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Association of PPARGC1A Gene Variants with Hypertension in Korean Population
Biomed Sci Letters 2021;27:12-18
Published online March 31, 2021;  https://doi.org/10.15616/BSL.2021.27.1.12
© 2021 The Korean Society For Biomedical Laboratory Sciences.

Hyun-Seok Jin1,* and Sangwook Park2,,*

1Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan 31499, Korea
2Department of Biomedical Laboratory Science, College of Health and Medical Science, Sangji University, Wonju 26339, Korea
Correspondence to: Sangwook Park. Department of Biomedical Laboratory Science, Sangji University, 83 Sangjidae-gil, Wonju, Gangwon-do 26339, Korea.
Tel: +82-33-738-7682, Fax: +82-33-738-7652, e-mail: spark367@sangji.ac.kr
*Professor.
Received February 24, 2021; Accepted March 25, 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
Hypertension (HTN) is one of the cardiovascular disease risk factors. Peroxisome proliferator-activated receptor 款 coactivator 1 alpha (PPARGC1A) is involved in a master modulator of mitochondrial biogenesis, and pulmonary arterial hypertension. In this study, we report results of PPARGC1A were associated with hypertension and its intermediate phenotype of systolic (SBP) and diastolic blood pressure (DBP) in the Korean population. In detail, identifying a susceptibility locus, 3 SNPs for HTN, 2 SNPs for SBP, 3 SNPs for DBP at P<0.05. Among them, rs1472095 in PPARGC1A gene statistically demonstrated one of the significant correlations with Hypertension (P-value=0.00359, OR=0.8, 95% CI=0.68~0.93). The minor allele (T) of PPARGC1A was statistically associated with the increased value of DBP, SBP, and the increase risk of hypertension. We aim to manifest a significant association between genetic variant in PPARGC1A and hypertension. This finding suggested that association of PPARGC1A genetic polymorphism and HTN accelerates our understanding of blood pressure control and underlines potential drug targets for treatment of hypertension.
Keywords : DBP, Hypertension, PPARGC1A, SBP
꽌 濡

쟾꽭怨꾩쟻쑝濡 떖삁愿 吏덈퀝쓽 二쇱슂 썝씤씤 怨좏삁븬 빐寃고빐빞 븷 몴쟻씤 꽭怨 怨듭쨷蹂닿굔 吏덈퀝 以 븯굹씠떎(꽭怨꾨낫嫄닿린援, WHO, 2013). 쟻뼱룄 9뼲 7泥쒕쭔 紐낆쓽 꽭怨꾩씤뱾씠 怨좏삁븬쓣 븪怨 엳怨 씠 닔移섎뒗 2021뀈源뚯 15뼲 씠긽源뚯 利앷븷 寃껋쑝濡 異붿젙븯怨 엳떎(Kearney et al., 2005). 떎젣濡, 슦由щ굹씪 嫄닿컯蹂댄뿕떖궗룊媛썝쓽 5뀈媛 떖궗뀈룄蹂(2015~2019뀈) 怨좏삁븬 솚옄닔쓽 異붿씠瑜 蹂대㈃ 留ㅻ뀈 20~ 30留뚮챸씠 袁몄엳 긽듅븯떎(Healthcare Bigdata, 2019). 怨좏삁븬(hypertension) 뿬윭 媛吏 썝씤쑝濡 삁븬씠 젙긽 踰붿쐞(120/80 mmHg)蹂대떎 넂븘吏 긽깭瑜 쓽誘명븯뒗뜲, 씠윭븳 怨좏삁븬 긽깭媛 삤옯룞븞 吏냽맆 寃쎌슦뿉뒗 떖삁愿 吏덊솚쓣 룷븿븳 떎뼇븳 궗吏덊솚쓽 諛쒖깮쓣 쑀諛쒗븳떎(Carretero and Oparil, 2000). 삉븳, 怨좏삁븬 諛쒖깮뿉 븳 떎뼇븳 쑀쟾쟻 뿰援щ 넻빐 쑀쟾쟻 씤옄쓽 쁺뼢씠 빟 30~60%뿉 빐떦븯怨 엳쓬쓣 留롮 뿰援щ뱾뿉 씤빐 諛앺議뚮떎(Singh et al., 2016; Cabrera et al., 2019). 씠뿉 怨좏삁븬뿉 븳 留롮 쟾옣쑀쟾泥 뿰愿 뿰援щ 넻빐 떎뼇븳 쑀쟾옄뱾씠 諛쒗몴릺뿀떎(Pan et al., 2015; Warren et al., 2017; El Rouby et al., 2019). 洹몃윭굹, 洹몃젃寃 諛쒗몴맂 쑀쟾옄뱾 以묒뿉 떎닔뒗 븳援씤뿉꽌쓽 옱쁽꽦 뿬遺媛 誘몄쿂 遺꾩꽍릺吏 븡 쑀쟾옄뱾룄 議댁옱븯湲곗뿉 씠윭븳 쑀쟾옄뱾뿉 븳 븳援씤뿉꽌쓽 怨좏삁븬 긽깭 삉뒗 쟾꽭怨꾩쟻쑝濡 떖삁愿 吏덈퀝쓽 二쇱슂 썝씤씤 怨좏삁븬 빐寃고빐빞 븷 몴쟻씤 꽭怨 怨듭쨷蹂닿굔 吏덈퀝 以 븯굹씠떎(꽭怨꾨낫嫄닿린援, WHO, 2013). 쟻뼱룄 9뼲 7泥쒕쭔 紐낆쓽 꽭怨꾩씤뱾씠 怨좏삁븬쓣 븪怨 엳怨 씠 닔移섎뒗 2021뀈源뚯 15뼲 씠긽源뚯 利앷븷 寃껋쑝濡 異붿젙븯怨 엳떎(Kearney et al., 2005). 떎젣濡, 슦由щ굹씪 嫄닿컯蹂댄뿕떖궗룊媛썝쓽 5뀈媛 떖궗뀈룄蹂(2015~2019뀈) 怨좏삁븬 솚옄닔쓽 異붿씠瑜 蹂대㈃ 留ㅻ뀈 20~ 30留뚮챸씠 袁몄엳 긽듅븯떎(Healthcare Bigdata, 2019). 怨좏삁븬(hypertension) 뿬윭 媛吏 썝씤쑝濡 삁븬씠 젙긽 踰붿쐞(120/80 mmHg)蹂대떎 넂븘吏 긽깭瑜 쓽誘명븯뒗뜲, 씠윭븳 怨좏삁븬 긽깭媛 삤옯룞븞 吏냽맆 寃쎌슦뿉뒗 떖삁愿 吏덊솚쓣 룷븿븳 떎뼇븳 궗吏덊솚쓽 諛쒖깮쓣 쑀諛쒗븳떎(Carretero and Oparil, 2000). 삉븳, 怨좏삁븬 諛쒖깮뿉 븳 떎뼇븳 쑀쟾쟻 뿰援щ 넻빐 쑀쟾쟻 씤옄쓽 쁺뼢씠 빟 30~60%뿉 빐떦븯怨 엳쓬쓣 留롮 뿰援щ뱾뿉 씤빐 諛앺議뚮떎(Singh et al., 2016; Cabrera et al., 2019). 씠뿉 怨좏삁븬뿉 븳 留롮 쟾옣쑀쟾泥 뿰愿 뿰援щ 넻빐 떎뼇븳 쑀쟾옄뱾씠 諛쒗몴릺뿀떎(Pan et al., 2015; Warren et al., 2017; El Rouby et al., 2019). 洹몃윭굹, 洹몃젃寃 諛쒗몴맂 쑀쟾옄뱾 以묒뿉 떎닔뒗 븳援씤뿉꽌쓽 옱쁽꽦 뿬遺媛 誘몄쿂 遺꾩꽍릺吏 븡 쑀쟾옄뱾룄 議댁옱븯湲곗뿉 씠윭븳 쑀쟾옄뱾뿉 븳 븳援씤뿉꽌쓽 怨좏삁븬 긽깭 삉뒗 삁븬 닔移섏쓽 뿰愿꽦 遺꾩꽍쓣 넻븳 옱쁽꽦 遺꾩꽍씠 븳援씤쓽 怨좏삁븬쓣 쑀쟾쟻 愿젏뿉꽌 씠빐븯湲 쐞빐 븘슂븯떎.

Peroxisome proliferator-activated receptors (PPAR) 빑샇瑜대が닔슜泥 superfamily뿉 냽븯뒗 由ш컙뱶 솢꽦솕 쟾궗씤옄씠硫 꽭룷 궡 뿉꼫吏 臾쇱쭏 궗瑜 議곗젅븳떎. 삉븳, 꽭룷 뿉꼫吏 궗뿉 以묒슂븳 뿭븷쓣 븯뒗 옄媛룷떇-由ъ냼醫 湲곕뒫 議곗젅뿉룄 뿭븷씠 諛앺議뚮떎(Sinha et al., 2020). PPAR 3媛쒖쓽 isotype (PPAR慣, PPAR棺/灌 PPAR款)濡 援ъ꽦맂 쟾궗씤옄濡쒖뜥 吏吏, 깂닔솕臾 궗 諛 誘명넗肄섎뱶由ъ븘 궗뿉 愿뿬븯뒗 쑀쟾옄瑜 議곗젅븯뒗 뿭븷쓣 븳떎(Li et al., 2018; Vargas-S찼nchez et al, 2020). 듅엳, PPAR款뒗 룷룄떦 궗 愿젴맂 쑀쟾옄뱾쓣 議곗젅븯뒗 吏諛⑹꽭룷 遺꾪솕쓽 二쇱슂 議곗젅옄濡 븣젮졇 엳쓣 肉먮쭔 븘땲씪 洹쇱쑁삎꽦怨 궛냼씉닔, 옒怨 씤궡젰怨 媛숈 뒪룷痢 쑀쟾옄쓽 뿰愿꽦뿉룄 愿뿬븳떎(Popov, 2018; Qiu, 2020). PPAR款 coactivator 1慣 (PPARGC1A)뒗 PGC-1慣씪怨좊룄 몴湲고븯硫 PPAR款怨 寃고빀븯뿬 꽭룷 궡 떎뼇븳 궗湲곕뒫뿉 愿뿬븳떎(Puigserver et al., 1998). 쁽옱源뚯 10媛 씠긽쓽 isoform씠 議댁옱븯硫 삁愿떊깮(Angiogenesis), 誘명넗肄섎뱶由ъ븘 깮빀꽦(Mitochondrial biogenesis), 洹쇱쑁鍮꾨利(Muscle hypertrophy), 룷룄떦 떊빀꽦(Gluconeogenesis) 벑뿉 쁺뼢쓣 以떎(Martinez-Redondo et al., 2015). 븳렪, 룓怨좏삁븬(pulmonary hypertension, PH) 룓룞留 룊솢洹 꽭룷쓽 利앹떇怨 삁愿옱삎꽦쓣 利앷떆궎뒗 궗蹂삎씠 듅吏뺤씠떎(Yeligar et al., 2018). 誘명넗肄섎뱶由ъ븘 쑀쟾옄 諛쒗쁽 諛 깮빀꽦쓣 議곗젅븯뒗 PPARGC1A 삊젰븯뒗 PPAR款뒗 궙 PH뿉꽌 룓룞留 룊솢洹 꽭룷쓽 利앹떇쓣 議곗젅븯湲곕룄 븳떎(Hart et al, 2018). 理쒓렐 10뿬뀈 룞븞 뒪룷痢 쑀쟾泥댄븰(sports genomics)쓣 二쇱젣濡 븳 怨쇳븰끉臾몃뱾 以 PPAR 쑀쟾옄 怨듬룞솢꽦泥(coactivator)뿉 븳 뿰援ш 留롮씠 씠猷⑥뼱吏怨 엳떎(Ahmetov and Fedotovskaya, 2015; Petr et al., 2019).

蹂 뿰援щ뒗 쟾옣쑀쟾泥 遺꾩꽍쓣 씠슜븯뿬 PPARGC1A 쑀쟾옄 쁺뿭뿉 쐞移섑븳 SNP뱾怨 怨좏삁븬쓽 吏덈퀝 긽愿꽦 遺꾩꽍쓣 넻빐 븳援씤뿉꽌룄 PPARGC1A 쑀쟾옄 蹂씠媛 怨좏삁븬 諛 삁븬怨쇱쓽 긽愿愿怨꾧 엳떎뒗 寃껋쓣 솗씤븯떎.

옱猷 諛 諛⑸쾿

뿰援 긽옄

븳援씤 쑀쟾泥댁뿭븰議곗궗궗뾽(Korean Genome and Epidemiology, KoGES)쓽 씪遺遺꾩쑝濡쒖뜥 븳援씤쑀쟾泥대텇꽍옄猷(Korean Association Resource, KARE)쓽 援궡 뿰援 긽옄瑜 긽쑝濡 蹂 뿰援щ 닔뻾븯떎(Cho et al., 2009). 궗슜맂 뿭븰젙蹂 諛 쑀쟾젙蹂대뒗 吏덈퀝愿由ъ껌 씤泥댁옄썝뻾쑝濡쒕꽣 遺꾩뼇쓣 諛쏆븘 궗슜븯떎(17100901-01-01). 蹂 젙蹂대뒗 吏덈퀝愿由ъ껌뿉꽌 2001뀈뿉 떆옉븳 肄뷀샇듃 뿰援щ줈뜥 寃쎄린룄 븞꽦떆 븞궛떆 二쇨굅씤뱾쓣 긽쑝濡 븳援씤 뿭븰 諛 쑀쟾泥 뿰援щ 닔뻾븯떎. 꽦씤(40~69꽭) 궓 10,038紐낆쓣 紐⑥쭛븯쑝硫, 씠뱾 以묒뿉꽌 젙룄愿由(Quality Control, QC) 怨쇱젙쓣 넻빐 쑀쟾泥 遺꾩꽍 湲곗뿉 쟻빀븯吏 븡 1,196紐낆씠 젣쇅릺뿀쑝硫 理쒖쥌쟻쑝濡 씠슜 媛뒫븳 뿰援 긽옄뒗 珥 8,842紐(궓꽦: 4,183紐, 뿬꽦: 4,659紐)씠뿀떎. 怨좏삁븬뿉 븳 쑀쟾蹂씠쓽 긽愿꽦 뿰援щ 쐞빐 8,842紐낆쓽 긽옄瑜 긽쑝濡 솚옄援(怨좏삁븬)怨 議곌뎔쓣 꽑蹂꾪븯떎. 삉븳, 怨좏삁븬 移섎즺 삉뒗 삁븬뿉 쁺뼢쓣 以 닔 엳뒗 빟臾 移섎즺瑜 諛쏆 1,291紐낆쓣 젣쇅븯怨 理쒖쥌 7,551紐낆쓣 뿰援 긽옄濡 꽑蹂꾪븯뿬 젙웾쟻 뿰愿꽦 遺꾩꽍쓣 닔뻾븯떎. 怨좏삁븬 移섎즺瑜 諛쏄퀬 엳뒗 솚옄 961紐낆쓣 怨좏삁븬 솚옄援(1,968紐)뿉 룷븿븯뿬 濡쒖뒪떛 쉶洹 遺꾩꽍쓣 닔뻾븯떎. 뵲씪꽌 쟾泥 솚옄援곗 珥 1,968紐낆쓣 꽑젙(닔異뺢린 삁븬 140 mmHg 씠긽 삉뒗 씠셿湲 삁븬 90 mmHg 씠긽)븯怨 닔異뺢린 삁븬씠 120 mmHg 誘몃쭔씠硫댁꽌 씠셿湲 삁븬씠 80 mmHg 誘몃쭔씠硫 嫄닿컯 議곌뎔(N=4,452)쑝濡 꽑蹂꾪븯떎. 솚옄援(怨좏삁븬)怨 議곌뎔(嫄닿컯씤)쓽 룊洹 뿰졊 49.4짹8.11꽭 56.8짹8.44꽭濡 쑀쓽븳 넻怨꾩쟻 李⑥씠瑜 굹깉떎. 蹂 뿰援 寃곌낵뒗 샇꽌븰援먯 吏덈퀝愿由щ낯遺(KNIH)濡쒕꽣 뿰援ъ쑄由 듅씤쓣 뼸 썑 쑀쟾젙蹂 遺꾩꽍쓣 닔뻾븯떎(1041231-170822-BR-062-01).

삁븬 痢≪젙 諛⑸쾿

蹂묒썝쓽 닕젴맂 媛꾪샇궗쓽 룄쑝濡 뿰援 긽옄쓽 뙏 몮젅瑜 쟻젅븳 而ㅽ봽瑜 씠슜븯뿬(닔 삁븬怨, W. A. Baum, Copiague, NY, USA)濡 삁븬쓣 痢≪젙븯떎. 긽옄뒗 泥 삁븬 痢≪젙 쟾뿉 5遺 룞븞 쑕떇쓣 痍⑦븯寃 븯떎. 洹몃━怨 늻슫 옄꽭瑜 쑀吏븳 梨 5遺 씠긽쓽 떆媛꾩감씠瑜 몢怨 3踰 痢≪젙븯쑝硫 洹 룊洹좉컪쓣 떎쓬 쑀쟾 遺꾩꽍뿉 궗슜븯떎.

쑀쟾삎 遺꾩꽍怨 떒씪뿼湲곗꽌뿴(Single Nucleotide Polymorphism, SNP) 꽑蹂

蹂 뿰援щ 쐞빐 쑀쟾삎 KARE 옄猷뚮 諛뷀깢쑝濡 떒씪뿼湲곗꽌뿴(SNP)쓣 꽑蹂꾪븯떎. 留먯큹삁븸쑝濡쒕꽣 뿰援 긽옄쓽 DNA 떆猷뚮 遺꾨━ 異붿텧븯怨, Genome-Wide Human SNP array 5.0 (Affymetrix, Inc., Santa Clara, CA, USA)瑜 궗슜븯뿬 쑀쟾삎 뙋룆쓣 븯떎. 쑀쟾삎 뙋룆 젙솗룄媛 98% 씠븯 삉뒗 넂 missing genotype call rate (4% 씠긽)쓣 굹궦 寃쎌슦, 30% 珥덇낵쓽 heterozygosity瑜 媛吏嫄곕굹, 꽦蹂꾩씠 遺덈텇紐낇븳 긽옄뱾 젣쇅릺뿀떎. 蹂 뿰援ъ뿉꽌 遺꾩꽍븳 PPARGC1A 쟾궗泥 뼇履 걹 留먮떒뿉꽌 짹5 kb뵫 솗옣븳 踰붿쐞뿉 쐞移섑븳 15媛쒖쓽 SNP뱾쓣 꽑깮븯떎. 꽑蹂꾨맂 SNP뱾쓽 뿼깋泥 쐞移섎뒗 UCSC Genome Browser (NCBI human gb36, 2006)瑜 湲곗쑝濡 븯떎.

넻怨 遺꾩꽍 諛 긽愿꽦 遺꾩꽍

넻怨 遺꾩꽍쓣 쐞빐 PLINK version 1.07 (http://pngu.mgh.harvard.edu/~purcell/plink)怨 SPSS (PASW Statistics v18.0, Chicago, IL, USA)쓣 궗슜븯떎. 濡쒖뒪떛 쉶洹 遺꾩꽍쓣 궗슜븯뿬 怨좏삁븬 솚옄援곌낵 嫄닿컯 議곌뎔뿉 빐 additive genetic model쓣 湲곕컲쑝濡 븳 쑀쟾쟻 蹂씠쓽 긽愿꽦 遺꾩꽍쓣 닔뻾븯떎. 닔異뺢린 삁븬(SBP) 諛 씠셿湲 삁븬(DBP)怨 쑀쟾쟻 蹂씠쓽 긽愿愿怨꾨뒗 꽑삎 쉶洹 遺꾩꽍쓣 궗슜븯떎. 洹몃━怨 쉶洹 遺꾩꽍 쟾뿉 굹씠, 吏뿭, 꽦蹂꾩 怨듬닔濡 泥섎━븯뿬 遺꾩꽍븯떎. 洹몃━怨 P 媛믪씠 0.05 씠븯쓽 遺꾩꽍 媛믪쓣 쑀쓽 닔以쓽 湲곗쑝濡 젙븯떎. 異붽쟻쑝濡, 듅젙 SNP뿉 븳 由 쑀쟾옄 鍮덈룄쓽 吏由ъ쟻 遺꾪룷瑜 솗씤븯湲 쐞빐꽌 Geography of Genetic Variants (GGV) browser (https://popgen.uchicago.edu/ggv)瑜 씠슜븯쑝硫 1000 Genome database瑜 湲곕컲쑝濡 븯떎(Marcus and Novembre, 2017).

寃 怨

PPARGC1A 쑀쟾옄 怨좏삁븬怨쇱쓽 濡쒖뒪떛 쉶洹 遺꾩꽍

뿰援 긽옄뱾쓽 엫긽 몴쁽삎 듅吏뺤쓣 Table 1뿉 굹깉떎. 怨좏삁븬 솚옄(N=1968)쓽 룊洹 굹씠, 룊洹 닔異뺢린 삁븬(SBP), 룊洹 씠셿湲 삁븬(DBP) 56.75짹8.44꽭, 139.42짹17.27 mmHg, 88.97짹10.90 mmHg쑝濡 굹궗떎(Table 1). 怨좏삁븬 솚옄援곗뿉꽌 紐⑤몢 넂 닔移섎 굹깉怨 Student t-寃젙쓣 넻빐 젙긽 삁븬援곌낵 怨좏삁븬 솚옄媛꾩뿉 SBP, DBP쓽 넻怨꾩쟻 쑀쓽李⑥씠媛 엳뿀떎(Table 1).

Basic characteristics of the subjects in the KoGES

Characterisitics Quantitative trait analysis* Case-control analysis**

Normotensive Hypertensive P value***
Number of subjects 7,551 4,452 1,968
Gender [men (%)/women (%)] 3,747 (49.6) / 3,804 (50.4) 2,061 (46.3) / 2,389 (53.7) 910 (46.2) / 1,058 (53.8) 0.955
Age (M years ± SD) 51.44±8.78 49.39±8.11 56.75±8.45 < 0.0001
Systolic blood pressure (SBP) (M mmHg ± SD) 115.65±17.25 104.69±9.15 139.42±17.27 < 0.0001
Diastolic blood pressure (DBP) (M mmHg ± SD) 74.21±11.27 67.68±7.72 88.97±10.90 < 0.0001
Total cholesterol (M mg/dL ± SD) 190.68±35.71 188.05±34.16 197.37±37.70 < 0.0001
High density lipoprotein cholesterol (M mg/dL ± SD) 44.85±10.03 45.05±9.92 43.73±10.26 < 0.0001
Triglyceride (M mg/dL ± SD) 159.97±105.54 146.90±95.75 190.22±115.38 < 0.0001

Abbreviations: M, mean value; SD, standard deviation. *Individuals who are not using hypertensive medications. **Controls (normotensive), SBP < 120 mmHg and DBP < 80 mmHg; Cases (hypertensive), SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg and/or antihypertensive medication. ***Significantdifferences in characteristics between the normotensive and hypertensive subjects were determined by the two-tailed Student's t-test



蹂 뿰援 긽씤 PPARGC1A쓽 遺꾩꽍 긽 SNP뱾 NCBI human genome build 36瑜 湲곗쑝濡 븯怨 4踰 뿼깋泥댁긽쓽 15媛 SNP뱾씠 遺꾩꽍 긽쑝濡 꽑蹂꾨릺뿀떎. 꽑蹂꾨맂 PPARGC1A쓽 15媛 SNP쓣 긽쑝濡 怨좏삁븬 솚옄援곌낵 嫄닿컯 議곌뎔뿉 븳 濡쒖뒪떛 쉶洹 遺꾩꽍뿉꽌룄 뿰졊, 꽦蹂, 吏뿭 怨듬닔濡 泥섎━븯떎. Additive genetic model쓣 쑀쟾 紐⑤뜽濡 꽑깮븯떎. 洹 寃곌낵 3媛 SNP뿉꽌 넻怨꾩쟻쑝濡 쑀쓽븳 긽愿愿怨(P<0.05)瑜 솗씤븷 닔 엳뿀떎(Table 2). 씠 以 媛옣 넂 쑀쓽 닔以(P=0.00359)쓣 蹂댁뿬二쇰뒗 SNP rs1472095濡 긽쟻 쐞뿕룄뒗 0.80 (95% 떊猶곌뎄媛: 0.68~ 0.93)씤 寃껋쑝濡 굹궗떎. rs472095쓽 minor allele뒗 T, major allele뒗 C씤뜲, T뿼湲곕 蹂댁쑀븷 寃쎌슦뿉 怨좏삁븬 諛쒕퀝뿉 븳 쐞뿕꽦씠 궙 寃쏀뼢쑝濡 쑀쓽븳 긽愿愿怨꾧 엳뒗 寃껋쓣 븣 닔 엳뿀떎. Rs1472095 SBP DBP뿉꽌룄 넻怨꾩쟻 쑀쓽꽦쓣 蹂댁뿬二쇨퀬 엳뒗뜲, minor allele瑜 媛吏 닔濡 젏吏꾩쟻쑝濡 삁븬 닔移섍 궙븘吏뒗 寃쏀뼢쓣 蹂댁씠怨 엳떎. 씠윭븳 寃곌낵뒗 minor allele瑜 蹂댁쑀븳 궗엺 怨좏삁븬뿉 븳 긽쟻 쐞뿕룄媛 궙븘吏뒗 솚옄-議곌뎔 遺꾩꽍 寃곌낵 씪移섑븯뒗 寃껋쓣 븣 닔 엳떎.

The association analysis results of SNPs in the PPARGC1A gene with blood pressure and hypertension in the Korean population

No. SNP Minor allele MAF Function Hypertension (controls 4,450: cases 1,968) SBP DBP




Cases Controls OR (95%CI) Add P beta ± se Add P beta ± se Add P
1 rs9790699 T 0.066 0.057 Downstream 1.21 (1.02~1.43) 0.031 0.06±0.56 0.910 0.01±0.38 0.977
2 rs2932966 C 0.075 0.088 Intron 0.80 (0.69~0.93) 4.60×10-3 -1.21±0.47 9.74×10-3 -0.94±0.32 2.98×10-3
3 rs10938963 T 0.438 0.427 Intron 1.04 (0.96~1.13) 0.354 0.22±0.26 0.397 0.27±0.18 0.125
4 rs1472095 T 0.074 0.087 Intron 0.80 (0.68~0.93) 3.59×10-3 -1.30±0.47 5.41×10-3 -0.90±0.32 4.60×10-3
5 rs3774908 G 0.217 0.214 Intron 1.03 (0.93~1.14) 0.558 -0.24±0.32 0.449 -0.29±0.22 0.178
6 rs3774907 G 0.223 0.216 Intron 1.05 (0.95~1.15) 0.367 0.58±0.31 0.061 0.41±0.21 0.053
7 rs2290604 G 0.216 0.213 Intron 1.03 (0.93~1.14) 0.539 -0.26±0.32 0.423 -0.29±0.22 0.188
8 rs6448226 C 0.488 0.487 Intron 1.02 (0.94~1.10) 0.667 0.07±0.26 0.787 -0.06±0.18 0.753
9 rs6448227 A 0.271 0.269 Intron 1.00 (0.91~1.10) 0.977 0.42±0.29 0.149 0.35±0.20 0.079
10 rs10007750 G 0.206 0.206 Intron 1.00 (0.90~1.11) 0.979 0.56±0.32 0.084 0.38±0.22 0.081
11 rs7656250 G 0.391 0.403 Intron 0.93 (0.86~1.01) 0.100 -0.44±0.27 0.096 -0.38±0.18 0.035
12 rs10212638 G 0.069 0.075 Intron 0.93 (0.79~1.09) 0.392 0.69±0.50 0.163 0.48±0.34 0.155
13 rs16874265 A 0.107 0.111 Intron 0.96 (0.84~1.10) 0.538 0.11±0.42 0.801 -0.07±0.28 0.810
14 rs17576121 G 0.026 0.021 Intron 1.09 (0.83~1.42) 0.553 0.74±0.89 0.409 0.73±0.61 0.227
15 rs2946386 G 0.391 0.389 Intron 1.01 (0.93~1.10) 0.812 -0.29±0.27 0.281 -0.28±0.18 0.129

Abbreviations: beta, regression coefficient; CI, confidence interval; MAF, minor allele frequency; OR, odds ratio; se, standard error; SNP, single nucleotide polymorphism; Controls (normotensive), SBP < 120 mmHg and DBP < 80 mmHg; Cases (hypertensive), SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg and/or antihypertensive medication. Statistically significant values (P<0.05) are indicated in bold and underline.



PPARGC1A 쑀쟾옄 삁븬怨쇱쓽 꽑삎 쉶洹 遺꾩꽍

15媛쒖쓽 SNP뱾쓣 긽쑝濡 SBP DBP뿉 빐꽌룄 긽愿 遺꾩꽍쓣 떆뻾븯떎. 꽑삎 쉶洹 遺꾩꽍쓣 븯쑝硫 뿭떆 뿰졊, 꽦蹂 諛 吏뿭쓣 怨듬닔濡 泥섎━븯떎. 쑀쟾 紐⑤뜽 additive genetic model쓣 湲곕컲쑝濡 븯떎. 洹 寃곌낵 SBP DBP뿉꽌 怨듯넻쟻쑝濡 2媛쒖쓽 SNP뱾씠 넻怨꾩쟻쑝濡 쑀쓽븳 긽愿愿怨꾨 蹂댁뿬二쇨퀬 엳뿀떎(Table 2).

SBP뿉꽌뒗 rs1472095媛 媛옣 넂 쑀쓽 닔以(棺=-1.30, P=0.00541)쓣 蹂댁뿬 二쇱뿀怨, DBP뿉꽌뒗 rs2932966뿉꽌 媛옣 넂 쑀쓽 닔以(棺=-0.94, P=0.00298)쓣 굹궡뿀떎. 씠뱾 SNP뱾 minor allele瑜 媛吏寃 맆닔濡 蹂댁뿬二쇰뒗 삁븬 닔移섏쓽 諛⑺뼢꽦 삉븳 SBP DBP 紐⑤몢뿉꽌 궙븘吏뒗 諛⑺뼢쑝濡 씪移섑븯怨 엳떎.

PPARGC1A 쑀쟾옄쓽 쑀쓽븳 SNP뱾뿉 븳 in silico 湲곕뒫 遺꾩꽍

怨좏삁븬뿉꽌 쑀쓽꽦쓣 蹂댁씠뒗 PPARGC1A쓽 SNP뱾씠 뼱뼸寃 쑀쟾옄 샊 떒諛깆쭏뿉 쁺뼢쓣 誘몄튌 寃껋씤吏瑜 HaploReg (https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php)뿉꽌 솗씤빐 蹂댁븯떎. 솗씤 寃곌낵 怨좏삁븬 긽깭 遺꾩꽍怨 SBP, DBP 紐⑤몢뿉꽌 쑀쓽꽦씠 엳뿀뜕 2媛쒖쓽 SNP뱾 enhancer histone marks motifs changed뿉꽌 SNP쓽 allele뿉 뵲씪 李⑥씠媛 굹뒗 寃껋쓣 蹂댁뿬二쇨퀬 엳뿀떎. 씠뒗 2媛쒖쓽 SNP쓽 뿼湲 蹂솕뿉 뵲씪 쑀쟾옄 諛쒗쁽 벑뿉 쁺뼢쓣 以 媛뒫꽦쓣 쓽誘명븯怨 엳떎(Table 3).

Results of the HaploReg of SNP in the KL gene on chromosome 20

No. SNP A1 A2 ASN freq Case freq of this study

Enhancer histone marks Motifs changed
1 rs2932966 C A 0.06 0.075 HRT 10 altered motifs
2 rs1472095 T C 0.06 0.074 4 tissues  8 altered motifs

Abbreviations: SNP, single nucleotide polymorphism; A1, minor allele; A2, major allele; +, affect; HaploReg is a tool for exploring annotations of candidate regulatory SNPs (https://pubs.broadinstitute.org/mammals/haploreg/haploreg_v4.php)


怨 李

븳援씤 쑀쟾泥대텇꽍옄猷(KARE)瑜 湲곕컲쑝濡 PPARGC1A 쑀쟾옄쓽 쁺뿭뿉 쐞移섑븳 15媛쒖쓽 SNP 쑀쟾蹂씠뱾쓣 긽쑝濡 怨좏삁븬(hypertension) 諛 以묎컙 몴쁽삎씤 닔異뺢린 삁븬(systolic blood pressure, SBP)怨 씠셿湲 삁븬(diastolic blood pressure, DBP) 벑怨쇱쓽 긽愿愿怨꾨 넻怨 遺꾩꽍븯뿬 솗씤븯떎. 씠 以 3媛쒖쓽 SNP뱾(rs9790699, rs2932966, rs1472095)씠 넻怨꾩쟻씤 쑀쓽꽦(P<0.05)쓣 굹궡뿀떎. 씠 以 rs1472095媛 怨좏삁븬怨 넻怨꾩쟻쑝濡 媛옣 쑀쓽븳 媛믪쓣 蹂댁떎(P-value, 0.00359).

떎웾쓽 exome怨 whole genome sequencing 봽濡쒖젥듃瑜 뜲씠꽣踰좎씠뒪뿉꽌 뼸 GnomAD (The Genome Aggregation Database)-븳援씤 1,909紐 룷븿맂 Whole Exome Sequencing-뿉꽌뒗 rs2932966 minor allele (C)瑜 吏땺 寃쎌슦 C=0.2659, major allele (A)瑜 吏땺 寃쎌슦뒗 A=0.7341씠뿀떎. 듅엳, 踰좏듃궓씤쓽 寃쎌슦 C=0.1121, A=0.8879濡 굹굹 긽쟻쑝濡 궙 minor allele (C)瑜 吏땲怨 엳뿀떎. 諛섎㈃뿉, rs1472095뒗 GnomAD뿉꽌뒗 minor allele (T)瑜 吏땺 寃쎌슦, T=0.3097, major allele (C)瑜 吏땺 寃쎌슦뒗 C=0.6903씠뿀떎. 蹂 뿰援ъ뿉꽌 遺꾩꽍븳 minor allele쓽 寃쎌슦 rs2932966 (C)뒗 0.075瑜 rs1472095 (T)뒗 T=0.074瑜 굹궡뼱 쑀읇씤씠 떎닔瑜 李⑥븯뒗 GnomAD뿉꽌쓽 minor allele 鍮덈룄닔蹂대떎 븳援씤씠 긽쟻쑝濡 뜑 궙 鍮덈룄닔(minor allele frequency)瑜 媛뽯뒗 떎뒗 젏쓣 븣寃 릺뿀떎(Fig. 1, Table 3). 븳렪, 1000 Genome Project瑜 湲곕컲쑝濡 븳 GGV browser HaploReg 遺꾩꽍봽濡쒓렇옩쓣 씠슜븯뿬 씤듃濡좎뿉 쐞移섑븳 PPARGC1A 쑀쟾蹂씠 rs2932966쓽 minor allele 吏뿭留덈떎 議곌툑뵫 떎瑜 뼇긽쓣 굹궡뿀떎. 븘봽由ъ뭅씤(C) C=0.22, 븘硫붾━移댁씤(C) C=0.38, 쑀읇씤(C) C=0.25, 븘떆븘씤 C=0.06쓣 蹂댁떎. 븘떆븘씤뱾 以 룞븘떆븘씤(C) C=0.08씠뿀怨 궓븘떆븘씤(C) C=0.2瑜 굹궡 二쇱뼱 룞뼇씤뱾 궗씠뿉룄 吏뿭뿉 뵲씪 쑀쟾蹂씠 뿼湲 鍮덈룄媛 겙 李⑥씠瑜 엳쓬쓣 솗씤븯怨 蹂 뿰援ъ쓽 Case 鍮덈룄(C)瑜 蹂대㈃ 0.075瑜 굹궡뼱 룞븘떆븘씤뱾怨 쑀궗븳 minor allele frequency瑜 굹궡뿀떎. 룞븘떆븘씤쓽 援ъ꽦 二쇰줈 븳議 以묎뎅씤怨 씪蹂몄씤 洹몃━怨 踰좏듃궓씤쑝濡 援ъ꽦릺뼱 엳떎. 鍮꾩듂븳 諛⑸쾿쑝濡 PPARGC1A rs1472095쓽 minor allele 븘봽由ъ뭅씤(T) T=0.39, 븘硫붾━移댁씤(T) T=0.40, 쑀읇씤(T) T=0.25, 븘떆븘씤(T) T=0.06쓣 蹂댁떎. 룞븘떆븘씤(T) T=0.08, 궓븘떆븘씤(T) T=0.21쓣 蹂댁떎. 蹂 뿰援ъ쓽 Case 鍮덈룄(T)뒗 0.074瑜 蹂댁뿬二쇱뼱꽌 rs2932966泥섎읆 rs1472095룄 룞븘떆븘씤뱾怨 쑀궗븳 minor allele frequency瑜 굹궡뿀떎. 룞븘떆븘씤 援ъ꽦 以묎뎅 븳議깆씤(T) T=0.09, 踰좏듃궓씤(T) T=0.2 洹몃━怨 씪蹂몄씤 T=0.05瑜 굹궡뼱 븳援씤怨 씪蹂몄씤뿉꽌 긽쟻쑝濡 궙 (T) 뿼湲 鍮덈룄닔瑜 굹궡뿀떎.

Fig. 1. The worldwide geographic distribution of genetic polymorphisms using 1000 Genomes Project Consortium data. A. Geographic distribution of genetic variant of PPARGC1A rs2932966 are distributed on maps of minor (C) allele frequencies in populations. B. Similarly, genetic polymorphism of PPARGC1A rs1472095 are distributed on maps of minor (T) allele frequency in populations over the globe. The blue slices of the pie chart show a minor allele frequency of each regional population globally.

2008뀈 Ingelsson 벑 PPARGC1A Gly482Ser 肄붾뵫 SNP媛 궓꽦쓽 醫뚯떖떎 씠셿 湲곕뒫옣븷 뿰愿꽦씠 엳쓬쓣 蹂닿퀬븯떎. 媛숈 빐 Vimaleswaran 벑 PPARGC1A Gly482Ser (rs8192678) missense 룎뿰蹂씠媛 삁븬쓣 議곗젅븳떎뒗 蹂닿퀬媛 엳떎. 씠뱾 뿰援ъ뿉 궗슜맂 肄뷀샇듃뒗 쑀읇, 븘떆븘, 븘硫붾━移 씤뵒뼵 꽦씤뱾怨 궓븘硫붾━移 泥냼뀈쓣 긽쑝濡 븯쑝硫 50꽭 씠븯쓽 꽦씤怨 뿰愿꽦씠 엳쓬쓣 굹궡뿀떎. 蹂 뿰援щ뒗 KARE 뜲씠꽣瑜 湲곕컲쑝濡 PPARGC1A쓽 쑀쟾蹂씠媛 怨좏삁븬(hypertension) 諛 以묎컙 몴쁽삎씤 SBP DBP쓽 뿰愿꽦 뿰援(case-control study)쓣 吏꾪뻾븯떎. 洹 寃곌낵, 湲곗〈뿉 삁븬뿉 빐꽌뒗 蹂닿퀬릺吏 븡븯뜕 2媛쒖쓽 쑀쟾蹂씠媛 삁븬 닔移섎 궙異붽퀬 怨좏삁븬뿉 븳 쐞뿕꽦쓣 넂씠뒗 寃쏀뼢쑝濡쒖쓽 긽愿愿怨꾧 엳쓬쓣 븳援씤쓣 긽쑝濡 븯뿬 諛앺삍떎. 씠윭븳 寃곌낵뒗 鍮꾨줉 쑀쟾옄 닔以뿉꽌쓽 怨좏삁븬怨쇱쓽 긽愿愿怨꾨뒗 議댁옱븯怨 엳뿀쑝굹, 씤醫낅퀎濡 李⑥씠瑜 蹂댁씠뒗 꽭遺쟻씤 쑀쟾蹂씠뱾뿉 빐꽌뒗 씤醫 듅씠쟻 샊 吏뿭 듅씠쟻씤 쁽긽쓣 諛앺 궡湲 쐞븳 뿰援ш 븘슂븯떎뒗 寃껋쓣 蹂댁뿬二쇨퀬 엳떎

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). 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 that they have no conflict of interest.

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