Analysis of mitochondrial transcription factor A SNPs in alcoholic cirrhosis

Tang,Chun; Liu,Hongming; Tang,Yongliang; Guo,Yong; Liang,Xianchun; Guo,Liping; Pi,Ruxian; Yang,Juntao

doi:10.3892/etm.2013.1353

Analysis of mitochondrial transcription factor A SNPs in alcoholic cirrhosis

Authors:
- Chun Tang
- Hongming Liu
- Yongliang Tang
- Yong Guo
- Xianchun Liang
- Liping Guo
- Ruxian Pi
- Juntao Yang
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
Published online on: October 21, 2013 https://doi.org/10.3892/etm.2013.1353
Pages: 73-79

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Genetic susceptibility to alcoholic cirrhosis (AC) exists. We previously demonstrated hepatic mitochondrial DNA (mtDNA) damage in patients with AC compared with chronic alcoholics without cirrhosis. Mitochondrial transcription factor A (mtTFA) is central to mtDNA expression regulation and repair; however, it is unclear whether there are specific mtTFA single nucleotide polymorphisms (SNPs) in patients with AC and whether they affect mtDNA repair. In the present study, we screened mtTFA SNPs in patients with AC and analyzed their impact on the copy number of mtDNA in AC. A total of 50 patients with AC, 50 alcoholics without AC and 50 normal subjects were enrolled in the study. SNPs of full‑length mtTFA were analyzed using the polymerase chain reaction (PCR) combined with gene sequencing. The hepatic mtTFA mRNA and mtDNA copy numbers were measured using quantitative PCR (qPCR), and mtTFA protein was measured using western blot analysis. A total of 18 mtTFA SNPs specific to patients with AC with frequencies >10% were identified. Two were located in the coding region and 16 were identified in non‑coding regions. Conversely, there were five SNPs that were only present in patients with AC and normal subjects and had a frequency >10%. In the AC group, the hepatic mtTFA mRNA and protein levels were significantly lower than those in the other two groups. Moreover, the hepatic mtDNA copy number was significantly lower in the AC group than in the controls and alcoholics without AC. Based on these data, we conclude that AC‑specific mtTFA SNPs may be responsible for the observed reductions in mtTFA mRNA, protein levels and mtDNA copy number and they may also increase the susceptibility to AC.

View Figures

View References

1	Chedid A, Mendenhall CL, Gartside P, French SW, Chen T and Rabin L: Prognostic factors in alcoholic liver disease. VA Cooperative Study Group. Am J Gastroenterol. 86:210–216. 1991.PubMed/NCBI
2	Stickel F and Osterreicher CH: The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol. 41:209–224. 2006. View Article : Google Scholar : PubMed/NCBI
3	Cichoz-Lach H, Partycka J, Nesina I, Celinski K, Slomka M and Wojcierowski J: Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Scand J Gastroenterol. 42:493–498. 2007. View Article : Google Scholar
4	Hernández-Nazará ZH, Ruiz-Madrigal B, Martínez-López E, Roman S and Panduro A: Association of the epsilon 2 allele of APOE gene to hypertriglyceridemia and to early-onset alcoholic cirrhosis. Alcohol Clin Exp Res. 32:559–566. 2008.PubMed/NCBI
5	Cichoz-Lach H, Partycka J, Nesina I, Celiński K and Slomka M: The influence of genetic polymorphism of CYP2E1 on the development of alcohol liver cirrhosis. Wiad Lek. 59:757–761. 2006.(In Polish).
6	Khan AJ, Ruwali M, Choudhuri G, Mathur N, Husain Q and Parmar D: Polymorphism in cytochrome P450 2E1 and interaction with other genetic risk factors and susceptibility to alcoholic liver cirrhosis. Mutat Res. 664:55–63. 2009. View Article : Google Scholar : PubMed/NCBI
7	Nahon P, Sutton A, Pessayre D, et al: Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death. Clin Gastroenterol Hepatol. 3:292–298. 2005. View Article : Google Scholar : PubMed/NCBI
8	Tang C, Liang X, Liu H, Guo L, Pi R and Yang J: Changes in mitochondrial DNA and its encoded products in alcoholic cirrhosis. Int J Clin Exp Med. 5:245–250. 2012.PubMed/NCBI
9	Polimeno L, Margiotta M, Marangi L, et al: Molecular mechanisms of augmenter of liver regeneration as immunoregulator: its effect on interferon-gamma expression in rat liver. Dig Liver Dis. 32:217–225. 2000. View Article : Google Scholar : PubMed/NCBI
10	Kang D, Kim SH and Hamasaki N: Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion. 7:39–44. 2007. View Article : Google Scholar : PubMed/NCBI
11	Choi YS, Kim S, Kyu Lee H, Lee KU and Pak YK: In vitro methylation of nuclear respiratory factor-1 binding site suppresses the promoter activity of mitochondrial transcription factor A. Biochem Biophys Res Commun. 314:118–122. 2004. View Article : Google Scholar : PubMed/NCBI
12	No authors listed. Fatty liver and alcoholic liver disease study group of the Chinese Liver Disease Association. Guidelines for diagnosis and treatment of alcoholic liver diseases. Chinese Journal of Hepatology. 14:164–166. 2006.
13	Garstka HL, Schmitt WE, Schultz J, et al: Import of mitochondrial transcription factor A (TFAM) into rat liver mitochondria stimulates transcription of mitochondrial DNA. Nucleic Acids Res. 31:5039–5047. 2003. View Article : Google Scholar : PubMed/NCBI
14	Ekstrand MI, Falkenberg M, Rantanen A, et al: Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet. 13:935–944. 2004. View Article : Google Scholar : PubMed/NCBI
15	Alam TI, Kanki T, Muta T, et al: Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res. 31:1640–1645. 2003. View Article : Google Scholar : PubMed/NCBI
16	Suliman HB, Carraway MS and Piantadosi CA: Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med. 167:570–579. 2003. View Article : Google Scholar : PubMed/NCBI
17	Nikiforov TT, Rendle RB, Goelet P, et al: Genetic Bit Analysis: a solid phase method for typing single nucleotide polymorphisms. Nucleic Acids Res. 22:4167–4175. 1994. View Article : Google Scholar : PubMed/NCBI
18	Srivastava P, Kapoor R and Mittal RD: Association of single nucleotide polymorphisms in promoter of matrix metalloproteinase-2, 8 genes with bladder cancer risk in Northern India. Urol Oncol. 31:247–254. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhu Y and Hein DW: Functional effects of single nucleotide polymorphisms in the coding region of human N-acetyltransferase 1. Pharmacogenomics J. 8:339–348. 2008. View Article : Google Scholar : PubMed/NCBI
20	Jiang Z, Kunej T, Michal JJ, et al: Significant associations of the mitochondrial transcription factor A promoter polymorphisms with marbling and subcutaneous fat depth in Wagyu x Limousin F2 crosses. Biochem Biophys Res Commun. 334:516–523. 2005. View Article : Google Scholar
21	Ayres DR, Souza FR, Mercadante ME, et al: Evaluation of TFAM and FABP4 gene polymorphisms in three lines of Nellore cattle selected for growth. Genet Mol Res. 9:2050–2059. 2010. View Article : Google Scholar : PubMed/NCBI
22	Clempson AM, Pollott GE, Brickell JS, Bourne NE, Munce N and Wathes DC: Polymorphisms in the autosomal genes for mitochondrial function TFAM and UCP2 are associated with performance and longevity in dairy cows. Animal. 5:1335–1343. 2011. View Article : Google Scholar : PubMed/NCBI
23	Günther C, von Hadeln K, Müller-Thomsen T, et al: Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease. Neurosci Lett. 369:219–223. 2004.PubMed/NCBI
24	Laumet G, Chouraki V, Grenier-Boley B, et al: Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis. 20:1181–1188. 2010.
25	Zhang Q, Yu JT, Wang P, et al: Mitochondrial transcription factor A (TFAM) polymorphisms and risk of late-onset Alzheimer’s disease in Han Chinese. Brain Res. 1368:355–360. 2011.
26	Rantanen A, Jansson M, Oldfors A and Larsson NG: Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis. Mamm Genome. 12:787–792. 2001. View Article : Google Scholar : PubMed/NCBI
27	Castro Mdel R, Suarez E, Kraiselburd E, et al: Aging increases mitochondrial DNA damage and oxidative stress in liver of rhesus monkeys. Exp Gerontol. 47:29–37. 2012.PubMed/NCBI
28	Miñana JB, Gómez-Cambronero L, Lloret A, et al: Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism. Hepatology. 35:1205–1214. 2002.PubMed/NCBI
29	Lieber CS: Ethanol metabolism, cirrhosis and alcoholism. Clin Chim Acta. 257:59–84. 1997. View Article : Google Scholar : PubMed/NCBI
30	Seitz HK and Stickel F: Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem. 387:349–360. 2006. View Article : Google Scholar : PubMed/NCBI