Korean Journal of Clinical Laboratory Science (대한임상검사과학회지)

Korean Society for Clinical Laboratory Science (대한임상검사과학회)
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MACROD2 Polymorphisms Are Associated with Hypertension in Korean Population

한국인에서의 MACROD2 유전자 다형성과 고혈압 상관성 연구

  • Ko, Bokyung (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University) ;
  • Jin, Hyun-Seok (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University)
  • 고보경 (호서대학교 생명보건대학 임상병리학과) ;
  • 진현석 (호서대학교 생명보건대학 임상병리학과)
  • Received : 2018.10.10
  • Accepted : 2019.01.09
  • Published : 2019.03.31
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Abstract

Hypertension is caused by a combination of genetic and environmental factors. In advanced countries, more than 30% of adults have hypertension. Among the genetic factors affecting hypertension, there are reports from European cohort studies that variants of the MACROD2 gene are correlated with blood pressure and the hypertension status. In this study, genetic polymorphisms of the MACROD2 gene region were selected and extracted based on Korean Genome and Epidemiology data, and logistic regression analysis was then performed for the hypertensive state. Linear regression analysis was also performed for the systolic and diastolic blood pressure. As a result, 16 SNPs showed a statistically significant association with a hypertensive state, and 2 SNPs (rs16996211, rs6034240) showed statistical significance, even in blood pressure. The most significant rs16996211 had a relative risk of hypertension of 0.85 (CI: 0.76~0.95, $P=3.1{\times}10^{-3}$), as well as an association with the systolic blood pressure (beta=-0.75, P=0.024) and diastolic blood pressure (beta=-0.59, P=0.01). These results suggest that polymorphisms of the MACROD2 gene are associated with hypertension in both Caucasians and Koreans, and highlight the potential genetic correlations with the pathogenesis of hypertension.

고혈압은 유전적, 환경적 요인들이 복합적으로 작용하여 발생하는 질환으로, 선진국들의 경우에는 성인들의 30% 이상이 고혈압 상태인 매우 유병률이 높은 만성 질환이다. 고혈압에 영향을 미치는 유전적 요인들 중에서 MACROD2 유전자의 변이들이 백인 중심의 코호트 연구에서 혈압 및 고혈압 상태와 상관관계가 있다는 보고들이 있다. 이에 본 연구에서는 질병관리본부에서 생산 구축한 한국인 유전체 역학 자료를 바탕으로 MACROD2 유전자 영역의 유전 변이들을 선택 추출한 후에 고혈압 상태에 대한 로지스틱 회귀분석을 시행하였고, 수축기 혈압과 이완기 혈압에 대해서는 선형 회기 분석을 진행하였다. 그 결과 고혈압 상태에서 16개 SNP들이 유의한 상관관계를 보여 주었고, 이들 중 2개의 SNP (rs16996211, rs6034240)은 혈압에서도 통계적 유의성을 보여주고 있다. 가장 유의성이 높은 rs16996211은 고혈압의 상대적 위험도가 0.85 (CI: 0.76~0.95, $P=3.1{\times}10^{-3}$)이고, 수축기 혈압은 (beta=-0.75, P=0.024)의 이완기 혈압은(beta=-0.59, P=0.01)의 상관 분석 결과를 보여주었다. 이러한 결과들을 통해 MACROD2 유전자의 다형성은 백인 중심의 서양인 뿐만 아니라 한국인에서도 고혈압과 상관관계가 있는 것을 확인할 있었으며, 이러한 사실은 고혈압의 병리 기전에 대한 유전적 상호관계의 이해를 높일 것으로 기대한다.

Keywords

References

  1. Carretero OA, Oparil S. Essential hypertension. Part I: definition and etiology. Circulation. 2000;101:329-335. https://doi.org/10.1161/01.CIR.101.3.329
  2. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44:398-404. https://doi.org/10.1161/01.HYP.0000142248.54761.56.
  3. Lawes CM, Vander Hoorn S, Rodgers A, International society of hypertension. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513-1518. https://doi.org/10.1161/HYPERTENSIONAHA.113.01148.
  4. Yannoutsos A, Dreyfuss Tubiana C, Safar ME, Blacher J. Optimal blood pressure target in stroke prevention. Curr Opin Neurol. 2017;30:8-14. https://doi.org/10.1097/WCO.0000000000000407.
  5. Jin HS, Hong KW. Replication of an African-American GWAS on blood pressure and hypertension in the Korean population. Genes & Genomics. 2011:33-127. https://doi.org/10.1007/s13258-010-0138-y.
  6. Ministry of Health and Welfare, Korea Health Industry Development Institute. Ministry of Health and Welfare, Korea Centers for Disease Control and Prevention. The 7th Korea National Health and Nutrition Examination Survey (KNHANES VII-1) [Internet]. Asan: Korea Centers for Disease Control and Prevention; 2018 [cited 2018 October 09]. Available from: https://knhanes.cdc.go.kr/knhanes/index.do.
  7. Yang L, Tian RG, Chang PY, Yan MR, Su XL. Association of SNPs in the PPARgamma gene and hypertension in a Mongolian population. Genet Mol Res. 2015;14:19295-19308. https://doi.org/10.4238/2015.December.29.39.
  8. Li W, Liu C. The -344C/T polymorphism in the CYP11B2 gene is associated with essential hypertension in the Chinese. JRAAS. 2014;15:150-155. https://doi.org/10.1177/1470320312466928.
  9. Qin L, Zhao P, Liu Z, Chang P. Associations SELE gene haplotype variant and hypertension in Mongolian and Han populations. Intern Med. 2015;54:287-293. https://doi.org/10.2169/internalmedicine.54.2797.
  10. Slavin TP, Feng T, Schnell A, Zhu X, Elston RC. Two-marker association tests yield new disease associations for coronary artery disease and hypertension. Hum Genet. 2011;130:725-733. https://doi.org/10.1007/s00439-011-1009-6.
  11. Chang YC, Hee SW, Lee WJ, Li HY, Chang TJ, Lin MW, et al. Genome-wide scan for circulating vascular adhesion protein-1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis. J Diabetes Investig. 2018. https://doi.org/10.1111/jdi.12805.
  12. Kelly TN, Takeuchi F, Tabara Y, Edwards TL, Kim YJ, Chen P, et al. Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure loci. Hypertension. 2013;62:853-859. https://doi.org/10.1161/HYPERTENSIONAHA.113.01148.
  13. Zhu X, Feng T, Li Y, Lu Q, Elston RC. Detecting rare variants for complex traits using family and unrelated data. Genet Epidemiol. 2010;34:171-187. https://doi.org/10.1002/gepi.20449.
  14. Maas NM, Van de Putte T, Melotte C, Francis A, Schrander-Stumpel CT, Sanlaville D, et al. The C20orf133 gene is disrupted in a patient with Kabuki syndrome. J Med Genet. 2007;44:562-569. http://dx.doi.org/10.1136/jmg.2007.049510.
  15. Pettersson M, Viljakainen H, Loid P, Mustila T, Pekkinen M, Armenio M, et al. Copy number variants are enriched in individuals with early-onset obesity and highlight novel pathogenic pathways. J Clin Endocrinol Metab. 2017;102:3029-3039. https://doi.org/10.1210/jc.2017-00565.
  16. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527-534. https://doi.org/10.1038/ng.357.
  17. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. Locus zoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336-2337. https://doi.org/10.1093/bioinformatics/btq419.
  18. Ciullo M, Bellenguez C, Colonna V, Nutile T, Calabria A, Pacente R, et al. New susceptibility locus for hypertension on chromosome 8q by efficient pedigree-breaking in an Italian isolate. Hum Mol Genet. 2006;15:1735-1743. https://doi.org/10.1093/hmg/ddl097.
  19. Cotsapas C, Speliotes EK, Hatoum IJ, Greenawalt DM, Dobrin R, Lum PY, et al. Common body mass index-associated variants confer risk of extreme obesity. Hum Mol Genet. 2009;18:3502-3507. https://doi.org/10.1093/hmg/ddp292.
  20. Mohseni M, Cidado J, Croessmann S, Cravero K, Cimino-Mathews A, Wong HY, et al. MACROD2 over expression mediates estrogen independent growth and tamoxifen resistance in breast cancers. Proc Natl Acad Sci U S A. 2014;111:17606-17611. https://doi.org/10.1073/pnas.1408650111.
  21. Sakthianandeswaren A, Parsons MJ, Mouradov D, MacKinnon RN, Catimel B, Liu S, et al. MACROD2 haploinsufficiency impairs catalytic activity of PARP1 and promotes chromosome instability and growth of intestinal tumors. Cancer Discov. 2018;8:988-1005. https://doi.org/10.1158/2159-8290.CD-17-0909.
  22. Jin HS, Sober S, Hong KW, Org E, Kim BY, Laan M, et al. Age-dependent association of the polymorphisms in the mitochondria-shaping gene, OPA1, with blood pressure and hypertension in Korean population. Am J Hypertens. 2011; 24:1127-1135. https://doi.org/10.1038/ajh.2011.131.
  23. Jin HS. Gender-specific association of the ANO1 genetic variations with hypertension. Biomed Sci Lett. 2015:144-151. https://doi.org/10.15616/BSL.2015.21.3.144.
  24. Hong KW, Jin HS, Lim JE, Cho YS, Go MJ, Jung J, et al. Non-synonymous single-nucleotide polymorphisms associated with blood pressure and hypertension. J Hum Hypertens. 2010;24:763-774. https://doi.org/10.1038/jhh.2010.9.
  25. Kim HK, Leem KH, Lee SN, Hong MS, Jung KH, Kim SK, et al. CACNA1A gene polymorphism is associated with hypertension in Korean population. Biomed Sci Lett. 2009;15:31-35.

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