BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Analysis of copy number variation in 8,842 Korean individuals reveals 39 genes associated with hepatic biomarkers AST and ALT

  • Kim, Hyo-Young (Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University) ;
  • Cho, Seo-Ae (Interdisciplinary Program in Bioinformatics, Seoul National University) ;
  • Yu, Jeong-Mi (Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University) ;
  • Sung, Sam-Sun (Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University) ;
  • Kim, Hee-Bal (Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University)
  • Received : 2010.04.17
  • Accepted : 2010.07.16
  • Published : 2010.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Biochemical tests such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are useful for diagnosing patients with liver disease. In this study, we tested the association between copy number variation and the hepatic biomarkers AST and ALT based on 8,842 samples from population-based cohorts in Korea. We used Affymetrix Genome-Wide Human 5.0 arrays and identified 10,534 CNVs using HelixTree software. Of the CNVs tested using univariate linear regression, 100 CNVs were significant for AST and 16 were significant for ALT (P < 0.05). We identified 39 genes located within the CNV regions. DKK1 and HS3ST3B1 were shown to play roles in heparan sulfate biosynthesis and the Wnt signaling pathway, respectively. NAF1 and NPY1R were associated with glycoprotein processes and neuropeptide Y receptor activity based on GO categories. PTER, SOX14 and TM7SF4 were expressed in liver. DPYS and CTSC were found to be associated with dihydropyrimidinuria and Papillon-Lefevre syndrome phenotypes using OMIM. NPY5R was found to be associated with dyslipidemia using the Genetic Association Database.

Keywords

References

  1. Gitzelmann, R., Spycher, M., Feil, G., Muller, J., Seilnacht, B., Stahl, M. and Bosshard, N. (1996) Liver glycogen synthase deficiency: a rarely diagnosed entity. Eur. J. Pediatr. 155, 561-567. https://doi.org/10.1007/BF01957905
  2. Pocai, A., Lam, T., Obici, S., Gutierrez-Juarez, R., Muse, E., Arduini, A. and Rossetti, L. (2006) Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081-1091. https://doi.org/10.1172/JCI26640
  3. Zhang, X. and Beynen, A. (2007) Influence of dietary fish proteins on plasma and liver cholesterol concentrations in rats. Br. J. Nutr. 69, 767-777. https://doi.org/10.1079/BJN19930077
  4. Bathum, L., Petersen, H., Rosholm, J., Hyltoft Petersen, P., Vaupel, J. and Christensen, K. (2001) Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin. Chem. 47, 81-87.
  5. Hanley, A., Williams, K., Festa, A., Wagenknecht, L., D’Agostino, R. and Haffner, S. (2005) Liver markers and development of the metabolic syndrome. Diabetes 54, 3140-3147. https://doi.org/10.2337/diabetes.54.11.3140
  6. Sattar, N., Scherbakova, O., Ford, I., O’Reilly, D., Stanley, A., Forrest, E., MacFarlane, P., Packard, C., Cobbe, S. and Shepherd, J. (2004) Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study. Diabetes 53, 2855-2860. https://doi.org/10.2337/diabetes.53.11.2855
  7. Clemenz, M., Frost, N., Schupp, M., Caron, S., Foryst-Ludwig, A., Bohm, C., Hartge, M., Gust, R., Staels, B. and Unger, T. (2008) Liver-specific peroxisome proliferatoractivated receptor α target gene regulation by the angiotensin type 1 receptor blocker telmisartan. Diabetes 57, 1405-1413. https://doi.org/10.2337/db07-0839
  8. Yuan, X., Waterworth, D., Perry, J., Lim, N., Song, K., Chambers, J., Zhang, W., Vollenweider, P., Stirnadel, H. and Johnson, T. (2008) Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520-528. https://doi.org/10.1016/j.ajhg.2008.09.012
  9. Iafrate, A., Feuk, L., Rivera, M., Listewnik, M., Donahoe, P., Qi, Y., Scherer, S. and Lee, C. (2004) Detection of large-scale variation in the human genome. Nature Genetics 36, 949-951. https://doi.org/10.1038/ng1416
  10. Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M. and Chi, M. (2004) Large-scale copy number polymorphism in the human genome. Science 305, 525-528. https://doi.org/10.1126/science.1098918
  11. Feuk, L., Carson, A. and Scherer, S. (2006) Structural variation in the human genome. Nature Reviews Genetics 7, 85-97. https://doi.org/10.1038/nrg1767
  12. Redon, R., Ishikawa, S., Fitch, K., Feuk, L., Perry, G., Andrews, T., Fiegler, H., Shapero, M., Carson, A. and Chen, W. (2006) Global variation in copy number in the human genome. Nature 444, 444-454. https://doi.org/10.1038/nature05329
  13. de Stahl, T., Sandgren, J., Piotrowski, A., Nord, H., Andersson, R., Menzel, U., Bogdan, A., Thuresson, A., Poplawski, A. and von Tell, D. (2008) Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BACclone-based array. Human Mutation 29, 398-408. https://doi.org/10.1002/humu.20659
  14. McCarroll, S., Kuruvilla, F., Korn, J., Cawley, S., Nemesh, J., Wysoker, A., Shapero, M., De Bakker, P., Maller, J. and Kirby, A. (2008) Integrated detection and populationgenetic analysis of SNPs and copy number variation. Nat Genet 40, 1166-1174. https://doi.org/10.1038/ng.238
  15. Marshall, C., Noor, A., Vincent, J., Lionel, A., Feuk, L., Skaug, J., Shago, M., Moessner, R., Pinto, D. and Ren, Y. (2008) Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477-488. https://doi.org/10.1016/j.ajhg.2007.12.009
  16. Yim, S., Kim, T., Hu, H., Kim, J., Kim, B., Lee, J., Han, B., Shin, S., Jung, S. and Chung, Y. (2009) Copy number variations in East-Asian population and their evolutionary and functional implications. Human Molecular Genetics. 19, 1001-1008. https://doi.org/10.1093/hmg/ddp564
  17. Kampstra, P. (2008) Beanplot: a boxplot alternative for visual comparison of distributions, Jour. 28, co1.
  18. Cooper, G., Johnson, J., Langaee, T., Feng, H., Stanaway, I., Schwarz, U., Ritchie, M., Stein, C., Roden, D. and Smith, J. (2008) A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 112, 1022-1027. https://doi.org/10.1182/blood-2008-01-134247
  19. Dennis, Jr, G., Sherman, B., Hosack, D., Yang, J., Gao, W., Lane, H. and Lempicki, R. (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 4, P3. https://doi.org/10.1186/gb-2003-4-5-p3
  20. Lyon, M., Deakin, J. and Gallagher, J. (1994) Liver heparan sulfate structure. A novel molecular design. J. Biol. Chem. 269, 11208-11215.
  21. Shworak, N., Liu, J., Petros, L., Zhang, L., Kobayashi, M., Copeland, N., Jenkins, N. and Rosenberg, R. (1999) Multiple isoforms of heparan sulfate D-glucosaminyl 3-Osulfotransferase. J. Biol. Chem. 274, 5170-5184. https://doi.org/10.1074/jbc.274.8.5170
  22. Armengol, C., Cairo, S., Fabre, M. and Buendia, M. (2009) Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model. Int. J. Biochem. Cell Biol. (in press)
  23. Fedi, P., Bafico, A., Soria, A., Burgess, W., Miki, T., Bottaro, D., Kraus, M. and Aaronson, S. (1999) Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J. Biol. Chem. 274, 19465-19472. https://doi.org/10.1074/jbc.274.27.19465
  24. Li, D. and Friedman, S. (1999) Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J. Gastroenterol. Hepatol. 14, 618-633. https://doi.org/10.1046/j.1440-1746.1999.01928.x
  25. Tsukada, S., Parsons, C. and Rippe, R. (2006) Mechanisms of liver fibrosis. Clinica Chimica Acta 364, 33-60. https://doi.org/10.1016/j.cca.2005.06.014
  26. Kladney, R., Bulla, G., Guo, L., Mason, A., Tollefson, A., Simon, D., Koutoubi, Z. and Fimmel, C. (2000) GP73, a novel Golgi-localized protein upregulated by viral infection. Gene 249, 53-65.
  27. Block, T., Comunale, M., Lowman, M., Steel, L., Romano, P., Fimmel, C., Tennant, B., London, W., Evans, A. and Blumberg, B. (2005) Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans. Proc. Natl. Acad. Sci. U.S.A. 102, 779-784. https://doi.org/10.1073/pnas.0408928102
  28. DING, W., Fujimura, M., Mori, A., Tooyama, I. and Kimura, H. (1991) Light and electron microscopy of neuropeptide Y-containing nerves in human liver, gallbladder, and pancreas. Gastroenterology 101, 1054-1059. https://doi.org/10.1016/0016-5085(91)90733-2
  29. El-Salhy, M. (2000) Neuropeptide levels in murine liver and biliary pathways. Ups. J. Med. Sci. 105, 207-213.
  30. Marceau, P., Biron, S., Hould, F., Marceau, S., Simard, S., Thung, S. and Kral, J. (1999) Liver pathology and the metabolic syndrome X in severe obesity. J. Clin. Endocrinol. Metab. 84, 1513-1517. https://doi.org/10.1210/jc.84.5.1513
  31. Van Gennip, A., De Abreu, R., Van Lenthe, H., Bakkeren, J., Rotteveel, J., Vreken, P. and Van Kuilenburg, A. (1997) Dihydropyrimidinase deficiency: confirmation of the enzyme defect in dihydropyrimidinuria. J. Inher. Metab. Dis. 20, 339-342. https://doi.org/10.1023/A:1005309423960
  32. Nyhan, W. (2005) Disorders of purine and pyrimidine metabolism. Mol. Genet. Metab. 86, 25-33. https://doi.org/10.1016/j.ymgme.2005.07.027
  33. Almuneef, M., Al Khenaizan, S., Al Ajaji, S. and Al-Anazi, A. (2003) Pyogenic liver abscess and Papillon-Lefevre syndrome: not a rare association. Pediatrics 111, e85. https://doi.org/10.1542/peds.111.1.e85
  34. Wu, C., Orozco, C., Boyer, J., Leglise, M., Goodale, J., Batalov, S., Hodge, C., Haase, J., Janes, J. and Huss, J. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biology 10, R130. https://doi.org/10.1186/gb-2009-10-11-r130
  35. Hou, X., Maser, R., Magenheimer, B. and Calvet, J. (1996) A mouse kidney-and liver-expressed cDNA having homology with a prokaryotic parathion hydrolase (phosphotriesterase)-encoding gene: abnormal expression in injured and polycystic kidneys. Gene 168, 157-163. https://doi.org/10.1016/0378-1119(95)00746-6
  36. Cho, Y., Go, M., Kim, Y., Heo, J., Oh, J., Ban, H., Yoon, D., Lee, M., Kim, D. and Park, M. (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nature Genetics. 41, 527-534. https://doi.org/10.1038/ng.357
  37. Lambert, C. (2005) $HelixTree^{\copyright}$ Genetics Analysis Software. Golden Helix. Inc. http//wwwgoldenhelixcom.
  38. McMurray, A., Pearson, P., Pace, R. and Scott, D. (2004) Research: a commonsense approach. Social Science Press.
  39. Harris, M., Clark, J., Ireland, A., Lomax, J., Ashburner, M., Foulger, R., Eilbeck, K., Lewis, S., Marshall, B. and Mungall, C. (2004) The Gene Ontology (GO) database and informatics resource. Nucleic. Acids Research 32, D258-261. https://doi.org/10.1093/nar/gkh036
  40. Kanehisa, M., Goto, S., Kawashima, S. and Nakaya, A. (2002) The KEGG databases at GenomeNet. Nucleic. Acids Research 30, 42-46. https://doi.org/10.1093/nar/30.1.42

Cited by

  1. Expression of New Loci Associated With Obesity in Diet-Induced Obese Rats: From Genetics to Physiology vol.20, pp.2, 2012, https://doi.org/10.1038/oby.2011.236
  2. Genome-Wide Scan for Copy Number Variation Association with Biomarker Quantitative Trait Loci in Aging vol.12, pp.2, 2014, https://doi.org/10.1177/1721727X1401200206
  3. A replication study of genome-wide CNV association for hepatic biomarkers identifies nine genes associated with liver function vol.44, pp.9, 2011, https://doi.org/10.5483/BMBRep.2011.44.9.578
  4. Polygenic Sex Determination System in Zebrafish vol.7, pp.4, 2012, https://doi.org/10.1371/journal.pone.0034397
  5. Semantic networks for genome-wide CNV associated with AST and ALT in Korean cohorts vol.9, pp.2, 2013, https://doi.org/10.1007/s13273-013-0014-3
  6. VCS: Tool for Visualizing Copy Number Variation and Single Nucleotide Polymorphism vol.27, pp.12, 2014, https://doi.org/10.5713/ajas.2014.14143
  7. Genome-wide analysis of copy number variations reveals that aging processes influence body fat distribution in Korea Associated Resource (KARE) cohorts vol.131, pp.11, 2012, https://doi.org/10.1007/s00439-012-1203-1
  8. Hepatic Transcriptome Profiles Differ Among Maturing Beef Heifers Supplemented with Inorganic, Organic, or Mixed (50 % Inorganic:50 % Organic) Forms of Dietary Selenium vol.160, pp.3, 2014, https://doi.org/10.1007/s12011-014-0050-4