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. 1997 Jun;225(6):718–725. doi: 10.1097/00000658-199706000-00009

Crohn's disease and ulcerative colitis are associated with the DNA repair gene MLH1.

R M Pokorny 1, A Hofmeister 1, S Galandiuk 1, A B Dietz 1, N D Cohen 1, H L Neibergs 1
PMCID: PMC1190876  PMID: 9230812

Abstract

OBJECTIVE: The purpose of this study was to determine whether there is an association between Crohn's disease and ulcerative colitis with MLH1. SUMMARY BACKGROUND DATA: Identification of genes involved in the etiology of inflammatory bowel disease may lead to the development of markers that objectively can define disease and permit therapy. The treatment of Crohn's disease of the colon and ulcerative colitis also is complicated by difficulties in differentiating the two conditions. METHODS: The DNA and clinical data were obtained on 126 unrelated individuals (45 Crohn's disease, 36 ulcerative colitis, and 45 control subjects without intestinal disease). Polymerase chain reaction products were analyzed by single-strand conformation polymorphisms (MLH1 exons 9, 11, 14, 15, and 16) and polyacrylamide gel electrophoresis (markers D3S1611 and D3S1768). All comparisons were analyzed by chi square test. The association between single haplotypes and disease was expressed as relative odds. RESULTS: MLH1 exons 9, 11, 14, and 16 were monomorphic. Two, four, and six alleles were detected in MLH1 exon 15, D3S1611, and D3S1768, respectively. Significant associations were observed for MLH1 exon 15/D3S1611 haplotypes AB (OR = 5.5; p = 0.007) and BA (p = 0.002) with Crohn's disease and for haplotypes AB (OR = 4.0; p = 0.042), BA (p = 0.035), and BC (OR = 6.1; p = 0.016) with ulcerative colitis. Family history of inflammatory bowel disease was associated with D3S1768/D3S1611 (p = 0.05) and MLH1 exon 15/D3S1611 haplotypes (p = 0.03). D3S1611/D3S1768 haplotype CD (OR = 11.3; p = 0.03) was associated with disease, whereas MLH1 exon 15/D3S1611 haplotype AA (OR = 0.25; p = 0.02) was protective. Comparisons of MLH1 exon 15/D3S1611 haplotypes of Crohn's colitis and patients with ulcerative colitis were significant (p = 0.037). CONCLUSIONS: This study identifies a novel genetic and clinical association between MLH1 and inflammatory bowel disease.

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Selected References

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  1. Bronner C. E., Baker S. M., Morrison P. T., Warren G., Smith L. G., Lescoe M. K., Kane M., Earabino C., Lipford J., Lindblom A. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994 Mar 17;368(6468):258–261. doi: 10.1038/368258a0. [DOI] [PubMed] [Google Scholar]
  2. Fishel R., Lescoe M. K., Rao M. R., Copeland N. G., Jenkins N. A., Garber J., Kane M., Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993 Dec 3;75(5):1027–1038. doi: 10.1016/0092-8674(93)90546-3. [DOI] [PubMed] [Google Scholar]
  3. Galandiuk S., Miseljic S., Yang A. R., Early M., McCoy M. D., Wittliff J. L. Expression of hormone receptors, cathepsin D, and HER-2/neu oncoprotein in normal colon and colonic disease. Arch Surg. 1993 Jun;128(6):637–642. doi: 10.1001/archsurg.1993.01420180035007. [DOI] [PubMed] [Google Scholar]
  4. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  5. Han H. J., Maruyama M., Baba S., Park J. G., Nakamura Y. Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC) Hum Mol Genet. 1995 Feb;4(2):237–242. doi: 10.1093/hmg/4.2.237. [DOI] [PubMed] [Google Scholar]
  6. Hardy G. H. MENDELIAN PROPORTIONS IN A MIXED POPULATION. Science. 1908 Jul 10;28(706):49–50. doi: 10.1126/science.28.706.49. [DOI] [PubMed] [Google Scholar]
  7. Kern S. E., Redston M., Seymour A. B., Caldas C., Powell S. M., Kornacki S., Kinzler K. W. Molecular genetic profiles of colitis-associated neoplasms. Gastroenterology. 1994 Aug;107(2):420–428. doi: 10.1016/0016-5085(94)90167-8. [DOI] [PubMed] [Google Scholar]
  8. Kim H., Jen J., Vogelstein B., Hamilton S. R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994 Jul;145(1):148–156. [PMC free article] [PubMed] [Google Scholar]
  9. Kolodner R. D., Hall N. R., Lipford J., Kane M. F., Morrison P. T., Finan P. J., Burn J., Chapman P., Earabino C., Merchant E. Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations. Cancer Res. 1995 Jan 15;55(2):242–248. [PubMed] [Google Scholar]
  10. Leach F. S., Nicolaides N. C., Papadopoulos N., Liu B., Jen J., Parsons R., Peltomäki P., Sistonen P., Aaltonen L. A., Nyström-Lahti M. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993 Dec 17;75(6):1215–1225. doi: 10.1016/0092-8674(93)90330-s. [DOI] [PubMed] [Google Scholar]
  11. Neibergs H. L., Dietz A. B., Womack J. E. Single-strand conformation polymorphisms (SSCPs) detected in five bovine genes. Anim Genet. 1993 Apr;24(2):81–84. doi: 10.1111/j.1365-2052.1993.tb00244.x. [DOI] [PubMed] [Google Scholar]
  12. Nicolaides N. C., Papadopoulos N., Liu B., Wei Y. F., Carter K. C., Ruben S. M., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994 Sep 1;371(6492):75–80. doi: 10.1038/371075a0. [DOI] [PubMed] [Google Scholar]
  13. Papadopoulos N., Nicolaides N. C., Wei Y. F., Ruben S. M., Carter K. C., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M., Adams M. D. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625–1629. doi: 10.1126/science.8128251. [DOI] [PubMed] [Google Scholar]
  14. Peltomäki P., Lothe R. A., Aaltonen L. A., Pylkkänen L., Nyström-Lahti M., Seruca R., David L., Holm R., Ryberg D., Haugen A. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res. 1993 Dec 15;53(24):5853–5855. [PubMed] [Google Scholar]
  15. Satsangi J., Parkes M., Louis E., Hashimoto L., Kato N., Welsh K., Terwilliger J. D., Lathrop G. M., Bell J. I., Jewell D. P. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet. 1996 Oct;14(2):199–202. doi: 10.1038/ng1096-199. [DOI] [PubMed] [Google Scholar]
  16. Suzuki H., Harpaz N., Tarmin L., Yin J., Jiang H. Y., Bell J. D., Hontanosas M., Groisman G. M., Abraham J. M., Meltzer S. J. Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers. Cancer Res. 1994 Sep 15;54(18):4841–4844. [PubMed] [Google Scholar]
  17. Toyoda H., Wang S. J., Yang H. Y., Redford A., Magalong D., Tyan D., McElree C. K., Pressman S. R., Shanahan F., Targan S. R. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology. 1993 Mar;104(3):741–748. doi: 10.1016/0016-5085(93)91009-7. [DOI] [PubMed] [Google Scholar]

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