Advertisement

Molecular Biology Reports

, Volume 43, Issue 12, pp 1359–1369 | Cite as

Association between PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), GCKR (rs780094), and elevated transaminase levels in overweight/obese Mexican adults

  • Yvonne N. FloresEmail author
  • Rafael Velázquez-Cruz
  • Paula Ramírez
  • Manuel Bañuelos
  • Zuo-Feng Zhang
  • Hal F. YeeJr.
  • Shen-Chih Chang
  • Samuel Canizales-Quinteros
  • Manuel Quiterio
  • Guillermo Cabrera-Alvarez
  • Nelly Patiño
  • Jorge Salmerón
Original Article

Abstract

There is scarce information about the link between specific single-nucleotide polymorphisms (SNPs) and risk of liver disease among Latinos, despite the disproportionate burden of disease among this population. Our aim was to investigate nine SNPs in or near the following genes: PNPLA3, LYPLAL1, PPP1R3B, GCKR, NCAN, IRS1, PPARG, and ADIPOR2 and examine their association with persistently elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels in Mexican adults. Data and samples were collected from 741 participants in the Mexican Health Worker Cohort Study, in Cuernavaca, Mexico. We identified 207 cases who had persistently elevated levels of ALT or AST (≥40 U/L) and 534 controls with at least two consecutive normal ALT or AST results in a 6 month period, during 2004–2006 and 2011–2013. TaqMan assays were used to genotype the SNPs. The risk allele of PNPLA3 rs738409 was found to be associated with persistently elevated levels of ALT or AST, adjusting for age, sex, BMI, type 2 diabetes, and ancestry: (OR 2.28, 95 % CI 1.13, 4.58). A significant association was found between the LYPLAL1, PPP1R3B, and GCKR risk alleles and elevated ALT or AST levels among overweight/obese adults. These results suggest that among Mexicans, the PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) polymorphisms may be associated with a greater risk of chronic liver disease among overweight adults. This study is the first to examine these nine SNPs in a sample of adults in Mexico.

Keywords

Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Candidate gene study Latinos Mexican adults Nonalcoholic fatty liver disease 

Notes

Acknowledgments

This research was supported by Grants from the Instituto Mexicano del Seguro Social (IMSS), Instituto Nacional de Medicina Genomica (INMEGEN) Grant #119-11/2012/I, and the Consejo Nacional de Ciencia y Tecnología (CONACyT) Grants #26267 M and SALUD-2011-01-161930. Dr. Flores received a Grant from the American Association for the Study of Liver Disease (AASLD) to support her work on this study, and was also supported by NIH/NCI K07CA197179. The authors express their gratitude to the Mexican Health Worker Cohort Study participants, their families, and the IMSS clinicians and staff.

Compliance with ethical standards

Conflict of interest

The authors have no disclosures to report.

Supplementary material

11033_2016_4058_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 25 kb)
11033_2016_4058_MOESM2_ESM.docx (22 kb)
Supplementary material 2 (DOCX 21 kb)

References

  1. 1.
    Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. doi: 10.1002/hep.23594 PubMedGoogle Scholar
  2. 2.
    Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE (2013) From NAFLD to NASH to cirrhosis—new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol. doi: 10.1038/nrgastro.2013.149 PubMedGoogle Scholar
  3. 3.
    Ertle J, Dechêne A, Sowa JP, Penndorf V, Herzer K, Kaiser G, Schlaak JF, Gerken G, Syn WK, Canbay A (2011) Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. doi: 10.1002/ijc.25797 PubMedGoogle Scholar
  4. 4.
    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40:1387–1395CrossRefPubMedGoogle Scholar
  5. 5.
    Clark JM, Brancati FL, Diehl AM (2003) The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98:960–967CrossRefPubMedGoogle Scholar
  6. 6.
    Clark JM (2006) The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40:S5–10PubMedGoogle Scholar
  7. 7.
    Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. doi: 10.1053/j.gastro.2010.09.038 Google Scholar
  8. 8.
    Weston SR, Leyden W, Murphy R, Bass NM, Bell BP, Manos MM, Terrault NA (2005) Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 41:372–379CrossRefPubMedGoogle Scholar
  9. 9.
    Wree A, Kahraman A, Gerken G, Canbay A (2011) Obesity affects the liver—the link between adipocytes and hepatocytes. Digestion. doi: 10.1159/000318741 Google Scholar
  10. 10.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. doi: 10.1002/hep.23527 PubMedGoogle Scholar
  11. 11.
    Smits MM, Ioannou GN, Boyko EJ, Utzschneider KM (2013) Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of a US national survey in three ethnic groups. J Gastroenterol Hepatol. doi: 10.1111/jgh.12106 PubMedGoogle Scholar
  12. 12.
    Bellentani S, Scaglioni F, Marino M, Bedogni G (2010) Epidemiology of non-alcoholic fatty liver disease. Dig Dis. doi: 10.1159/000282080 Google Scholar
  13. 13.
    Méndez-Sánchez N, Villa AR, Chávez-Tapia NC, Ponciano-Rodriguez G, Almeda-Valdés P, González D, Uribe M (2005) Trends in liver disease prevalence in Mexico from 2005 to 2050 through mortality data. Ann Hepatol 4(52):55Google Scholar
  14. 14.
    Kim W, Flamm S, Di Bisceglie A, Bodenheimer HC (2008) Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology. doi: 10.1002/hep.22109 Google Scholar
  15. 15.
    Pratt DS, Kaplan MM (2000) Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 342:1266–1271CrossRefPubMedGoogle Scholar
  16. 16.
    Ruhl C, Everhart J (2003) Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 124:71–79CrossRefPubMedGoogle Scholar
  17. 17.
    Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I (2004) Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. doi: 10.1136/bmj.38050.593634.63 PubMedPubMedCentralGoogle Scholar
  18. 18.
    Deboer MD, Wiener RC, Barnes BH, Gurka MJ (2013) Ethnic differences in the link between insulin resistance and elevated ALT. Pediatrics. doi: 10.1542/peds.2012-3584 Google Scholar
  19. 19.
    Flores YN, Yee HF Jr, Leng M, Escarce JJ, Bastani R, Salmerón J, Morales LS (2008) Risk factors for chronic liver disease in blacks, Mexican Americans, and whites in the United States: results from NHANES IV, 1999–2004. Am J Gastroenterol. doi: 10.1111/j.1572-0241.2008.02022.x PubMedPubMedCentralGoogle Scholar
  20. 20.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. doi: 10.1038/ng.257 PubMedPubMedCentralGoogle Scholar
  21. 21.
    Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD et al (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. doi: 10.1371/journal.pgen.1001324 PubMedPubMedCentralGoogle Scholar
  22. 22.
    Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P et al (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. doi: 10.1038/ng.970 Google Scholar
  23. 23.
    Hooper AJ, Adams LA, Burnett JR (2011) Genetic determinants of hepatic steatosis in man. J Lipid Res. doi: 10.1194/jlr.R008896 PubMedPubMedCentralGoogle Scholar
  24. 24.
    Anstee QM, Day CP (2013) The genetics of NAFLD. Nat Rev Gastroenterol Hepatol. doi: 10.1038/nrgastro.2013 Google Scholar
  25. 25.
    Larrieta-Carrasco E, Acuña-Alonzo V, Velázquez-Cruz R, Barquera-Lozano R, León-Mimila P, Villamil-Ramírez H et al (2014) PNPLA3 I148 M polymorphism is associated with elevated alanine transaminase levels in Mexican indigenous and Mestizo populations. Mol Biol Rep. doi: 10.1007/s11033-014-3341-0 PubMedGoogle Scholar
  26. 26.
    Hernaez R, McLean J, Lazo M, Brancati FL, Hirschhorn JN, Borecki IB, Harris TB; Genetics of Obesity-Related Liver Disease (GOLD) Consortium, Nguyen T, Kamel IR, Bonekamp S, Eberhardt MS, Clark JM, Kao WH, Speliotes EK (2013) Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol. doi:  10.1016/j.cgh.2013.02.011
  27. 27.
    Global Lipids Genetics Consortium (2013) Discovery and refinement of loci associated with lipid levels. Nat Genet. doi: 10.1038/ng.2797 Google Scholar
  28. 28.
    Morales LS, Flores YN, Leng M, Sportiche N, Gallegos-Carrillo K, Salmerón J (2014) risk factors for cardiovascular disease among Mexican–American adults in the United States and Mexico: a comparative study. Salud Pub Mex 56(2):197–205Google Scholar
  29. 29.
    Denova-Gutiérrez E, Castañón S, Talavera JO, Flores M, Macías N, Rodríguez-Ramírez S, Flores YN, Salmerón J (2011) Dietary patterns are associated with different indexes of adiposity and obesity in an urban Mexican population. J Nutr. doi: 10.3945/jn.110.132332 PubMedGoogle Scholar
  30. 30.
    Kosoy R, Nassir R, Tian C, White PA, Butler LM, Silva G, Kittles R, Alarcon-Riquelme ME, Gregersen PK, Belmont JW, De La Vega FM, Seldin MF (2009) Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Hum Mutat. doi: 10.1002/humu.20822 PubMedPubMedCentralGoogle Scholar
  31. 31.
    Velázquez-Cruz R, García-Ortiz H, Castillejos-López M, Quiterio M, Valdés-Flores M, Orozco L, Villarreal-Molina T, Salmerón J (2014) WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening. Age. doi: 10.1007/s11357-014-9635-2 PubMedPubMedCentralGoogle Scholar
  32. 32.
    US Department of Health and Human Services (1998) Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. US Department of Health and Human Services, Washington, DC. http://www.nhlbi.nih.gov/files/docs/guidelines/ob_gdlns.pdf. Accesssed 24 Aug 2016
  33. 33.
    Clarke GM, Anderson CA, Pettersson FH, Cardon LR, Morris AP, Zondervan KT (2011) Basic statistical analysis in genetic case–control studies. Nat Protoc. doi: 10.1038/nprot.2010.182 PubMedPubMedCentralGoogle Scholar
  34. 34.
    Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart AF, Birkett N (2009) Strengthening the reporting of genetic association studies (STREGA): an extension of the strengthening the reporting of observational studies in epidemiology (STROBE) statement. J Clin Epidemiol. doi: 10.1016/j.jclinepi.2008.12.004 PubMedGoogle Scholar
  35. 35.
    Li Q, Qu HQ, Rentfro AR, Grove ML, Mirza S, Lu Y, Hanis CL, Fallon MB, Boerwinkle E, Fisher-Hoch SP, McCormick JB (2012) PNPLA3 polymorphisms and liver aminotransferase levels in a Mexican American population. Clin Invest Med 35:E237–245PubMedPubMedCentralGoogle Scholar
  36. 36.
    Xu R, Tao A, Zhang S, Deng Y, Chen G (2015) Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Sci Rep. doi: 10.1038/srep09284 Google Scholar
  37. 37.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin. doi: 10.3322/caac.21153 Google Scholar
  38. 38.
    American Cancer Society (2015) Cancer facts & figures 2015. American Cancer Society, AtlantaGoogle Scholar
  39. 39.
    US Department of Health and Human Services Office of Minority Health. Chronic liver disease and hispanic americans. http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=62. Accessed 24 Aug 2016
  40. 40.
    Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH (2011) Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology. doi: 10.1002/hep.24072 PubMedPubMedCentralGoogle Scholar
  41. 41.
    Sookoian S, Castaño G, Gianotti TF, Gemma C, Rosselli MS, Pirola CJ (2008) Genetic variants in STAT3 are associated with nonalcoholic fatty liver disease. Cytokine. doi: 10.1016/j.cyto.2008.08.001 PubMedGoogle Scholar
  42. 42.
    Sookoian S, Castaño G, Gianotti TF, Gemma C, Pirola CJ (2009) Polymorphisms of MRP2 (ABCC2) are associated with susceptibility to nonalcoholic fatty liver disease. J Nutr Biochem. doi: 10.1016/j.jnutbio.2008.07.005 PubMedGoogle Scholar
  43. 43.
    Instituto Nacional de Estadística y Geografía (INEGI) (2013) Defunciones generales totales por principales causas de mortalidad. http://www3.inegi.org.mx/sistemas/sisept/Default.aspx?t=mdemo107&s=est&c=23587. Accessed Nov 20 2015
  44. 44.
    Sistema Nacional de Información en Salud (2011) Principales causas de mortalidad en edad productiva (de 15 a 64 años), 2008. http://www.dgis.salud.gob.mx/contenidos/sinais/e_mortalidadgeneral.html. Accessed Nov 20 2015
  45. 45.
    Ioannou G, Boyko E, Lee S (2006) The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999–2002. Am J Gastroenterol 101:76–82CrossRefPubMedGoogle Scholar
  46. 46.
    Secretaría de Economía (2014) Programa nacional de protección a los derechos del consumidor 2013–2018. Diario Oficial de la Federación, MexicoGoogle Scholar
  47. 47.
    Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, Koteish A, Brancati FL, Clark JM (2013) Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol. doi: 10.1093/aje/kws448 PubMedPubMedCentralGoogle Scholar
  48. 48.
    Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S (2005) Prevalence of and risk factors for nonalcoholic fatty liver disease: the dionysos nutrition and liver study. Hepatology. doi: 10.1002/hep.20734 PubMedGoogle Scholar
  49. 49.
    León-Mimila P, Vega-Badillo J, Gutiérrez-Vidal R, Villamil-Ramírez H, Villareal-Molina T, Larrieta-Carrasco E, López-Contreras BE, Kauffer LR, Maldonado-Pintado DG, Méndez-Sánchez N, Tovar AR, Hernández-Pando R, Velázquez-Cruz R, Campos-Pérez F, Aguilar-Salinas CA, Canizales-Quinteros S (2015) A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity. Exp Mol Pathol. doi: 10.1016/j.yexmp.2015.01.012 PubMedGoogle Scholar
  50. 50.
    Rtveladze K, Marsh T, Barquera S, Sanchez Romero LM, Levy D, Melendez G, Webber L, Kilpi F, McPherson K, Brown M (2014) Obesity prevalence in Mexico: impact on health and economic burden. Public Health Nutr. doi: 10.1017/S1368980013000086 Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Yvonne N. Flores
    • 1
    • 2
    Email author
  • Rafael Velázquez-Cruz
    • 3
  • Paula Ramírez
    • 1
  • Manuel Bañuelos
    • 1
    • 3
  • Zuo-Feng Zhang
    • 4
  • Hal F. YeeJr.
    • 5
  • Shen-Chih Chang
    • 4
  • Samuel Canizales-Quinteros
    • 6
  • Manuel Quiterio
    • 7
  • Guillermo Cabrera-Alvarez
    • 8
  • Nelly Patiño
    • 3
  • Jorge Salmerón
    • 1
    • 7
  1. 1.Unidad de Investigación Epidemiológica y en Servicios de SaludInstituto Mexicano del Seguro Social (IMSS)CuernavacaMexico
  2. 2.UCLA Department of Health Policy and ManagementFielding School of Public Health and Jonsson Comprehensive Cancer CenterLos AngelesUSA
  3. 3.Instituto Nacional de Medicina GenómicaMexicoMexico
  4. 4.UCLA Department of EpidemiologyFielding School of Public HealthLos AngelesUSA
  5. 5.Los Angeles County Department of Health ServicesLos AngelesUSA
  6. 6.Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de QuímicaUNAM/Instituto Nacional de Medicina Genómica (INMEGEN)Mexico CityMexico
  7. 7.Centro de Investigación en Salud PoblacionalInstituto Nacional de Salud PúblicaCuernavacaMexico
  8. 8.Clínica de HígadoIMSS Hospital General Regional con UMF 1CuernavacaMexico

Personalised recommendations