Association between SMAD2 Gene and Serum Liver Enzyme Levels in the Korean Population

  • Ahn, Hyo-Jun (Department of Laboratory Medicine, National Health Insurance Service Ilsan Hospital) ;
  • Sull, Jae Woong (Department of Biomedical Laboratory Science, College of Health Science, Eulji University) ;
  • Eom, Yong-Bin (Department of Biomedical Laboratory Science, Korea Nazarene University)
  • Received : 2013.03.11
  • Accepted : 2013.05.28
  • Published : 2013.06.29

Abstract

Genome-wide association studies (GWAS) have identified a number of common variants associated with serum liver enzyme homeostasis in population. In the previous study, single nucleotide polymorphisms (SNPs) in several genes have been reported to be associated with serum liver enzyme levels in European population. We aimed to confirm whether the genetic variation of SMAD2 (SMAD family member 2) gene influence the serum liver enzyme levels in Korean population. We genotyped variants in or near SMAD2 in a population-based sample including 994 unrelated Korean adult. Here, we performed association analysis to elucidate the possible relations of genetic polymorphisms in SMAD2 gene with serum liver enzyme levels. By examining genotype data of a total of 944 subjects in 5 hospital health promotion center, we discovered the SMAD2 gene polymorphisms are associated with serum liver enzyme levels. The common and highest significant polymorphism was rs17736760 (${\beta}$=3.51, P=5.31E-07) with glutamic oxaloacetic transferase (GOT), rs17736760 (${\beta}$=5.99, P=1.25E-05) with glutamic pyruvate transaminase (GPT), and rs17736760 (${\beta}$=15.68, P=9.93E-07) with gamma glutamyl transferase (GGT) in all group. Furthermore, the SNP rs17736760 was consistently associated with GOT (${\beta}$=5.25, P=1.72E-06), GPT (${\beta}$=9.97, P=1.16E-05), GGT (${\beta}$=26.13, P=3.43E-06) in men group. Consequently, we found statistically significant SNP in SMAD2 gene that are associated with serum levels of GOT, GPT, and GGT. In addition, these results suggest that the individuals with the minor alleles of the SNP in the SMAD2 gene may be more elevated serum liver enzyme levels in the Korean population.

Keywords

References

  1. Bathum L, Petersen HC, Rosholm JU, Hyltoft Petersen P, Vaupel J, Christensen K. Evidence for a substantial genetic influence on biochemical liver function tests: results from a populationbased Danish twin study. Clin Chem. 2001. 47: 81-87.
  2. Forlani G, Di Bonito P, Mannucci E, Capaldo B, Genovese S, Orrasch M, Scaldaferri L, Di Bartolo P, Melandri P, Dei Cas A, Zavaroni I, Marchesini G. Prevalence of elevated liver enzymes in Type 2 diabetes mellitus and its association with the metabolic syndrome. J Endocrinol Invest. 2008. 31: 146-152. https://doi.org/10.1007/BF03345581
  3. French D, Yang W, Cheng C, Raimondi SC, Mullighan CG, Downing JR, Evans WE, Pui CH, Relling MV. Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia. Blood. 2009. 113: 4512-4520. https://doi.org/10.1182/blood-2008-07-172106
  4. Ju W, Ogawa A, Heyer J, Nierhof D, Yu L, Kucherlapati R, Shafritz DA, Bottinger EP. Deletion of SMAD2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol. 2006. 26: 654-667. https://doi.org/10.1128/MCB.26.2.654-667.2006
  5. Kazemi-Shirazi L, Endler G, Winkler S, Schickbauer T, Wagner O, Marsik C. Gamma glutamyltransferase and long-term survival: is it just the liver? Clin Chem. 2007. 53: 940-946. https://doi.org/10.1373/clinchem.2006.081620
  6. Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008. 148: 348-352. https://doi.org/10.7326/0003-4819-148-5-200803040-00005
  7. Lee DH, Silventoinen K, Hu G, Jacobs DR Jr, Jousilahti P, Sundvall J, Tuomilehto J. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur Heart J. 2006. 27: 2170-2176. https://doi.org/10.1093/eurheartj/ehl086
  8. Ma X, Xu L, Wang S, Chen H, Xu J, Li X, Ning G. Loss of steroid receptor co-activator-3 attenuates carbon tetrachloride-induced murine hepatic injury and fibrosis. Lab Invest. 2009. 89: 903-914. https://doi.org/10.1038/labinvest.2009.51
  9. Monami M, Bardini G, Lamanna C, Pala L, Cresci B, Francesconi P, Buiatti E, Rotella CM, Mannucci E. Liver enzymes and risk of diabetes and cardiovascular disease: results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism. 2008. 57: 387-392. https://doi.org/10.1016/j.metabol.2007.10.015
  10. Stepec S, Makuc J, Markovic S, Medica I, Peterlin B. Distribution of HFE gene mutations in Slovenian patients with hereditary hemochromatosis. Ann Hematol. 2008. 87: 667-669. https://doi.org/10.1007/s00277-008-0463-2
  11. Whitfield JB, Zhu G, Nestler JE, Heath AC, Martin NG. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascular risk factors. Clin Chem. 2002. 48: 1426-1431.
  12. Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov. 2007. 6: 904-916. https://doi.org/10.1038/nrd2423
  13. Yuan X, Waterworth D, Perry JR, Lim N, Song K, Chambers JC, Zhang W, Vollenweider P, Stirnadel H, Johnson T, Bergmann S, Beckmann ND, Li Y, Ferrucci L, Melzer D, Hernandez D, Singleton A, Scott J, Elliott P, Waeber G, Cardon L, Frayling TM, Kooner JS, Mooser V. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008. 83: 520-528. https://doi.org/10.1016/j.ajhg.2008.09.012