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Replicated Association Study for Metabolic Syndrome of the Gene Cluster in Chromosome 11q23.3
Biomed Sci Letters 2020;26:368-375
Published online December 31, 2020;  https://doi.org/10.15616/BSL.2020.26.4.368
© 2020 The Korean Society For Biomedical Laboratory Sciences.

Sung-Soo Kim*, Sangjung Park,** and Hyun-Seok 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, 20 Hoseo-ro 79 Beon-gil, Asan-si, Chungnam 31499, Korea.
Tel: +82-41-540-9968, Fax: +82-41-540-9997, e-mail: jinhs@hoseo.edu
Sangjung Park. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, 20 Hoseo-ro 79 Beon-gil, Asan-si, Chungnam 31499, Korea.
Tel: +82-41-540-9967, Fax: +82-41-540-9997, e-mail: sangjung@hoseo.edu
*Graduate student, **Professor.
Received December 8, 2020; Revised December 15, 2020; Accepted December 15, 2020.
 Abstract
Metabolic syndrome (MetS) is a disease that is accompanied by various metabolic related problems and refers to a disease in which various adult diseases occur along with obesity. These metabolic syndromes appear according to the individual's genetic background. APOA5-ZPR1-BUD13, a gene cluster belonging to chromosome 11q23.3, is well known for its risk of plasma triglycerides and coronary artery disease. Recently, the GWAS results for metabolic syndrome were published in Koreans. The results included the APOA5-ZPR1-BUD13, and the SNPs that first appeared in Koreans in the ZPR1 and BUD13 were also discovered. In this study, the reproducibility was investigated for the newly discovered ZPR1 (rs964184) and BUD13 (rs2075295, rs1558861) using The Health Examinees (HEXA) cohort and showed significance. In addition, BUD13 (rs117548857, rs10488698, rs149527022, rs10790162), ZPR1 (rs2075290, rs145796806, rs201247587), APOA5 (rs12791103, rs1263173, rs7396835, rs17520254) were additionally discovered and significant results were obtained. For the SNPs that showed significant results, the effect on protein expression and the effect of expression quantitative trait loci (eQTL) were also confirmed. This study is expected to contribute to the prevention and treatment of diseases with differences in onset based on individual genetic patterns as well as presenting the effect of genetic mutations in the APOA5-ZPR1-BUD13 on metabolic syndrome and blood lipid levels.
Keywords : Metabolic syndrome (MetS), APOA5, ZPR1, BUD13, SNP
꽌 濡

궗利앺썑援(metabolic syndrome; MetS) 뿬윭 媛吏 떊吏꾨궗 愿젴맂 臾몄젣媛 룞諛섎릺뒗 吏덊솚쑝濡 怨좎쨷꽦吏諛⑺삁利, 궙 怨좊룄肄쒕젅뒪뀒濡, 怨좏삁븬 諛 떦눊蹂묒쓣 鍮꾨’븳 媛곸쥌 꽦씤蹂묒씠 蹂듬 鍮꾨쭔怨 븿猿 諛쒖깮븯뒗 吏덊솚씠떎(Eckel et al., 2005). 쟾꽭怨꾩쟻쑝濡 궗利앺썑援 쑀蹂묐쪧 怨꾩냽빐꽌 利앷븯뒗 異붿꽭씠硫 援궡뿉꽌뒗 빟 30%쓽 쑀蹂묐쪧쓣 蹂댁씠怨 엳떎(Wang et al., 2007; Aguilar et al., 2015; Lee et al., 2018). 씠윭븳 궗利앺썑援곗 諛쒕퀝 썑 諛⑹튂븯寃 릺硫 뇤議몄쨷怨 삊떖利앹쓣 鍮꾨’븳 떖삁愿吏덊솚쓽 쐞뿕꽦씠 겕寃 利앷븳떎(Mottillo et al., 2010; Lee et al., 2019). 뵲씪꽌 궗利앺썑援곗쓽 삁諛⑷낵 移섎즺쓽 以묒슂꽦씠 넂븘吏怨 엳떎. 궗利앺썑援곗쓽 諛쒕퀝뿉뒗 媛쒖씤쓽 쑀쟾쟻 슂냼媛 쁺뼢쓣 以떎(Sung et al., 2009). 뵲씪꽌 궗利앺썑援곗쓽 諛쒕퀝怨 愿젴맂 쐞뿕 슂씤쑝濡 옉슜븯뒗 湲곗쟾怨 쑀쟾옄쓽 洹쒕챸뿉 븳 以묒슂꽦씠 遺媛곷릺怨 엳떎(Kim et al., 2011; Kraja et al., 2011).

씠쟾 뿰援ъ뿉꽌뒗 뿼깋泥 11q23.3쓽 냽븳 쑀쟾옄 겢윭뒪꽣(SIK3-BUD13-ZPR1-APOA5-APOA4)媛 삁옣 以묒꽦吏諛⑷낵 愿긽 룞留μ쭏솚쓽 쐞뿕꽦怨 愿젴씠 엳쓬쓣 蹂닿퀬븳 諛 엳떎(Fu et al., 2015; Kim et al., 2019). 理쒓렐 Oh 벑 븳援씤쓣 긽쑝濡 궗利앺썑援곗뿉 븳 genome-wide association study (GWAS)瑜 닔뻾븯뿬 떎뼇븳 쑀쟾옄뿉꽌 쑀쓽꽦씠 굹궃 SNP쓣 諛쒗몴븯떎(Oh et al., 2020). 諛쒗몴맂 쑀쟾옄뱾 以묒뿉뒗 11q23.3 쑀쟾옄 겢윭뒪꽣씤 BUD13-ZPR1-APOA5 쑀쟾옄룄 룷븿릺뼱 엳뿀쑝硫 BUD13, ZPR1 쑀쟾옄뒗 븳援씤뿉꽌 泥섏쓬 굹궃 SNP룄 諛쒓뎬릺뿀떎. 뵲씪꽌 씠踰 뿰援ъ뿉꽌뒗 븵꽑 뿰援ъ뒗 떎瑜 肄뷀샇듃 옄猷뚮 솢슜븯뿬 BUD13-ZPR1-APOA5瑜 긽쑝濡 쑀쟾쟻 蹂씠媛 궗利앺썑援 諛쒕퀝뿉 誘몄튂뒗 쁺뼢쓣 솗씤빐蹂닿퀬옄 븯떎. 삉븳, 以묒꽦吏諛⑷낵 愿젴븯뿬 븳援씤뿉꽌 泥섏쓬 굹궃 BUD13쓽 rs2075295, rs1558861怨 ZPR1쓽 rs964184媛 씠踰 뿰援ъ뿉꽌 MetS 뿰愿꽦씠 엳뒗吏 븣븘蹂댁븯떎.

긽 諛 諛⑸쾿

뿰援щ긽옄

뿰援щ긽옄뒗 븳援씤 쑀쟾泥 뿭븰 議곗궗 궗뾽(Korean Genome and Epidemiology Study; KoGES)쓽 씪솚씤 HEXA (The Health Examinees) 肄뷀샇듃 옄猷뚮 遺꾩뼇 諛쏆븘 솢슜븯떎(Health Examinees Study Group, 2015) (KBN-2017-046). HEXA 肄뷀샇듃 옄猷뚮뒗 40꽭 씠긽쓽 궓瑜 紐⑥쭛븯쑝硫 씪遺씤 28,445(궓꽦: 10,261紐, 뿬꽦: 18,184紐)紐낆쓽 쑀쟾삎쓣 遺꾩꽍븯떎. 28,455紐낆 씠踰 뿰援ъ쓽 遺꾩꽍긽옄濡 쟻빀븯쑝硫 Table 1怨 媛숇떎. 궗利앺썑援 솚옄援곗 援궡뿉꽌 궗슜븯뒗 궗利앺썑援 吏꾨떒 湲곗씤 National Cholesterol Education Program (NCEP) Adult Treatment Panel III 吏移⑥뿉꽌 蹂듬 鍮꾨쭔쓣 븳援씤쓽 湲곗뿉 留욊쾶 궗슜븯떎(Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001; Oh and Kim, 2016). 뵲씪꽌 뿀由щ몮젅(궓옄 90 cm, 뿬옄 85 cm 씠긽), 以묒꽦吏諛 150 mg/dL 씠긽 삉뒗 愿젴 빟臾 蹂듭슜), HDL cholesterol (궓옄 40 mg/dL, 뿬옄 50 mg/dL 씠븯), 닔異뺢린 삁븬 130 mmHg 삉뒗 씠셿湲 삁븬 85 mmHg 씠긽 삉뒗 삁븬빟 蹂듭슜옄, 怨듬났삁떦(100 mg/dL 씠긽 삉뒗 떦눊蹂 怨쇨굅젰 삉뒗 떦눊 愿젴 빟臾 蹂듭슜)씠씪뒗 珥 5醫낅쪟쓽 吏몴뱾 以묒뿉 3媛吏 씠긽뿉 빐떦븯硫 궗利앺썑援 솚옄濡 遺꾨쪟븯뿬 6,329紐낆쓣 꽑蹂꾪븯떎. 嫄닿컯 議곌뎔쑝濡쒕뒗 궗利앺썑援곗쓣 룷븿븳 怨좏삁븬, 떦눊蹂, 怨좎삁利, 뇤議몄쨷, 삊떖利, 湲됱꽦 媛 吏덊솚, 吏諛⑷컙, 愿젅뿼, 怨⑤떎怨듭쬆, 넻뭾쓣 吏꾨떒諛쏆 怨쇨굅젰씠 뾾뒗 11,773紐낆쓣 꽑蹂꾪븯떎. 씠踰 뿰援ъ뿉 솢슜븳 쑀쟾젙蹂대뒗 吏덈퀝愿由щ낯遺(KNIH) 샇꽌븰援먯뿉꽌 뿰援ъ쑄由 듅씤(IRB No.: 1041231-170822-BR-062-01)쓣 諛쏆븘 닔뻾븯떎.

Basic characteristics of subjects according to metabolic syndrome in HEXA

Characteristics Total MetS* Controls**
Number of subjects 28,445 6,329 11,773
Age (M years ± SD) 53.84±7.98 56.56±7.61 50.95±7.53
Sex [male (%)] 10,261 (36.1%) 2,861 (45.2%) 3,849 (32.7%)
WC (M cm ± SD) 80.86±8.65 87.93±7.74 78.01±7.76
TG (M mg/dL ± SD) 126.44±86.63 197.75±117.77 102.91±61.22
HDL-C (M mg/dL ± SD) 52.77±12.66 44.18±9.53 55.83±12.42
GLU (M mg/dL ± SD) 94.39±19.52 106.61±27.37 88.83±10.56
SBP (M mmHg ± SD) 122.39±14.65 130.93±13.98 118.06±13.50
DBP (M mmHg ± SD) 75.99±9.66 80.46±9.36 73.50±9.31

Abbreviations: DBP, diastolic blood pressure; GLU, fasting glucose; HDL-C, high density lipoprotein cholesterol; HEXA, The Health Examinees; M, mean; MetS, metabolic syndrome; SBP, systolic blood pressure; SD, standard deviation; TG, triglyceride; WC, waist circumference. *MetS have 3 or more of 5 indicators that can be diagnosed as metabolic syndrome. **The controls are the group without metabolic syndrome and various diseases and diseases



쑀쟾삎 遺꾩꽍怨 SNP 꽑蹂

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 쑀쟾삎쓣 솗씤븳 寃곌낵瑜 궗슜븯떎(Moon et al., 2019). 洹 怨쇱젙뿉꽌 DNA 떆猷뚮뒗 뿰援 李몄뿬옄쓽 留먯큹삁븸뿉꽌 遺꾨━ 異붿텧븯怨, 쑀쟾삎 뙋룆 젙솗룄媛 96~99% 씠븯씠嫄곕굹, 怨쇰룄븳 heterozygosity瑜 媛吏嫄곕굹, 꽦蹂 遺덉씪移섍 議댁옱븯뒗 긽옄뱾 젣쇅븯떎. 蹂 뿰援ъ뿉꽌뒗 BUD13, ZPR1, APOA5 쑀쟾옄 씤洹쇱쓽 SNP뱾쓣 긽쑝濡 遺꾩꽍븯떎. 뿼깋泥 긽쓽 쐞移섎뒗 UCSC (University of Colombo school of computing) Genome browser on human Feb, 2009 (Genome Reference Consortium Human Build 37)瑜 湲곗쑝濡 븯떎.

넻怨 遺꾩꽍

遺遺꾩쓽 넻怨 遺꾩꽍뿉뒗 PLINK version 1.90 beta (http://pngu.mgh.harvard.edu/~purcell/plink) PASW Statistics version 21.0 (SPSS Inc. Chicago, IL, USA)쓣 궗슜븯떎. 궗利앺썑援 솚옄援곌낵 嫄닿컯 議곌뎔뿉 븳 쑀쟾 蹂씠쓽 긽愿 遺꾩꽍 濡쒖뒪떛 쉶洹 遺꾩꽍쓣 궗슜븯怨 궗利앺썑援곌낵 愿젴맂 몴쁽삎뿉 븳 遺꾩꽍 꽑삎쉶洹 遺꾩꽍쓣 궗슜븯떎. 삉븳, 꽑삎쉶洹 遺꾩꽍뿉꽌뒗 젙솗븳 遺꾩꽍쓣 쐞빐 빟臾 蹂듭슜怨 媛숈 移섎즺瑜 諛쏅뒗 寃쎌슦 젣쇅븯떎. 쑀쟾 紐⑦삎 additive model쓣 湲곗쑝濡 븯떎. 쉶洹 遺꾩꽍쓽 떆뻾뿉 엳뼱꽌 굹씠 꽦蹂꾩쓣 怨듬닔濡 議곗젙븯뿬 遺꾩꽍븯怨 遺꾩꽍 媛믪뿉 븳 쑀쓽꽦쓽 湲곗 0.05 誘몃쭔쓣 湲곗쑝濡 븯떎. 遺꾩꽍븳 쑀쟾 젙蹂대 諛뷀깢쑝濡 Haploview version 4.2 (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) 봽濡쒓렇옩쓣 궗슜븯뿬 뿰愿遺덇퇏삎(linkage disequilibrium)쓣 솗씤븯떎.

寃 怨

궗利앺썑援곗뿉 븳 濡쒖뒪떛 쉶洹遺꾩꽍 寃곌낵

꽭 쑀쟾옄뿉 븳 珥 20媛쒖쓽 SNP씠 궗利앺썑援 諛쒕퀝뿉 誘몄튂뒗 쁺뼢 Table 2 媛숇떎. BUD13 쑀쟾옄 씤洹쇱쓽 쁺뿭源뚯 룷븿븯뿬 7媛쒖쓽 SNP씠 議댁옱븯쑝硫 紐⑤몢 궗利앺썑援곌낵 쑀쓽븳 寃곌낵瑜 굹깉떎(P<0.05). ZPR1 쑀쟾옄 쁺뿭뿉뒗 5媛쒖쓽 SNP씠 룷븿릺뿀쑝硫 3媛쒖쓽 SNP (rs964184, rs2075290, rs603446)씠 쑀쓽꽦쓣 蹂댁떎. APOA5 쑀쟾옄 씤洹쇱쓽 쁺뿭源뚯 룷븿빐 8媛쒖쓽 SNP씠 議댁옱븯쑝硫 6媛쒖쓽 SNP (rs2266788, rs2075291, rs662799, rs12791103, rs1263173, rs7396835)씠 쑀쓽븳 寃곌낵瑜 蹂댁떎. 媛옣 넂 쑀쓽꽦(P=1.45횞10-37)쓣 蹂댁씠뒗 APOA5쓽 rs662799뒗 minor allele씤 G 뿼湲곕 蹂댁쑀븷 寃쎌슦 궗利앺썑援곗뿉 긽쟻 쐞뿕룄(OR)媛 1.38 (95% CI: 1.32~1.45)濡 利앷븯뒗 寃껋쑝濡 굹궗떎. Oh 벑쓽 뿰援ъ뿉꽌뒗 TG 愿젴븯뿬 븳援씤뿉寃 泥섏쓬쑝濡 諛쒓껄맂 BUD13쓽 rs1558861, rs2075295怨 ZPR1쓽 rs964184뒗 긽쟻 쐞뿕룄(95% CI)媛 媛 1.27 (1.20~1.34), 0.84 (0.80~0.88), 1.27 (1.21~1.35)濡 굹궗怨 씠踰 뿰援ъ뿉꽌룄 쑀쓽븳 寃곌낵瑜 굹깉떎(Oh et al., 2020). BUD13쓽 rs117548857, rs10488698, rs149527022, rs10790162 ZPR1쓽 rs2075290怨 APOA5쓽 rs12791103, rs1263173, rs7396835뒗 븳援씤쓣 긽쑝濡 븳 씠踰 뿰援щ 넻빐 궗利앺썑援곌낵 愿젴븯뿬 泥섏쓬쑝濡 諛쒓뎬맂 SNP씠떎.

Association results for metabolic syndrome targeting SNPs of three genes BUD13, ZPR1 and APOA5 located on chromosome 11

Gene No. SNP BP Function A1 A2 MAF OR (95% CI) *P value

Cases (n=6,329) Control (n=11,773)
BUD13 1 rs117548857 116604167 3' UTR near G T 0.016 0.020 0.80 (0.67~0.96) 0.015
2 rs1558861 116607437 3' UTR near C T 0.251 0.213 1.27 (1.20~1.34) 8.63×10-18
3 rs11216126 116617240 3' UTR near C A 0.175 0.202 0.83 (0.78~0.88) 9.44×10-10
4 rs2075295 116628401 Intron C T 0.430 0.470 0.84 (0.80~0.88) 1.87×10-13
5 rs10488698 116633947 Missense A G 0.062 0.067 0.90 (0.82~0.99) 0.029
6 rs149527022 116635570 Intron G A 0.009 0.013 0.69 (0.55~0.87) 1.62×10-3
7 rs10790162 116639104 Intron A G 0.244 0.206 1.27 (1.20~1.34) 9.41×10-18

ZPR1 8 rs964184 116648917 3' UTR G C 0.247 0.209 1.27 (1.21~1.35) 3.66×10-18
9 rs145796806 116650184 Intron T C 0.012 0.013 0.94 (0.76~1.16) 0.575
10 rs2075290 116653296 Intron C T 0.250 0.213 1.26 (1.19~1.33) 9.36×10-17
11 rs603446 116654435 Intron T C 0.208 0.232 0.86 (0.82~0.91) 2.05×10-7
12 rs201247587 116658553 Missense G T 0.013 0.013 1.05 (0.85~1.30) 0.642

APOA5 13 rs2266788 116660686 3' UTR G A 0.248 0.210 1.27 (1.21~1.34) 4.59×10-18
14 rs2075291 116661392 Missense A C 0.100 0.074 1.41 (1.30~1.53) 5.84×10-17
15 rs662799 116663707 5' UTR G A 0.349 0.285 1.38 (1.32~1.45) 1.45×10-37
16 rs17520254 116665553 5' UTR near G C 0.015 0.018 0.83 (0.69~1.00) 0.054
17 rs117730008 116666341 5' UTR near A G 0.052 0.053 0.99 (0.89~1.10) 0.834
18 rs12791103 116673315 5' UTR near T G 0.036 0.043 0.82 (0.72~0.92) 8.94×10-4
19 rs1263173 116681008 5' UTR near A G 0.272 0.286 0.94 (0.89~0.98) 0.011
20 rs7396835 116684028 5' UTR near T C 0.336 0.311 1.13 (1.08~1.19) 1.14×10-6

Abbreviations: 3' UTR, three prime untranslated region; 5' UTR, five prime untranslated region; A1, minor allele; A2, major allele; BP, base pair; CI, confidence interval; MAF, minor allele frequency; No, number; OR, odds ratio; SNP, single nucleotide polymorphism. *P value <0.05 are indicated in bold. The genetic model of the analysis was performed with an additive model and covariates with sex and age



BUD13, ZPR1, APOA5 SNP뱾쓽 꽑삎쉶洹 遺꾩꽍 寃곌낵

珥 20媛쒖쓽 SNP뿉 븯뿬 궗利앺썑援곗쓣 吏꾨떒븯뒗 吏몴씤 뿀由щ몮젅(waist circumference; WC), 以묒꽦吏諛(triglyceride; TG), 怨좊퉬以묒떒諛-肄쒕젅뒪뀒濡(high density lipoprotein cholesterol; HDL-C), 怨듬났삁떦(fasting glucose; GLU), 닔異뺢린 삁븬(systolic blood pressure; SBP), 씠셿湲 삁븬(diastolic blood pressure; DBP)뿉 誘몄튂뒗 쁺뼢쓣 솗씤븯怨 쑀쓽꽦쓣 굹궦 TG, HDL-C, GLU쓽 愿븳 寃곌낵뒗 Table 3怨 媛숇떎. 궗利앺썑援곗뿉 愿빐 媛옣 쑀쓽븳 寃곌낵瑜 굹궦 rs662799뒗 꽑삎쉶洹 遺꾩꽍 寃곌낵 minor allele瑜 媛吏 븣 TG쓽 湲곗슱湲곌 利앷븯怨 HDL-C쓽 湲곗슱湲 媛먯냼, GLU쓽 湲곗슱湲 利앷濡 궗利앺썑援 諛쒕퀝 쐞뿕怨 愿젴맂 寃곌낵瑜 굹깉떎. 씠윭븳 寃곌낵뒗 MetS쓽 긽쟻 쐞뿕룄媛 넂寃 굹궃 寃곌낵 씪移섑븯怨 떎瑜 遺遺꾩쓽 SNP 삉븳 TG 삉뒗 HDL-C 삉뒗 GLU쓽 꽑삎쉶洹 湲곗슱湲곗 MetS쓽 긽쟻 쐞뿕룄媛 씪移섑븯뒗 寃곌낵瑜 굹깉떎. Oh 벑쓽 뿰援ъ뿉꽌 깉濡 諛쒓껄맂 SNP씤 rs964184, rs2075295, rs1558861 TG 뿰愿맂 寃곌낵瑜 蹂댁쑝굹, 씠踰 뿰援 寃곌낵뿉꽌뒗 TG肉먮쭔 븘땲씪 HDL-C뿉룄 뿰愿맂 寃곌낵瑜 굹깉떎(Oh et al., 2020). BUD13쓽 rs149527022뒗 씠踰 뿰援ъ뿉꽌 븳援씤쓣 긽쑝濡 궗利앺썑援곌낵 뿰愿릺뼱 泥섏쓬쑝濡 諛쒓뎬맂 SNP씠吏留 TG HDL-C뿉뒗 뿰愿꽦씠 굹굹吏 븡븯떎. 諛섎㈃뿉 궗利앺썑援곌낵 뿰愿꽦쓣 굹궡吏 븡븯뜕 ZPR1쓽 rs145796806怨 rs201247587, APOA5쓽 rs17520254뒗 TG HDL-C뿉꽌 뿰愿꽦씠 굹궗怨 븳援씤쓣 긽쑝濡쒕뒗 泥섏쓬 諛쒓뎬맂 SNP씠떎.

Association results of metabolic syndrome related indicators in SNPs of three genes BUD13, ZPR1 and APOA5

Gene No. SNP A1 TG HDL-C GLU



β ± s.e P value β ± s.e P value β ± s.e P value
BUD13 1 rs117548857 G -12.78±2.60 8.68×10-7 0.71±0.38 0.061 0.66±0.47 0.163
2 rs1558861 C 16.42±0.86 4.96×10-81 -1.57±0.13 1.04×10-35 0.21±0.16 0.174
3 rs11216126 C -13.90±0.91 1.39×10-52 1.75±0.13 9.63×10-40 -0.53±0.16 0.001
4 rs2075295 C -12.39±0.72 4.68×10-66 1.59±0.11 1.48×10-51 -0.30±0.13 0.024
5 rs10488698 A -8.92±1.43 4.42×10-10 1.52±0.21 3.47×10-13 0.40±0.26 0.120
6 rs149527022 G -5.98±3.30 0.070 0.45±0.48 0.353 -0.08±0.60 0.892
7 rs10790162 A 16.83±0.87 6.70×10-83 -1.66±0.13 9.64×10-39 0.27±0.16 0.086

ZPR1 8 rs964184 G 16.75±0.87 1.07×10-82 -1.67±0.13 2.26×10-39 0.23±0.16 0.148
9 rs145796806 T -14.68±3.21 4.76×10-6 1.44±0.47 0.002 -0.60±0.57 0.295
10 rs2075290 C 16.52±0.86 1.13×10-81 -1.64±0.13 7.79×10-39 0.18±0.16 0.252
11 rs603446 T -12.29±0.86 1.36×10-46 0.96±0.13 2.16×10-44 0.00±0.15 0.990
12 rs201247587 G 12.41±3.28 1.55×10-4 -2.22±0.48 3.53×10-6 -0.41±0.59 0.483

APOA5 13 rs2266788 G 16.91±0.86 1.63×10-84 -1.67±0.13 1.61×10-39 0.21±0.16 0.191
14 rs2075291 A 33.66±1.32 1.21×10-141 -4.08±0.19 4.17×10-98 0.48±0.24 0.046
15 rs662799 G 25.35±0.77 9.50×10-234 -2.76±0.11 4.59×10-130 0.31±0.14 0.030
16 rs17520254 G -7.63±2.74 0.005 1.62±0.40 4.81×10-5 0.15±0.49 0.763
17 rs117730008 A -2.19±1.63 0.179 0.18±0.24 0.444 -0.45±0.29 0.127
18 rs12791103 T -10.72±1.79 2.33×10-9 1.73±0.26 3.49×10-11 -0.03±0.32 0.938
19 rs1263173 A -2.47±0.81 0.002 0.15±0.12 0.216 -0.47±0.15 0.001
20 rs7396835 T 8.80±0.77 6.42×10-30 -0.55±0.11 1.22×10-6 0.25±0.14 0.069

Abbreviations: β, regression coefficient; A1, minor allele; GLU, fasting glucose; HDL-C, high density lipoprotein cholesterol; s.e, standard error; SNP, single nucleotide polymorphism; TG, triglyceride. P value <0.05 are indicated in bold. The genetic model of the analysis was performed with an additive model and covariates with sex and age. Systolic blood pressure and diastolic blood pressure were not significant



BUC13, ZPR1, APOA5 쑀쟾옄쓽 Linkage disequilibrium 援ъ“

궗利앺썑援곌낵 愿젴맂 BUD13, ZPR1, APOA5쓽 SNP뱾쓣 긽쑝濡 Haploview 봽濡쒓렇옩쓣 넻빐 Linkage disequilibrium (LD, r2)쓣 솗씤븯떎(Fig. 1). Block 1뿉꽌뒗 BUD13 쑀쟾옄 ZPR1 쑀쟾옄 쁺뿭쓽 SNP씠 룷븿릺뼱 엳뿀怨 rs149527022, rs145796806, rs201247587 MAF (minor allele frequency)媛 궙븘 룷븿릺吏 븡 寃껋쑝濡 삁痢〓릺뿀떎. Block 2뒗 APOA5 쑀쟾옄쓽 SNP씠 룷븿릺뿀쑝硫 block 3 씤洹 吏뿭쓽 SNP뱾씠 LD block쓣 삎꽦븯떎. 궗利앺썑援곌낵 넂 쑀쓽꽦쓣 굹궦 SNP뱾씠 遺遺 r2媛 넂寃 굹굹 꽌濡 뿰愿꽦쓣 媛吏뒗 寃껋쓣 븣 닔 엳뿀떎.

Fig. 1. Linkage disequilibrium results between three genes BUD13, ZPR1 and APOA5 belonging to the gene cluster of 11q23.3. Linkage disequilibrium (LD) blocks were formed between SNPs using Haploview program based on HEXA data. A total of 3 blocks were formed, and Block 1 contained the SNPs of BUD13 and ZPR1. Among them, 3 SNPs showing a low minor allele frequency were excluded. Block 2 contained the SNP of the APOA5, and the direction to the metabolic syndrome was consistent. Block 3 included SNPs near the APOA5.

Regulome DB GTEx Portal쓣 넻븳 in silico 湲곕뒫 遺꾩꽍

븵꽑 寃곌낵뿉꽌 쑀쓽꽦쓣 蹂댁씠뒗 SNP뱾씠 뿼湲곗뿉 뵲씪 쑀쟾옄 삉뒗 떒諛깆쭏 諛쒗쁽뿉 쁺뼢쓣 二쇰뒗吏 븣븘蹂닿린 쐞빐 Regulome DB (https://regulomedb.org/regulome-search/) GTEx Portal (https://gtexportal.org/home/)쓣 솢슜븯뿬 븣븘蹂댁븯떎(Table 4) (GTEx Consortium, 2013). Regulome DB쓽 寃곌낵뿉꽌뒗 ZPR1쓽 rs964184 rs603446, APOA5쓽 rs1263173, rs7396835媛 1f 씠긽쓽 score瑜 굹궡 eQTL (expression quantitative trait loci)뿉 룷븿맂 SNP엫쓣 븣 닔 엳뿀怨 DNase peak쓽 李⑥씠瑜 굹깉떎. 삉븳, rs7396835뒗 CDX2 떒諛깆쭏 寃고빀 諛섏쓳뿉 쁺뼢쓣 誘몄낀떎. Rs964184뒗 1d쓽 score濡 쟾궗 씤옄媛 寃고빀뿉 쁺뼢쓣 以 肉먮쭔 븘땲씪 POLR2A 떒諛깆쭏 寃고빀 諛섏쓳怨 FOXJ2 motif 옉슜뿉 쁺뼢쓣 誘몄낀떎. GTEx Portal쓽 寃곌낵뿉꽌뒗 minor allele瑜 媛吏 寃쎌슦 쑀쟾옄 諛쒗쁽웾쓣 Fig. 2 媛숇떎. BUD13쓽 rs11216126怨 rs2075295뒗 쟾삁(whole blood)뿉꽌 minor allele瑜 媛吏 븣 BUD13 쑀쟾옄쓽 諛쒗쁽웾씠 利앷븯뒗 寃껋쓣 븣 닔 엳뿀怨 븵꽌 궗利앺썑援 諛쒕퀝뿉 궙 쐞뿕룄瑜 굹궦 寃곌낵 愿젴씠 엳쓣 寃껋쑝濡 삁긽뻽떎. Rs964184뒗 뵾븯 吏諛(adipose subcutaneous)뿉꽌 minor allele瑜 媛吏 븣 ZPR1 쑀쟾옄쓽 諛쒗쁽웾씠 媛먯냼븯怨 留덉갔媛吏濡 븵꽑 寃곌낵쓽 궗利앺썑援 諛쒕퀝쓽 쐞뿕 利앷 愿젴맆 寃껋쑝濡 삁긽뻽떎.

Regulome DB and GTEx Portal results of SNPs as eQTL in three genes BUD13, ZPR1 and APOA5

Gene SNP BP A1 Regulome DB GTEx portal


Score TFBS DNase Proteins bound Motifs eQTL NES eQTL Tissue
BUD13 rs11216126 116617240 C 7 - - - - - 0.22 Whole Blood
rs2075295 116628401 C 6 - - - - - 0.14 Whole Blood
ZPR1 rs964184 116648917 G 1d + + POLR2A FOXJ2 + -0.13 Adipose Subcutaneous
rs603446 116654435 T 1f - + - - + - -
APOA5 rs1263173 116681008 A 1f - + - - + - -
rs7396835 116684028 T 1f - + CDX2 - + - -

Abbreviations: A1, minor allele; BP, base pair; eQTL, expression quantitative trait loci; NES, normalized effect size; SNP, single nucleotide polymorphism; TFBS, transcription binding factor site; +, affected; -, unaffected. Normalized effect size (NES) is defined as the slope of the linear regression, and is computed as the effect of the minor allele (A1) relative to the major allele



Fig. 2. Confirmation of gene expression results of SNP included in expression quantitative trait loci (eQTL) using GTEx Portal. Gene expression for each genotype in a specific tissue was confirmed and statistically significant. In (A), expression is higher when rs11216126 of the BUD13 gene has a minor allele, C allele, in whole blood. (B) has a higher expression in the same tissue and gene as in (A) when it has a C allele, a minor allele of rs2075295. In (C) Adipose-Subcutaneous, rs964184 of the ZPR1 gene has low gene expression when it has a minor allele, G allele.
怨 李

뿼깋泥 11q23.3뿉 쐞移섑븳 쑀쟾옄 겢윭뒪꽣씤 BUD13-ZPR1-APOA5뒗 삁옣 以묒꽦吏諛⑷낵 愿긽 룞留μ쭏솚쓽 쐞뿕꽦怨 愿젴븯뿬 옒 븣젮吏 쑀쟾옄뱾씠떎(Fu et al., 2015; Kim et al., 2019). BUD13 떒諛깆쭏 빑 pre-mRNA retention뿉 쁺뼢쓣 誘몄튂뒗 splicing 씤옄쓽 꽌釉 쑀떅 以 븯굹濡 吏吏덈궗 愿젴맂 紐낇솗븳 硫붿빱땲利섏씠 븘吏 諛앺吏吏 븡븯떎(Brooks et al., 2009). ZPR1 꽭룷 利앹떇 諛 떊샇 쟾떖怨 愿젴맂 議곗젅 떒諛깆쭏씠硫 ZPR1쓽 봽濡쒕え꽣 遺쐞뒗 peroxisome proliferator-activated receptor gamma (PPARG) 떒諛깆쭏 1, 2뿉 寃고빀븯뿬 씤뒓由 媛먯닔꽦怨 鍮꾨쭔뿉 以묒슂븳 뿭븷쓣 媛졇 궗利앺썑援곌낵 愿젴맆 寃껋쑝濡 깮媛곷맂떎(Galcheva-Gargova et al., 1996; Galcheva-Gargova et al., 1998; Corton et al., 2000). APOA5뒗 HDL-C쓽 援ъ꽦 슂냼濡쒖뜥 TG瑜 留롮씠 븿쑀븳 吏떒諛깆쭏쓽 媛닔 遺꾪빐(hydrolysis) 吏떒諛깆쭏 옍議대Ъ(lipoprotein remnants)쓽 꽭룷 궡 씠엯쓣 넻빐 泥대궡쓽 TG 냽룄瑜 議곗젅븳떎(Forte et al., 2009). 뵲씪꽌 媛 쑀쟾옄쓽 쑀쟾 蹂씠뿉 뵲씪 삁以 吏吏 냽룄뿉 쁺뼢쓣 誘몄퀜 궗利앺썑援 諛쒕퀝뿉 쁺뼢쓣 以 寃껋쑝濡 삁긽븳떎. BUD13쓽 rs11216126, ZPR1쓽 rs603446, APOA5쓽 rs2266788, rs2075291, rs662799뒗 븳援씤쓣 긽쑝濡 븳 씠쟾 뿰援ъ뿉꽌 TG 삉뒗 HDL-C 愿젴븯뿬 諛앺吏 쟻씠 엳쑝硫 씠踰 뿰援 寃곌낵뿉꽌룄 냽룄 利앷 媛먯냼쓽 뙣꽩씠 씪移섑븯怨 쑀쓽꽦씠 굹궗떎(Melegh et al., 2012; Song et al., 2013; Gombojav et al., 2016). Oh 벑쓽 뿰援ъ뿉꽌 븳援씤쓣 긽쑝濡 TG 愿젴븯뿬 泥섏쓬쑝濡 諛쒓뎬맂 ZPR1쓽 rs964184 BUD13쓽 rs2075295, rs1558861 씠踰 뿰援ъ뿉꽌 옱쁽릺뼱 TG肉먮쭔 븘땲씪 궗利앺썑援곗뿉 愿젴맂 SNP엫쓣 븣 닔 엳뿀떎(Oh et al., 2020). 삉븳, 궗利앺썑援곗뿉 愿븳 BUD13 (rs117548857, rs10488698, rs149527022, rs10790162), ZPR1 (rs2075290), APOA5 (rs12791103, rs1263173, rs7396835)怨 뜑遺덉뼱 TG HDL-C뿉 愿븳 ZPR1 (rs145796806, rs201247587), APOA5 (rs17520254)媛 븳援씤쓣 긽쑝濡 븳 씠踰 뿰援щ 넻빐 깉濡寃 諛쒓뎬릺뿀떎. 쑀쓽꽦쓣 蹂댁씤 SNP뱾뿉 븯뿬 떒諛깆쭏 諛쒗쁽源뚯쓽 誘몄튂뒗 쁺뼢怨 eQTL뿉 빐떦븯뿬 쑀쟾옄 諛쒗쁽웾쓽 議곗젅 뿬遺瑜 븣븘蹂댁븯怨 SNP媛꾩쓽 LD block쓣 솗씤븯떎. 뵲씪꽌 HEXA 肄뷀샇듃 옄猷뚮 솢슜븳 蹂 뿰援 寃곌낵瑜 넻빐 궗利앺썑援 諛쒕퀝怨 삁以 吏吏 냽룄쓽 쁺뼢쓣 誘몄튌 닔 엳뒗 쑀쟾 씤옄뱾쓣 젣떆븷 肉먮쭔 븘땲씪 吏덊솚쓣 씠빐븯뒗뜲 룄씠 맆 寃껋쑝濡 깮媛곷맂떎. 삉븳, 媛쒖씤쓽 쑀쟾쟻 뼇긽쓣 諛뷀깢쑝濡 諛쒕퀝뿉 李⑥씠瑜 굹궡뒗 吏덊솚쓽 삁諛⑷낵 移섎즺뿉 씠諛붿븷 寃껋쑝濡 湲곕븳떎.

ACKNOWLEDGEMENT

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.

CONFLICT OF INTEREST

The authors have no conflicts of interest to disclose.

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