Influence of ethnicity on the distribution of genetic polymorphisms associated with risk of chronic liver disease in South American populations

BMC Genetics

Diego Flichman²  Daniel Corach⁵  Pablo Argibay⁶  Adrián Gadano¹  Félix Nuñez⁷  Oscar Torres³  Analía Frías³  Leandro Burgos Pratx⁷  Lisandro Fortuny⁷  Mariela Caputo⁵  María Laura Hulaniuk⁴  Julieta Trinks⁶  Ana Cecilia Pontoriero⁴ 

[1] Servicio de Hepatología, Hospital Italiano de Buenos Aires, Juan D. Perón 4190, Buenos Aires, C1181ACH, Argentina;Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, Buenos Aires, C1113AAD, Argentina;Servicio de Medicina Transfusional, Hospital Materno Infantil “Ramón Sardá”, Esteban de Luca 2151, Buenos Aires, C1246ABQ, Argentina;Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Hospital Italiano de Buenos Aires, Potosí 4240, Buenos Aires, C1199ACL, Argentina;Servicio de Huellas Digitales Genéticas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, Buenos Aires, C1113AAD, Argentina;National Scientific and Technical Research Council (CONICET), Av. Rivadavia 1917, Buenos Aires, C1033AAJ, Argentina;Servicio de Medicina Transfusional, Hospital Italiano de Buenos Aires, Juan D. Perón 4190, Buenos Aires, C1181ACH, Argentina

关键词: South America;    Ethnicity;    Polymorphism;    VDR gene;    PNPLA3 gene;    Liver cancer;    Chronic liver disease;   

Others  :  1221492
DOI  :  10.1186/s12863-015-0255-3

 received in 2015-02-10, accepted in 2015-07-17,  发布年份 2015

【 摘 要 】

Background

The global burden of chronic liver disease is rising. Besides environmental, behavioral, viral and metabolic factors, genetic polymorphisms in patatin-like phospholipase-3 (PNPLA3) and vitamin D receptor (VDR) genes have been related to the development of chronic liver disease and progression towards liver cancer. Although their prevalence differs remarkably among ethnic groups, the frequency of these polymorphisms in South American populations -whose genetic background is highly admixed- has been poorly studied. Hence, the aim of this study was to characterize polymorphisms related to chronic liver disease and their association with the genetic ancestry of South American populations.

Results

DNA samples from 258 healthy unrelated male volunteers were analyzed. The frequencies of G and C alleles of rs738409 polymorphism (PNPLA3 gene) were 74 % and 26 %, respectively; whereas the bAt (CCA) haplotype (VDR gene) was observed in 32.5 % of the samples. The GG genotype of PNPLA3 rs738409 and the bAt (CCA) haplotype -associated with an increased risk of chronic liver disease and progression towards liver cancer- were significantly more frequent among samples exhibiting maternal and paternal Native American haplogroups (63.7 % and 64.6 %), intermediate among admixed samples (45.1 % and 44.9 %; p = 0.03) and the lowest for Non-native American ancestry (30.1 % and 29.6 %; p = 0.001 and p = 0.0008).

Conclusions

These results suggest that individuals with Native American ancestry might have a high risk of chronic liver disorders and cancer. Furthermore, these data not only support the molecular evaluation of ancestry in multi-ethnic population studies, but also suggest that the characterization of these variants in South American populations may be useful for establishing public health policies aimed at high risk ethnic communities.

【 授权许可】

   
2015 Pontoriero et al.

【 图 表 】

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【 参考文献 】

• [1]Bell BP, Manos MM, Zaman A, Terrault N, Thomas A, Navarro VJ et al.. The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance. Am J Gastroenterol. 2008; 103:2727-36.
• [2]Kim Y, Ejaz A, Tayal A, Spolverato G, Bridges JF, Anders RA et al.. Temporal trends in population-based death rates associated with chronic liver disease and liver cancer in the United States over the last 30 years. Cancer. 2014; 120:3058-65.
• [3]Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009; 27:1485-91.
• [4]Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013; 47 Suppl:S2-6.
• [5]Serfaty L, Lemoine M. Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. Diabetes Metab. 2008; 34:634-7.
• [6]Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011; 34:274-85.
• [7]Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006; 43(2 Suppl 1):S99-112.
• [8]Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010; 51:1972-8.
• [9]Nguyen GC, Thuluvath PJ. Racial disparity in liver disease: biological, cultural, or socioeconomic factors. Hepatology. 2008; 47:1058-66.
• [10]Verma S, Bonacini M, Govindarajan S, Kanel G, Lindsay KL, Redeker A. More advanced hepatic fibrosis in hispanics with chronic hepatitis C infection: role of patient demographics, hepatic necroinflammation, and steatosis. Am J Gastroenterol. 2006; 101:1817-23.
• [11]Cheung RC, Currie S, Shen H, Ho SB, Bini EJ, Anand BS et al.. Chronic hepatitis C in Latinos: natural history, treatment eligibility, acceptance, and outcomes. Am J Gastroenterol. 2005; 100:2186-93.
• [12]Weston SR, Leyden W, Murphy R, Bass NM, Bell BP, Manos MM et al.. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005; 41:372-9.
• [13]Dongiovanni P, Romeo S, Valenti L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol. 2014; 20:12945-55.
• [14]Nahon P, Zucman-Rossi J. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol. 2012; 57:663-74.
• [15]Sookoian S, Pirola CJ. The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis. 2012; 16:467-85.
• [16]Sookoian S, Castaño GO, Scian R, Mallardi P, Fernández Gianotti T, Burgueño AL et al.. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology. 2015; 61:515-25.
• [17]Kitamoto T, Kitamoto A, Yoneda M, Hyogo H, Ochi H, Nakamura T et al.. Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan. Hum Genet. 2013; 132:783-92.
• [18]Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA et al.. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008; 40:1461-5.
• [19]Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S et al.. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013; 19:6969-78.
• [20]Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009; 50:2111-6.
• [21]Trépo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, Gustot T et al.. Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology. 2011; 54:60-9.
• [22]Zhang L, You W, Zhang H, Peng R, Yao A, Li X, et al. PNPLA3 Polymorphisms (rs738409) and Non-Alcoholic Fatty Liver Disease Risk and Related Phenotypes: A Meta-Analysis. J Gastroenterol Hepatol. 2015; 16. doi:10.1111/jgh.12889.
• [23]Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010; 55:2624-8.
• [24]Kitson MT, Roberts SK. D-livering the message: The importance of vitamin D status in chronic liver disease. J Hepatol. 2012; 57:897-909.
• [25]Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G et al.. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007; 17:517-24.
• [26]Dasarathy J, Periyalwar P, Allampati S, Bhinder V, Hawkins C, Brandt P et al.. Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease. Liver Int. 2014; 34:e118-27.
• [27]Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004; 338:143-56.
• [28]Falleti E, Bitetto D, Fabris C, Cussigh A, Fontanini E, Fornasiere E et al.. Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis. World J Gastroenterol. 2010; 16:3016-24.
• [29]Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Eloranta JJ et al.. Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D receptor (NR 1I1) variants on fibrosis progression rate in HCV patients. Liver Int. 2012; 32:635-43.
• [30]Hung CH, Chiu YC, Hu TH, Chen CH, Lu SN, Huang CM et al.. Significance of vitamin d receptor gene polymorphisms for risk of hepatocellular carcinoma in chronic hepatitis C. Transl Oncol. 2014; 7:503-7.
• [31]Catelli ML, Alvarez-Iglesias V, Gómez-Carballa A, Mosquera-Miguel A, Romanini C, Borosky A et al.. The impact of modern migrations on present-day multi-ethnic Argentina as recorded on the mitochondrial DNA genome. BMC Genet. 2011; 12:77. BioMed Central Full Text
• [32]Corach D, Lao O, Bobillo C, van Der Gaag K, Zuniga S, Vermeulen M et al.. Inferring continental ancestry of argentineans from Autosomal, Y-chromosomal and mitochondrial DNA. Ann Hum Genet. 2010; 74:65-76.
• [33]Flichman DM, Blejer JL, Livellara BI, Re VE, Bartoli S, Bustos JA et al.. Prevalence and trends of markers of hepatitis B virus, hepatitis C virus and human Immunodeficiency virus in Argentine blood donors. BMC Infect Dis. 2014; 14:218. BioMed Central Full Text
• [34]Guy J, Peters MG. Liver disease in women: the influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol Hepatol (N Y). 2013; 9:633-9.
• [35]Méndez-Sánchez N, Ridruejo E, Alves de Mattos A, Chávez-Tapia NC, Zapata R, Paraná R et al.. Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma. Ann Hepatol. 2014; 13 Suppl 1:4-40.
• [36]Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011; 53:1883-94.
• [37]Ingles SA, Haile RW, Henderson BE, Kolonel LN, Nakaichi G, Shi CY et al.. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies. Cancer Epidemiol Biomarkers Prev. 1997; 6:93-8.
• [38]Lins TC, Vieira RG, Grattapaglia D, Pereira RW. Population analysis of vitamin D receptor polymorphisms and the role of genetic ancestry in an admixed population. Genet Mol Biol. 2011; 34:377-85.
• [39]Liu N, Sawyer SL, Mukherjee N, Pakstis AJ, Kidd JR, Kidd KK et al.. Haplotype block structures show significant variation among populations. Genet Epidemiol. 2004; 27:385-400.
• [40]Sawyer SL, Mukherjee N, Pakstis AJ, Feuk L, Kidd JR, Brookes AJ et al.. Linkage disequilibrium patterns vary substantially among populations. Eur J Hum Genet. 2005; 13:677-86.
• [41]Klimentidis YC, Miller GF, Shriver MD. Genetic admixture, self-reported ethnicity, self-estimated admixture, and skin pigmentation among Hispanics and Native Americans. Am J Phys Anthropol. 2009; 138:375-83.
• [42]Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A et al.. Genetic structure, self-identified race/ethnicity, and confounding in case–control association studies. Am J Hum Genet. 2005; 76:268-75.
• [43]Trinks J, Hulaniuk ML, Caputo M, Pratx LB, Ré V, Fortuny L et al.. Distribution of genetic polymorphisms associated with hepatitis C virus (HCV) antiviral response in a multiethnic and admixed population. Pharmacogenomics J. 2014; 14:549-54.
• [44]Li Q, Qu HQ, Rentfro AR, Grove ML, Mirza S, Lu Y et al.. PNPLA3 polymorphisms and liver aminotransferase levels in a Mexican American population. Clin Invest Med. 2012; 35:237-45.
• [45]Hong H, Tong W. Emerging efforts for discovering new biomarkers of liver disease and hepatotoxicity. Biomark Med. 2014; 8:143-6.
• [46]Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000; 132:365-86.
• [47]Quesada JM, Casado A, Díaz C, Barrios L, Cuenca-Acevedo R, Dorado G. Allele-frequency determination of BsmI and FokI polymorphisms of the VDR gene by quantitative real-time PCR (QRT-PCR) in pooled genomic DNA samples. J Steroid Biochem Mol Biol. 2004; 89–90:209-14.
• [48]Gunes S, Bilen CY, Kara N, Asci R, Bagci H, Yilmaz AF. Vitamin D receptor gene polymorphisms in patients with urolithiasis. Urol Res. 2006; 34:47-52.
• [49]Zuccarelli G, Alechine E, Caputo M, Bobillo C, Corach D, Sala A. Rapid screening for Native American mitochondrial and Y-chromosome haplogroups detection in routine DNA analysis. Forensic Sci Int Genet. 2011; 5:105-8.