥 삁븸븰쟻 듅꽦쓣 씠빐븯뒗뜲 룄쓣 二쇨퀬 愿젴 吏덊솚쓽 蹂묐━ 湲곗쟾뿉 湲곕컲븳 移섎즺踰뺤쓣 媛쒕컻븯뒗뜲 룄쓣 以 닔 엳떎(Chami and Lettre, 2014).

삁븸븰쟻 듅꽦뿉 븳 쟾옣쑀쟾泥댁뿰援(Genome-wide association study, GWAS)뱾 솢諛쒗엳 吏꾪뻾릺怨 엳怨 떎뼇븳 寃곌낵媛 諛쒗몴릺뿀떎(Kamatani et al., 2010; Chen et al., 2013). 洹 以묒뿉꽌 Oh et al.뿉꽌뒗 8,842紐낆쓽 븳援씤쓣 긽쑝濡 븳 KARE (Korean Association REsource) 肄뷀샇듃 옄猷뚮 솢슜븯뿬 삁냼뙋 닔移(PLT)뿉 븳 쟾옣쑀쟾泥댁뿰援 寃곌낵瑜 諛쒗몴븯떎(Oh et al., 2014). 뵲씪꽌 蹂 뿰援ъ뿉꽌뒗 븵꽑 뿰援 끉臾몄뿉꽌 긽씠 릺뒗 븳援씤 肄뷀샇듃뒗 떎瑜 HEXA (The Health Examinees) 肄뷀샇듃 옄猷뚮 솢슜븯뿬 삁냼뙋 닔移섏뿉 븳 쟾옣쑀쟾泥댁뿰援щ 닔뻾븯怨 넻怨꾩쟻 쑀쓽꽦쓣 蹂댁씤 쑀쟾蹂씠뱾뿉 빐꽌뒗 삉븳, 쟾꽭怨꾩쓽 쟾옣쑀쟾泥댁뿰援ш껐怨 뜲씠꽣踰좎씠뒪씤 GWAS catalog (https://www.ebi.ac.uk/gwas)뿉꽌 젣怨듯븯뒗 寃곌낵 鍮꾧탳빐 蹂닿퀬옄 븯떎. 쑀쟾삎 젙蹂대뒗 샇꽌븰援먯 吏덈퀝愿由ъ껌(KDCA)뿉꽌 뿰援ъ쑄由 듅씤쓣 諛쏆 썑 닔뻾릺뿀떎(IRB approval no.: 1041231-150811-BR-034-03).

뿰援щ긽옄뒗 븳援씤 쑀쟾泥 뿭븰 議곗궗 궗뾽(Korean Genome and Epidemiology Study; KoGES)쓽 씪솚씤 HEXA 肄뷀샇듃 옄猷뚮 遺꾩뼇 諛쏆븘 솢슜븯떎(KBN-2019-004). HEXA 肄뷀샇듃 옄猷뚮뒗 40꽭 씠긽쓽 궓瑜 紐⑥쭛븯쑝硫 28,455紐낆쓽 쑀쟾삎 옄猷뚮 遺꾩꽍븯떎. 쑀쟾삎 遺꾩꽍 K-CHIP consortium뿉꽌 젣怨듯븯뒗 Affymetrix AxiomTM KORV1.0-96 Array (Affymetrix, Santa Clara, CA, USA)씤 Korean Chip (K-CHIP)쓣 궗슜븯뿬 遺꾩꽍릺뿀떎(Moon et al., 2019). 삁븸븰쟻 삎吏덈뱾씠 議곗궗맂 28,455紐낆쓣 蹂 뿰援ъ쓽 뿰援щ긽옄濡 꽑젙븯떎. 뿰援щ긽옄쓽 PLT (Platelet count)뿉 븯뿬 GWAS瑜 닔뻾븯怨, 遺꾩꽍 봽濡쒓렇옩쑝濡쒕뒗 PLINK version 1.07 (http://pngu.-mgh.harvard.edu/~purcell/plink)쓣 씠슜븯떎. 씠븣 遺꾩꽍뿉 궗슜맂 쟾泥 SNP 462,531媛쒖怨, 넻怨꾩쟻 쑀쓽꽦 Bonferroni correction쓣 湲곗쑝濡(P < 10-8 (462,531 / 0.05 = 10-8) 꽕젙븯떎. PLT뿉 븳 긽愿 遺꾩꽍 additive 쑀쟾 紐⑤뜽쓣 湲곗쑝濡 遺꾩꽍븯怨, PLT뿉 쁺뼢쓣 以 닔 엳뒗 굹씠 꽦蹂꾩 怨듬닔濡 泥섎━븯떎. SNP뱾쓽 뿼깋泥 긽쓽 쐞移섎뒗 UCSC Genome browser on human Feb, 2009 (Genome Reference Consortium Human Build 37)瑜 湲곗쑝濡 븯떎. 삁냼뙋 닔移섏뿉 븳 쟾옣쑀쟾泥대텇꽍(GWAS) 寃곌낵뒗 Haploview version 4.2 (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) 봽濡쒓렇옩쓣 씠슜븯뿬 Manhattan plot쑝濡 굹궡뿀떎. 삉븳, 쑀쓽꽦 엳뒗 쑀쟾蹂씠뱾씠 쑀쟾泥 긽쓽 reginal plot쓣 솗씤븯湲 쐞빐 LocusZoom Version 1.1 (http://csg.sph.umich.edu/locuszoom)씠씪뒗 쎒 봽濡쒓렇옩쓣 궗슜븯뿬 SNP뱾 媛꾩쓽 recombination rate (Cm/Mb) r2瑜 솗씤븷 닔 엳뿀떎. 삉븳, 쟾옣쑀쟾泥대텇꽍 寃곌낵 쑀쓽꽦쓣 蹂댁씤 SNP뱾쓣 湲 諛쒗몴맂 GWAS catalog쓽 寃곌낵 鍮꾧탳븯뿬 PLT 긽愿꽦쓣 蹂댁뜕 SNP뱾쓣 꽑蹂꾪븯떎.

븳援씤 HEXA 肄뷀샇듃瑜 긽쑝濡 쟾옣쑀쟾泥대텇꽍쓣 떆뻾븳 寃곌낵 Bonferroni correction (P < 10-8)쓣 留뚯”븯뒗 쑀쓽븳 SNP뱾뿉 빐떦븯뒗 쐞移섏뿉 議댁옱븯뒗 쑀쟾옄뒗 珥 32媛쒖떎(supplementary Table 1). 32媛쒖쓽 쑀쟾옄 以 5媛쒖쓽 쑀쟾옄(THPO, BAK1, GGNBP1, ACDAD10, ABCC4)뒗 GWAS catalog瑜 솗씤븳 寃곌낵 삁냼뙋怨 쑀쓽꽦쓣 蹂댁씤 寃곌낵媛 엳뿀떎(Table 1). 5媛쒖쓽 쑀쟾옄 쁺뿭뿉 룷븿릺硫 쑀쓽꽦쓣 蹂댁씤 SNP THPO 쑀쟾옄쓽 rs6141, BAK1 쑀쟾옄쓽 rs210314, rs9296095, GGNBP1 쑀쟾옄쓽 rs75080135, ACAD10 쑀쟾옄쓽 rs6490294, ABCC4 쑀쟾옄쓽 rs4148441濡 珥 6媛쒖씠떎. 쟾泥 462,531媛쒖쓽 SNP뿉 븳 쟾옣쑀쟾泥대텇꽍 寃곌낵瑜 Manhattan plot쑝濡 굹깉怨 쑀쓽꽦 엳뒗 6媛쒖쓽 SNP뱾쓣 몴떆븯떎(Fig. 1). 媛옣 넂 쑀쓽 닔以쓣 蹂댁씠뒗 rs9296095 (P = 1.07 × 10-19)뒗 씠踰 뿰援 寃곌낵뿉꽌 쉶洹怨꾩닔(regression coefficient; Beta) 몴以삤李(standard error; SE)媛 5.46±0.60쑝濡 굹굹 minor allele씤 C 뿼湲곕 蹂댁쑀븷닔濡 삁냼뙋 닔移섍 넂 寃쏀뼢쓣 蹂댁뿬二쇨퀬 엳뿀떎. rs9296095뒗 KARE 肄뷀샇듃 옄猷뚮 湲곕컲쑝濡 븳 씠쟾 뿰援ъ뿉꽌룄 諛쒗몴릺뿀뜕 SNP씠뿀뒗뜲, 蹂 뿰援 寃곌낵뿉꽌 옱쁽꽦쓣 솗씤븷 닔 엳뿀떎(Oh et al., 2014). rs6141, rs210314, rs75080135, rs6490294, rs4148441 蹂 뿰援ъ뿉꽌 삁냼뙋 닔移섏 愿젴븯뿬 븳援씤뿉꽌 泥섏쓬쑝濡 諛쒓뎬맂 SNP뱾씠떎.

Comparison of identified SNPs for platelet count (PLT) in GWAS catalog and HEXA cohort

CHR GENE SNP Minor/Major allele HEXA result EA GWAS catalog Ref
Beta ± SE P-value Platelets count unit P-value
3 THPO rs6141 T/C 3.02±0.50 1.24×10-9 T 0.08 [0.052~0.100] 5.00×10-11 Kamatani Y
T 2.47 [1.57~3.36] 6.00×10-8 Gieger C
T 0.06 [0.056~0.073] 7.00×10-50 Kanai M
6 BAK1 rs210134 A/G -3.36±0.55 8.86×10-10 G -8.92 [5.82~12.02] 2.00×10-8 Li J
G -6.16 [4.63~7.69] 2.00×10-15 Qayyum R
A -4.94 [3.25~6.63] 9.00×10-9 Schick U
G 4.96 [4.18~5.73] 7.00×10-36 Gieger C
A 4.66 [NR] 6.00×10-8 Shameer K
G 5.73 [4.63~6.83] 2.00×10-24 Wojcik G
6 BAK1 rs9296095 C/T 5.46±0.60 1.07×10-19 C 4.8 [2.51~7.09] 1.00×10-15 Oh J
- 5.46 [4.33~6.58] 2.00×10-21 Wojcik G
6 GGNBP1 rs75080135 C/A 5.58±0.60 2.80×10-20 C 0.1 [0.093~0.111] 6.00×10-101 Astle W
12 ACAD10 rs6490294 C/A -4.29±0.66 6.92×10-11 A -4.38 [2.91~5.85] 5.00×10-9 Qayyum R
- 2.99 [1.92~4.07] 5.00×10-8 Wojcik G
13 ABCC4 rs4148441 A/G -3.73±0.61 9.37×10-10 G 4.12 [2.94~5.29] 7.00×10-12 Gieger C
- 3.65 [2.09~5.21] 5.00×10-6 Wojcik G

The P-values lower than the genome wide association study significance level (P < 10-8). Abbreviations: CHR, chromosome; EA, effect allele; HEXA, The health examinees; se, standard error, SNP, single nucleotide polymorphism. The SNP positions are based on UCSC Genome Browser on Human Feb. 2009 (GRCh37/hg19). The beta ± se of HEXA result is based on the minor allele



Fig. 1. Manhattan plot of genome-wide association study (GWAS) for platelet count (PLT) in HEXA cohort. The highest P-value is single nucleotide polymorphism(SNP) in chromosome 6. Nine genomic regions contain SNPs that exceed the genome-wide significance threshold of P-value (1 × 10-8). The red circles are SNPs associated with PLT that were repeatedly identified in this study.

븳援씤 HEXA 肄뷀샇듃쓽 긽愿꽦 遺꾩꽍 寃곌낵 GWAS catalog 뜲씠踰좎씠뒪뿉꽌 삁냼뙋 닔移섏뿉 븳 궡슜쓣 鍮꾧탳빐 蹂댁븯쓣 븣 rs6141, rs9296095, rs75080135뒗 minor allele瑜 蹂댁쑀븯쓣 븣 삁냼뙋 닔移 蹂솕쓽 諛⑺뼢꽦씠 씪移섑븯떎. 븳援씤 HEXA 肄뷀샇듃뿉꽌뒗 rs4148441 (P = 9.37 × 10-10) A 뿼湲곕 蹂댁쑀븷 븣 Beta SE 媛믪씠 -3.73±0.61濡 굹궗怨 GWAS catalog뿉꽌뒗 G 뿼湲곕 蹂댁쑀븷 븣 Platelets count unit씠 4.12 [2.94~5.29]濡 굹굹 뿼湲곗쓽 湲곗씠 룞씪븷 寃쎌슦 삁냼뙋 닔移섏쓽 諛⑺뼢꽦씠 씪移섑븯뒗 寃껋쓣 븣 닔 엳뿀떎. rs6490294 (P = 6.92 × 10-11)쓽 寃쎌슦뿉뒗 씤醫낅퀎濡 뿼湲곕씠쓽 李⑥씠媛 엳뒗 듅닔븳 SNP씤뜲, 븳援씤쓣 鍮꾨’븳 以묎뎅씤, 씪蹂몄씤뿉꽌뒗 C 뿼湲곗쓽 떎삎꽦씠 愿李곕릺怨, 꽌뼇씤뿉꽌뒗 A 뿼湲곗쓽 떎삎꽦씠 愿李곕맂떎뒗 듅꽦쓣 蹂댁씠怨 엳떎. 蹂 뿰援 寃곌낵뿉꽌뒗 븳援씤뱾씠 C 뿼湲곕 蹂댁쑀븷 븣 -4.29±0.66씠怨, GWAS catalog뿉 벑濡앸맂 끉臾 湲곗뿉꽌뒗 A 뿼湲곕 蹂댁쑀븷 寃쎌슦 -4.38 (2.91~ 5.85)濡 굹굹 寃곌낵쟻쑝濡 湲곗李몄“꽌뿴怨쇰뒗 떎瑜 蹂씠媛 엳쓣 븣 삁냼뙋 닔移섎 궙寃 븯뒗 寃쏀뼢꽦쓣 蹂댁씤떎뒗 寃껋뿉꽌뒗 씪移섑븯뒗 寃껋쓣 븣 닔 엳뿀떎(Table 1). Wojcik쓽 諛쒗몴 끉臾(Wojcik et al., 2019) 뿬윭 誘쇱”뱾쓣 넻빀븯뿬 遺꾩꽍븳 끉臾몄쑝濡 씤醫낆씠굹 誘쇱”뱾 留덈떎 minor allele쓽 鍮덈룄 뿼湲곗쓽 李⑥씠媛 엳湲 븣臾몄뿉 듅젙 뿼湲곕줈 紐낇솗븯寃 몴湲고븯吏뒗 紐삵븯떎(Table 1).

LocusZoom 봽濡쒓렇옩쓣 궗슜븯뿬 GWAS 쑀쓽 닔以쓣 留뚯”븯뒗 6媛쒖쓽 SNP뱾쓽 二쇰쓽 SNP뱾怨쇱쓽 recombination rate (Cm/Mb) r2瑜 굹궡뒗 regional plot쑝濡 굹궡뿀뒗뜲(Fig. 2), 洹 湲곗 hg19 version ASN (Asian population)쑝濡 븯떎. 옄二쇱깋 떎씠븘紐щ뱶뒗 regional plot 긽뿉꽌 媛옣 넂 쑀쓽꽦쓣 蹂댁씠뒗 SNP씠떎. 媛옣 쑀쓽븳 SNP怨 뿰愿릺뼱 엳쑝硫댁꽌 r2 媛믪씠 넂 SNP뱾 遺됱깋쑝濡 몴떆맂떎. rs210134, rs75080135, rs6490294뒗 二쇰뿉 遺됱깋쑝濡 몴떆맂 SNP뱾씠 룷吏꾨릺뼱 꽌濡 媛꾩뿉 뿰愿릺뼱 엳쓬쓣 븣 닔 엳떎.

Fig. 2. Regional plots of six discovered variants. Regional plot of six discovered variants (A-F). These plots showing the association signals in the region of THPO on chromosome 3 (A), BAK1 on chromosome 6 (B), (C), GGNBP1 on chromosome 6 (D), ACAD10 on chromosome 12(E), and ABCC4 on chromosome 13(F).

THPO 쑀쟾옄뒗 삁냼뙋 꽦닕怨쇱젙뿉꽌 嫄고빑꽭룷쓽 利앹떇怨 遺꾪솕瑜 議곗젅븯뒗 삁냼뙋삎꽦씤옄(TPO) 떒諛깆쭏쓣 肄붾뵫븳떎(Larsen et al., 2017; Cornish et al., 2020). TPO뒗 TPO 닔슜泥댁뿉 寃고빀븯뿬 삁냼뙋 깮궛쓣 옄洹뱁븳떎(Kuter 2013; Hitchcock and Kaushansky, 2014). 쟾 뿰援ъ뿉 뵲瑜대㈃ THPO 쑀쟾옄 룎뿰蹂씠뒗 TPO 떒諛깆쭏쓽 踰덉뿭쓣 利앷떆耳 TPO 닔슜泥댁쓽 떊샇쟾떖 寃쎈줈瑜 鍮꾩젙긽쟻쑝濡 솢꽦솕떆궓떎. 洹 寃곌낵 嫄고빑꽭룷쓽 怨쇱엵 깮궛怨 삁냼뙋 닔瑜 利앷떆耳 蹂명깭꽦 삁냼뙋 媛먯냼利앹쓣 씪쑝궗 닔 엳떎(Ghilardi et al., 1998; Wiestner et al., 1998; Ghilardi and Skoda RC, 1999; Majka et al., 2002). 뵲씪꽌 THPO뿉 냽븳 SNP 뿼湲곗뿉 뵲씪 쟾궗씤옄 삉뒗 떒諛깆쭏뿉 誘몄튂뒗 쁺뼢뿉 李⑥씠媛 엳쓣 寃껋씠씪 삁긽릺怨, 씠뒗 TPO 떒諛깆쭏 踰덉뿭뿉 李⑥씠瑜 遺덈윭 PLT뿉 쁺뼢쓣 誘몄낀쓣 寃껋쑝濡 삁긽븳떎. 삁냼뙋 슚쑉쟻씤 硫붿빱땲利섏쓣 넻빐 留ㅼ씪 닔諛깆뼲 媛쒓 닚솚怨쇱젙뿉꽌 젣嫄곕맂떎. 誘명넗肄섎뱶由ъ븘 留 닾怨쇱꽦(MMP) BCL2 떒諛깆쭏뿉 쓽빐 꽭룷옄硫몄궗瑜 넻젣븳떎(Kroemer et al., 2007; Suhaili et al., 2017; Peña-Blanco and García-Sáez, 2018). 利, BCL2 떒諛깆쭏 怨꾩뿴쓽 씪썝씤 BAK1 쑀쟾옄뒗 꽭룷궗硫 議곗젅옄 뿭븷쓣 븳떎(Kroemer et al., 2007; Peña-Blanco and García-Sáez, 2018; Yu et al., 2019). BAK1쓽 遺덊솢꽦솕 BCL2 媛꾩쓽 긽샇옉슜 誘명넗肄섎뱶由ъ븘쓽 젣븳쟻씤 꽭룷옄硫몄궗瑜 쑀諛쒗븯뿬 삁냼뙋 媛먯냼利앹쓣 쑀諛쒗븷 닔 엳떎(Kroemer et al., 2007; Suhaili et al., 2017; Peña-Blanco and García-Sáez, 2018). GGNBP1 GGN1 떒諛깆쭏濡 씠猷⑥뼱吏 pseudogene씠떎. 씠 쑀쟾옄뒗 씤媛꾩뿉寃 떒씪 쑀궗 쑀쟾옄濡 삁냼뙋 닔쓽 硫붿빱땲利섏 븘吏 諛앺吏吏 븡븯떎(Zhang et al., 2005; Jamsai et al., 2008). ACAD10 쑀쟾옄쓽 룎뿰蹂씠뒗 吏諛⑹쓣 遺꾪빐븯뒗뜲 以묒슂븳 Acyl-CoA Dehydrogenase (MCAD) 슚냼쓽 寃고븤쓣 쑀諛쒗븳떎(Merritt and Chang, 2000). MCAD 슚냼쓽 寃고븤 HELLP 利앺썑援곗쓣 씪쑝궗 닔 엳뒗뜲, 씠뒗 엫떊以묐룆利앹뿉 슜삁 hemolysis (H), 媛꾧린뒫옣븷 elevated liver enzymes (EL), 삁냼뙋 媛먯냼 low platelets (LP)瑜 빀蹂묓븯뿬 遺숈뿬吏 씠由꾩씠떎(Shekhawat et al., 2005). 뵲씪꽌 삁냼뙋怨 긽愿愿怨꾨 媛졇 쑀쟾쟻 떎삎꽦뿉 뵲씪 삁냼뙋 닔뿉 쁺뼢쓣 誘몄튌 寃껋쑝濡 깮媛곷맂떎. ABCC4 닔슜泥대뒗 씤媛 삁냼뙋쓽 뜽-怨쇰┰뿉꽌 諛쒗쁽릺怨 ADP 닔넚뿉 愿뿬븳떎(Jedlitschky et al., 2010). 뜽-怨쇰┰뿉뒗 ADP, ATP, 꽭濡쒗넗땶, Ca2+ 벑쓣 留롮씠 븿쑀븯怨 엳쑝硫 吏삁쓣 쐞빐 삁냼뙋쓣 쓳吏묒떆궓떎. 뵲씪꽌 ABCC4쓽 寃고븿 삁냼뙋씠 젙긽 뜽-怨쇰┰쓽 議곕┰怨 肄쒕씪寃먭낵쓽 쑀룄 쓳吏묒쓣 넀긽쓣 떆궓떎(Jedlitschky et al., 2010; Cheepala et al., 2015).

理쒓렐 듅젙 吏덈퀝 삉뒗 몴쁽삎怨 쑀쟾쟻 떎삎꽦 궗씠뿉 긽愿 愿怨꾨 遺꾩꽍븯뿬 吏덈퀝 諛쒕퀝뿉 誘몄튂뒗 쑀쟾쟻씤 슂씤쓣 룞젙븯뒗 뿰援щ뱾씠 솢諛쒗엳 吏꾪뻾릺怨 엳떎(Kroemer et al., 2007; Eicher et al., 2018; Gill et al., 2018). 蹂 뿰援щ뒗 湲곗〈뿉 KARE 肄뷀샇듃 옄猷뚮 넗濡 諛쒗몴맂 寃곌낵 떎瑜 뿰援щ긽옄씤 HEXA 肄뷀샇듃 옄猷뚮 솢슜븯뿬 삁냼뙋 닔移섏 뿰愿꽦씠 굹궃 쑀쟾쟻 떎삎꽦쓣 諛쒓뎬븯怨, 옱쁽꽦쓣 솗씤븯떎. 洹 寃곌낵, BAK1 쑀쟾옄쓽 rs9296095뒗 몢 肄뷀샇듃뿉꽌 紐⑤몢 삁냼뙋 닔移섏 뿰愿맂 SNP엫쓣 諛앺 옱쁽꽦씠 솗씤릺뿀떎. 삉븳, THPO 쑀쟾옄쓽 rs6141, BAK1 쑀쟾옄쓽 rs210134, GGNBP1 쑀쟾옄쓽 rs75080135, ABCC4 쑀쟾옄쓽 rs4148441 븳援씤뿉꽌 泥섏쓬쑝濡 삁냼뙋 닔 愿젴븯뿬 諛쒓뎬맂 SNP씠뿀떎. 뵲씪꽌 HEXA 肄뷀샇듃 옄猷뚮 솢슜븳 蹂 뿰援 寃곌낵瑜 넻빐 삁냼뙋 닔뿉 쁺뼢쓣 誘몄튌 닔 엳뒗 쑀쟾씤옄뱾쓣 떎떆 븳 踰 옱솗씤븯怨 깉濡쒖슫 媛뒫꽦 엳뒗 쑀쟾蹂씠뱾쓣 젣떆븷 肉먮쭔 븘땲씪 빐떦 쑀쟾옄뱾쓽 삁냼뙋怨 愿젴맂 꽭룷깮臾쇳븰쟻 湲곗쟾怨쇱쓽 愿젴꽦쓣 넻빐 삁냼뙋 愿젴 吏덊솚뿉 븳 쑀쟾븰쟻 씠빐瑜 利앹쭊 떆궗 寃껋쑝濡 湲곕븳떎.

SUPPLEMENTRARY MATERIALS
bsl-27-3-187-supple.pdf
ACKNOWLEDGEMENT

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [NRF-2017R1D1A3B03034752].

CONFLICT OF INTEREST

All authors declare no competing interests.

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