Skip to main content
PMC home page
Gut logoLink to Gut
. 2000 Apr;46(4):540–545. doi: 10.1136/gut.46.4.540

Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease

J Grove 1, A Daly 1, M Bassendine 1, E Gilvarry 1, C Day 1
PMCID: PMC1727883  PMID: 10716685

Abstract

BACKGROUND—The factors determining why less than 10% of heavy drinkers develop advanced alcoholic liver disease (ALD) remain elusive, although genetic factors may be important. Interleukin 10 (IL-10) is an important cytokine with anti-inflammatory, anti-immune, and antifibrotic functions. Several polymorphisms have been identified in the IL-10 promoter and recent evidence suggests that some of these may have functional effects on IL-10 secretion.
AIMS—To test the hypothesis that IL-10 promoter region polymorphisms are associated with susceptibility to ALD.
METHODS—The allele frequencies for the two single base pair substitutions at positions −627 (C→A) and −1117 (A→G) in the IL-10 promoter were determined in 287 heavy drinkers with biopsy proved advanced ALD, 107 heavy drinkers with no evidence of liver disease or steatosis only on biopsy, and 227 local healthy volunteers.
RESULTS—At position −627, 50% of patients with advanced ALD had a least one A allele compared with 33% of controls (p<0.0001) and 34% of drinkers with no or mild disease (p=0.017). At position −1117, the slight excess of the A allele in drinkers with advanced disease was because of linkage disequilibrium between the A alleles at the two sites.
CONCLUSIONS—Among heavy drinkers, possession of the A allele at position −627 in the IL-10 promoter is associated with an increased risk of advanced liver disease. This is consistent with recent functional data that the −627*A allele is associated with low IL-10 expression which will favour inflammatory, immune mediated, and profibrotic mechanisms of alcohol related liver injury.


Keywords: ethyl alcohol; cirrhosis; interleukin 10; genetic polymorphism

Full Text

The Full Text of this article is available as a PDF (147.5 KB).

Figure 1  .

Figure 1  

Open in a new tab

Genotyping for the C-627A polymorphism by PCR-RFLP (restriction fragment length polymorphism) analysis. Samples were amplified by PCR followed by digestion with Rsa I. Lane 1, homozygous mutant (AA); lane 2, homozygous wild type (CC); lane 3, heterozygous (CA); lane 4, heterozygous (CA).

Figure 2  .

Figure 2  

Open in a new tab

Genotyping for A-1117G polymorphism by SSCP analysis. Samples were amplified by PCR followed by denaturation and analysis by SSCP on an MDE gel. A constant band seen with both genotypes is indicated together with two bands which represent the wild type allele (A) and variant allele (G) respectively. Lane 1, homozygous wild type (AA); lane 2, homozygous wild type (AA); lane 3, homozygous mutant (GG); lane 4, heterozygous (AG); lane 5, heterozygous (AG); lane 6, homozygous mutant (GG).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alfrey E. J., Most D., Wang X., Lee L. K., Holm B., Krieger N. R., Sibley R. K., Huie P., Dafoe D. C. Interferon-gamma and interleukin-10 messenger RNA are up-regulated after orthotopic liver transplantation in tolerant rats: evidence for cytokine-mediated immune dysregulation. Surgery. 1995 Aug;118(2):399–405. doi: 10.1016/s0039-6060(05)80351-4. [DOI] [PubMed] [Google Scholar]
  2. Arai T., Hiromatsu K., Kobayashi N., Takano M., Ishida H., Nimura Y., Yoshikai Y. IL-10 is involved in the protective effect of dibutyryl cyclic adenosine monophosphate on endotoxin-induced inflammatory liver injury. J Immunol. 1995 Dec 15;155(12):5743–5749. [PubMed] [Google Scholar]
  3. Bashir R., Day C. P., James O. F., Ogilvie D. J., Sykes B., Bassendine M. F. No evidence for involvement of type 1 collagen structural genes in 'genetic predisposition' to alcoholic cirrhosis. J Hepatol. 1992 Nov;16(3):316–319. doi: 10.1016/s0168-8278(05)80662-2. [DOI] [PubMed] [Google Scholar]
  4. Bassendine M. F., Day C. P. The inheritance of alcoholic liver disease. Baillieres Clin Gastroenterol. 1998 Jun;12(2):317–335. doi: 10.1016/s0950-3528(98)90137-3. [DOI] [PubMed] [Google Scholar]
  5. Becker U., Deis A., Sørensen T. I., Grønbaek M., Borch-Johnsen K., Müller C. F., Schnohr P., Jensen G. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996 May;23(5):1025–1029. doi: 10.1002/hep.510230513. [DOI] [PubMed] [Google Scholar]
  6. Bellentani S., Saccoccio G., Costa G., Tiribelli C., Manenti F., Sodde M., Saveria Crocè L., Sasso F., Pozzato G., Cristianini G. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997 Dec;41(6):845–850. doi: 10.1136/gut.41.6.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Borish L., Aarons A., Rumbyrt J., Cvietusa P., Negri J., Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996 Jun;97(6):1288–1296. doi: 10.1016/s0091-6749(96)70197-5. [DOI] [PubMed] [Google Scholar]
  9. Bruguera M., Bordas J. M., Rodés J. Asymptomatic liver disease in alcoholics. Arch Pathol Lab Med. 1977 Dec;101(12):644–647. [PubMed] [Google Scholar]
  10. Carr L. G., Hartleroad J. Y., Liang Y., Mendenhall C., Moritz T., Thomasson H. Polymorphism at the P450IIE1 locus is not associated with alcoholic liver disease in Caucasian men. Alcohol Clin Exp Res. 1995 Feb;19(1):182–184. doi: 10.1111/j.1530-0277.1995.tb01489.x. [DOI] [PubMed] [Google Scholar]
  11. Clot P., Parola M., Bellomo G., Dianzani U., Carini R., Tabone M., Aricò S., Ingelman-Sundberg M., Albano E. Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol. Gastroenterology. 1997 Jul;113(1):265–276. doi: 10.1016/s0016-5085(97)70104-5. [DOI] [PubMed] [Google Scholar]
  12. Crawley E., Kay R., Sillibourne J., Patel P., Hutchinson I., Woo P. Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum. 1999 Jun;42(6):1101–1108. doi: 10.1002/1529-0131(199906)42:6<1101::AID-ANR6>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  13. Day C. P., James O. F., Bassendine M. F., Crabb D. W., Li T. K. Alcohol dehydrogenase polymorphisms and predisposition to alcoholic cirrhosis. Hepatology. 1993 Jul;18(1):230–232. [PubMed] [Google Scholar]
  14. Defrance T., Vanbervliet B., Brière F., Durand I., Rousset F., Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med. 1992 Mar 1;175(3):671–682. doi: 10.1084/jem.175.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Del Prete G., De Carli M., Almerigogna F., Giudizi M. G., Biagiotti R., Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993 Jan 15;150(2):353–360. [PubMed] [Google Scholar]
  16. Edwards-Smith C. J., Jonsson J. R., Purdie D. M., Bansal A., Shorthouse C., Powell E. E. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology. 1999 Aug;30(2):526–530. doi: 10.1002/hep.510300207. [DOI] [PubMed] [Google Scholar]
  17. Eskdale J., Gallagher G., Verweij C. L., Keijsers V., Westendorp R. G., Huizinga T. W. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9465–9470. doi: 10.1073/pnas.95.16.9465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Eskdale J., Kube D., Tesch H., Gallagher G. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence. Immunogenetics. 1997;46(2):120–128. doi: 10.1007/s002510050250. [DOI] [PubMed] [Google Scholar]
  19. Eskdale J., McNicholl J., Wordsworth P., Jonas B., Huizinga T., Field M., Gallagher G. Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility. Lancet. 1998 Oct 17;352(9136):1282–1283. doi: 10.1016/S0140-6736(05)70489-X. [DOI] [PubMed] [Google Scholar]
  20. Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
  21. Gazzinelli R. T., Wysocka M., Hieny S., Scharton-Kersten T., Cheever A., Kühn R., Müller W., Trinchieri G., Sher A. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. J Immunol. 1996 Jul 15;157(2):798–805. [PubMed] [Google Scholar]
  22. Grove J., Brown A. S., Daly A. K., Bassendine M. F., James O. F., Day C. P. The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: effect on age of presentation and dependence on alcohol dehydrogenase genotype. Pharmacogenetics. 1998 Aug;8(4):335–342. doi: 10.1097/00008571-199808000-00007. [DOI] [PubMed] [Google Scholar]
  23. Grove J., Daly A. K., Bassendine M. F., Day C. P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis. Hepatology. 1997 Jul;26(1):143–146. doi: 10.1002/hep.510260119. [DOI] [PubMed] [Google Scholar]
  24. Grove J., Daly A. K., Burt A. D., Guzail M., James O. F., Bassendine M. F., Day C. P. Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease. Gut. 1998 Aug;43(2):262–266. doi: 10.1136/gut.43.2.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hobbs K., Negri J., Klinnert M., Rosenwasser L. J., Borish L. Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma. Am J Respir Crit Care Med. 1998 Dec;158(6):1958–1962. doi: 10.1164/ajrccm.158.6.9804011. [DOI] [PubMed] [Google Scholar]
  26. Israel Y. Antibodies against ethanol-derived protein adducts: pathogenic implications. Gastroenterology. 1997 Jul;113(1):353–355. [PubMed] [Google Scholar]
  27. Järveläinen H. A., Fang C., Ingelman-Sundberg M., Lindros K. O. Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines. Hepatology. 1999 May;29(5):1503–1510. doi: 10.1002/hep.510290508. [DOI] [PubMed] [Google Scholar]
  28. Kasama T., Strieter R. M., Lukacs N. W., Burdick M. D., Kunkel S. L. Regulation of neutrophil-derived chemokine expression by IL-10. J Immunol. 1994 Apr 1;152(7):3559–3569. [PubMed] [Google Scholar]
  29. Lazarus M., Hajeer A. H., Turner D., Sinnott P., Worthington J., Ollier W. E., Hutchinson I. V. Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol. 1997 Dec;24(12):2314–2317. [PubMed] [Google Scholar]
  30. Lim S., Crawley E., Woo P., Barnes P. J. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet. 1998 Jul 11;352(9122):113–113. doi: 10.1016/S0140-6736(98)85018-6. [DOI] [PubMed] [Google Scholar]
  31. Louis H., Le Moine O., Peny M. O., Gulbis B., Nisol F., Goldman M., Devière J. Hepatoprotective role of interleukin 10 in galactosamine/lipopolysaccharide mouse liver injury. Gastroenterology. 1997 Mar;112(3):935–942. doi: 10.1053/gast.1997.v112.pm9041256. [DOI] [PubMed] [Google Scholar]
  32. Louis H., Le Moine O., Peny M. O., Quertinmont E., Fokan D., Goldman M., Devière J. Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice. Hepatology. 1997 Jun;25(6):1382–1389. doi: 10.1002/hep.510250614. [DOI] [PubMed] [Google Scholar]
  33. Louis H., Van Laethem J. L., Wu W., Quertinmont E., Degraef C., Van den Berg K., Demols A., Goldman M., Le Moine O., Geerts A. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology. 1998 Dec;28(6):1607–1615. doi: 10.1002/hep.510280621. [DOI] [PubMed] [Google Scholar]
  34. Moore K. W., O'Garra A., de Waal Malefyt R., Vieira P., Mosmann T. R. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
  35. Reed T., Page W. F., Viken R. J., Christian J. C. Genetic predisposition to organ-specific endpoints of alcoholism. Alcohol Clin Exp Res. 1996 Dec;20(9):1528–1533. doi: 10.1111/j.1530-0277.1996.tb01695.x. [DOI] [PubMed] [Google Scholar]
  36. Rosenwasser L. J., Borish L. Genetics of atopy and asthma: the rationale behind promoter-based candidate gene studies (IL-4 and IL-10). Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 2):S152–S155. doi: 10.1164/ajrccm.156.4.12tac-14. [DOI] [PubMed] [Google Scholar]
  37. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  39. Thompson K. C., Trowern A., Fowell A., Marathe M., Haycock C., Arthur M. J., Sheron N. Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation In vitro. Hepatology. 1998 Dec;28(6):1518–1524. doi: 10.1002/hep.510280611. [DOI] [PubMed] [Google Scholar]
  40. Thompson K., Maltby J., Fallowfield J., McAulay M., Millward-Sadler H., Sheron N. Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. Hepatology. 1998 Dec;28(6):1597–1606. doi: 10.1002/hep.510280620. [DOI] [PubMed] [Google Scholar]
  41. Turner D. M., Williams D. M., Sankaran D., Lazarus M., Sinnott P. J., Hutchinson I. V. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997 Feb;24(1):1–8. doi: 10.1111/j.1365-2370.1997.tb00001.x. [DOI] [PubMed] [Google Scholar]
  42. Wang S. C., Ohata M., Schrum L., Rippe R. A., Tsukamoto H. Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. J Biol Chem. 1998 Jan 2;273(1):302–308. doi: 10.1074/jbc.273.1.302. [DOI] [PubMed] [Google Scholar]
  43. Westendorp R. G., Langermans J. A., Huizinga T. W., Elouali A. H., Verweij C. L., Boomsma D. I., Vandenbroucke J. P., Vandenbrouke J. P. Genetic influence on cytokine production and fatal meningococcal disease. Lancet. 1997 Jan 18;349(9046):170–173. doi: 10.1016/s0140-6736(96)06413-6. [DOI] [PubMed] [Google Scholar]
  44. Whitfield J. B. Meta-analysis of the effects of alcohol dehydrogenase genotype on alcohol dependence and alcoholic liver disease. Alcohol Alcohol. 1997 Sep-Oct;32(5):613–619. doi: 10.1093/oxfordjournals.alcalc.a008303. [DOI] [PubMed] [Google Scholar]
  45. Willems F., Marchant A., Delville J. P., Gérard C., Delvaux A., Velu T., de Boer M., Goldman M. Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunol. 1994 Apr;24(4):1007–1009. doi: 10.1002/eji.1830240435. [DOI] [PubMed] [Google Scholar]
  46. Wu A., Slavin G., Levi A. J. Elevated serum gamma-glutamyl-transferase (transpeptidase) and histological liver damage in alcoholism. Am J Gastroenterol. 1976 Apr;65(4):318–323. [PubMed] [Google Scholar]
  47. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES