Advertisement

Digestive Diseases and Sciences

, Volume 52, Issue 10, pp 2707–2715 | Cite as

Paraoxonase (PON)1 192R Allele Carriage is Associated with Reduced Risk of Inflammatory Bowel Disease

  • Amir Karban
  • Corina HartmanEmail author
  • Rami Eliakim
  • Matti Waterman
  • Shula Nesher
  • Ofra Barnett-Griness
  • Raanan Shamir
Original Paper

Abstract

The paraoxonase (PON) genes family maps to chromosome 7q21-q22, within a loci that also showed evidence of susceptibility genes for both Crohn’s disease (CD) and ulcerative colitis (UC). In this case-control study we investigated the possible relationship between PON1 and PON2 polymorphisms and the risk of inflammatory bowel disease (IBD). PON1 192Q/R, PON1 55L/M, and PON2 311S/C polymorphisms were investigated by RFLP analysis in DNA samples from 224 patients with CD, 58 patients with UC, and 311 healthy controls. The PON1 192R allele was significantly less common among IBD Ashkenazi patients (allelic OR = 0.61, P = 0.004, 95% CI = 0.44–0.85). In agreement with the individual SNP analysis, Ashkenazi IBD patients had a higher frequency of haplotype PON1 192Q/PON1 55L/PON2 311S (26.3% vs 17.3%; P=0.003) and a lower frequency of haplotype PON1 192R/PON1 55L/PON2 311S (18.9% vs 27.7%; P=0.008). Our results suggest that in this Ashkenazi Jewish population, carriage of PON1 R192 allele may confer protection against the development of IBD.

Keywords

Paraoxonase Lactonase Polymorphism Crohn’s disease Inflammatory bowel disease 

Notes

Acknowledgments

This work was partially supported by Israeli Scientific Foundation Grant No. 373/03-18.1 and a Keren Ezvonot Grant.

References

  1. 1.
    Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3:521–533PubMedCrossRefGoogle Scholar
  2. 2.
    Duerr RH (2003) Update on the genetics of inflammatory bowel disease. J Clin Gastroenterol 37:358–367PubMedCrossRefGoogle Scholar
  3. 3.
    Mackness B, Mackness MI, Durrington PN, Connelly PW, Hegele RA (1996) Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol 7:69–76PubMedGoogle Scholar
  4. 4.
    Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN (1996) The human serum paraoxonase/ arylesterase gene (PON1) is one member of a multigene family. Genomics 33:498–507PubMedCrossRefGoogle Scholar
  5. 5.
    Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop, GM, Bell JI, Jewell DP (1996) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature Genet 14:199–202PubMedCrossRefGoogle Scholar
  6. 6.
    Dechairo B, Dimon C, van Heel D, Mackay I, Edwards M, Scambler P, Jewell D, Cardon L, Lench N, Carey A (2001) Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3). Eur J Hum Genet 9:627–633PubMedCrossRefGoogle Scholar
  7. 7.
    La Du BN, Adkins S, Kuo CL, Lipsig D (1993) Studies on human serum paraoxonase/arylesterase. Chem Biol Interact 87:25–34PubMedCrossRefGoogle Scholar
  8. 8.
    Broomfield CA (1992) A purified recombinant organophosphorus acid anhydrase protects mice against soman. Pharmacol Toxicol 70:65–66PubMedCrossRefGoogle Scholar
  9. 9.
    Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C, La Du BN (2000) Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab Dispos 28:1335–1342PubMedGoogle Scholar
  10. 10.
    Teiber JF, Draganov DI, La Du BN (2003) Lactonase and lactonizing activities of human serum paraoxonase (PON1) and rabbit serum PON3. Biochem Pharmacol 66:887–896PubMedCrossRefGoogle Scholar
  11. 11.
    Heinecke JW, Lusis AJ (1998) Paraoxonase-gene polymorphisms associated with coronary heart disease: support for the oxidative damage hypothesis? Am J Hum Genet 62:20–24PubMedCrossRefGoogle Scholar
  12. 12.
    Mackness MI, Arrol S, Abbott C et al (1993) Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 104:129–135PubMedCrossRefGoogle Scholar
  13. 13.
    Aviram M, Hardak E, Vaya J et al (2000) Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities. Circulation 101:2510–2517PubMedGoogle Scholar
  14. 14.
    Fuhrman B, Volkova N, Aviram M (2002) Oxidative stress increases the expression of the CD36 scavenger receptor and the cellular uptake of oxidized low-density lipoprotein in macrophages from atherosclerotic mice: protective role of antioxidants and paraoxonase. Atherosclerosis 161:307–316PubMedCrossRefGoogle Scholar
  15. 15.
    Watson AD, Berliner JA, Hama SY et al (1995) Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 96:2882–2891PubMedCrossRefGoogle Scholar
  16. 16.
    Ng CJ, Wadleigh DJ, Gangopadhyay A, Hama S, Grijalva VR, Navab M, Fogelman AM, Reddy ST (2001) Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 276:44444–44449PubMedCrossRefGoogle Scholar
  17. 17.
    Draganov DI, Stetson PL, Watson CE, Billecke SS, La Du BN (2000) Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J Biol Chem 275:33435–33442PubMedCrossRefGoogle Scholar
  18. 18.
    Reddy ST, Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopadhyay A, Shih DM, Lusis AJ, Navab M, Fogelman AM (2001) Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler Thromb Vasc Biol 21:542–547PubMedGoogle Scholar
  19. 19.
    Ferre N, Camps J, Fernandez-Ballart J, Arija V, Murphy MM, Ceruelo S, Biarnes E, Vilella E, Tous M, Joven J (2003) Regulation of serum paraoxonase activity by genetic, nutritional, and lifestyle factors in the general population. Clin Chem 49:1491–1497PubMedCrossRefGoogle Scholar
  20. 20.
    Costa LG, Vitalone A, Cole TB, Furlong CE (2005) Modulation of paraoxonase (PON1) activity. Biochem Pharmacol 69:541–550PubMedCrossRefGoogle Scholar
  21. 21.
    Cole TB, Jampsa RL, Walter BJ, Arndt TL, Richter RJ, Shih DM, Tward A, Lusis AJ, Jack RM, Costa LG, Furlong CE (2003) Expression of human paraoxonase (PON1) during development. Pharmacogenetics 13:357–364PubMedCrossRefGoogle Scholar
  22. 22.
    Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE (1993) The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet 3:73–76PubMedCrossRefGoogle Scholar
  23. 23.
    Hassett C, Richter RJ, Humbert R, Chapline C, Crabb JW, Omiecinski CJ, Furlong CE (1991) Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence. Biochemistry 30:10141–10149PubMedCrossRefGoogle Scholar
  24. 24.
    Leviev I, James RW (2000) Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations. Arterioscler Thromb Vasc Biol 20:516–521PubMedGoogle Scholar
  25. 25.
    Suehiro T, Nakamura T, Inoue M, Shiinoki T, Ikeda Y, Kumon Y, Shindo M, Tanaka H, Hashimoto K (2000) A polymorphism upstream from the human paraoxonase (PON1) gene and its association with PON1 expression. Atherosclerosis 150:295–298PubMedCrossRefGoogle Scholar
  26. 26.
    Brophy VH, Hastings MD, Clendenning JB, Richter RJ, Jarvik GP, Furlong CE (2001) Polymorphisms in the human paraoxonase (PON1) promoter. Pharmacogenetics 11:77–84PubMedCrossRefGoogle Scholar
  27. 27.
    Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh J (2004) Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Lancet 363:689–695PubMedCrossRefGoogle Scholar
  28. 28.
    Mochizuki H, Scherer SW, Xi T, Nickle DC, Majer M, Huizenga JJ, Tsui LC, Prochazka M (1998) Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. Gene 213:149–157PubMedCrossRefGoogle Scholar
  29. 29.
    Sanghera DK, Aston CE, Saha N, Kamboh MI (1998) DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Am J Hum Genet 62:36–44PubMedCrossRefGoogle Scholar
  30. 30.
    Hong SH, Song J, Min WK, Kim JQ (2001) Genetic variations of the paraoxonase gene in patients with coronary artery disease. Clin Biochem 34:475–481PubMedCrossRefGoogle Scholar
  31. 31.
    Campo S, Sardo AM, Campo GM, Avenoso A, Castaldo M, D’Ascola A, Giunta E, Calatroni A, Saitta A (2004) Identification of paraoxonase 3 gene (PON3) missense mutations in a population of southern Italy. Mutat Res 546:75–80PubMedGoogle Scholar
  32. 32.
    Shamir R, Hartman C, Karry R, Pavlotzky E, Eliakim R, Lachter J, Suissa A, Aviram M (2005) Paraoxonases (PONs) 1, 2, and 3 are expressed in human and mouse gastrointestinal tract and in Caco-2 cell line: selective secretion of PON1 and PON2. Free Radic Biol Med 39:336–344PubMedCrossRefGoogle Scholar
  33. 33.
    Gasche C, Schomerich J, Brynskov J et al (2000) A simple classification of Crohn’s disease: report of the Working Party for the World Congress of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 6:8–15PubMedCrossRefGoogle Scholar
  34. 34.
    Karban A, Waterman M, Panhuysen CI, Pollak RD, Nesher S, Datta L, Weiss B, Suissa A, Shamir R, Brant SR, Eliakim R (2004) NOD2/CARD15 genotype and phenotype differences between Ashkenazi and Sephardic Jews with Crohn’s disease. Am J Gastroenterol 99:1134–1140PubMedCrossRefGoogle Scholar
  35. 35.
    Schaid DJ, Rowland CM, Tines DE, Jaobson RM, Poland GA (2002) Score tests for association traits with haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434PubMedCrossRefGoogle Scholar
  36. 36.
    Li HL, Liu DP, Liang CC (2003) Paraoxonase gene polymorphisms, oxidative stress, and diseases. J Mol Med 81:766–779PubMedCrossRefGoogle Scholar
  37. 37.
    Ruiz J, Blanche H, James RW, Garin MC, Vaisse C, Charpentier G, Cohen N, Morabia A, Passa P, Froguel P (1995) Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet 346:869–872PubMedCrossRefGoogle Scholar
  38. 38.
    Odawara M, Tachi Y, Yamashita K (1997) Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82:2257–2260PubMedCrossRefGoogle Scholar
  39. 39.
    Zama T, Murata M, Matsubara Y, Kawano K, Aoki N, Yoshino H, Watanabe G, Ishikawa K, Ikeda Y (1997) A 192Arg variant of the human paraoxonase (HUMPONA) gene polymorphism is associated with an increased risk for coronary artery disease in the Japanese. Arterioscler Thromb Vasc Biol 17:3565–3569PubMedGoogle Scholar
  40. 40.
    Ko YL, Ko YS, Wang SM, Hsu LA, Chang CJ, Chu PH, Cheng NJ, Chen WJ, Chiang CW, Lee YS (1998) The Gln-Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan. Atherosclerosis 141:259–264PubMedCrossRefGoogle Scholar
  41. 41.
    Ombres D, Pannitteri G, Montali A, Candeloro A, Seccareccia F, Campagna F, Cantini R, Campa PP, Ricci G, Arca M (1998) The gln-Arg192 polymorphism of human paraoxonase gene is not associated with coronary artery disease in italian patients. Arterioscler Thromb Vasc Biol 18:1611–1616PubMedGoogle Scholar
  42. 42.
    Gardemann A, Philipp M, Hess K, Katz N, Tillmanns H, Haberbosch W (2000) The paraoxonase Leu-Met54 and Gln-Arg191 gene polymorphisms are not associated with the risk of coronary heart disease. Atherosclerosis 152:421–431PubMedCrossRefGoogle Scholar
  43. 43.
    Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J, Furlong CE (1996) The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet 14:334–336PubMedCrossRefGoogle Scholar
  44. 44.
    Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN (1998) Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Lett 423:57–60PubMedCrossRefGoogle Scholar
  45. 45.
    Aviram M, Hardak E, Vaya J, Mahmood S, Milo S, Hoffman A, Billicke S, Draganov D, Rosenblat M (2000) Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities. Circulation 101:2510–2517PubMedGoogle Scholar
  46. 46.
    Heijmans BT, Westendorp RG, Lagaay AM, Knook DL, Kluft C, Slagboom PE (2000) Common paraoxonase gene variants, mortality risk and fatal cardiovascular events in elderly subjects. Atherosclerosis 149:91–97PubMedCrossRefGoogle Scholar
  47. 47.
    Leus FR, Wittekoek ME, Prins J, Kastelein JJ, Voorbij HA (2000) Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia. Atherosclerosis 149:371–377PubMedCrossRefGoogle Scholar
  48. 48.
    Draganov DI, La Du BN (2004) Pharmacogenetics of paraoxonases: a brief review. Naunyn Schmiedebergs Arch Pharmacol 369:78–88PubMedCrossRefGoogle Scholar
  49. 49.
    Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN (2005) Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res 46:1239–1247PubMedCrossRefGoogle Scholar
  50. 50.
    Teiber JF, Draganov DI, La Du BN (2004) Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH. J Lipid Res 45:2260–2268PubMedCrossRefGoogle Scholar
  51. 51.
    Murata M, Maruyama T, Suzuki Y, Saruta T, Ikeda Y (2004) Paraoxonase 1 Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus. Diabet Med 21:837–844PubMedCrossRefGoogle Scholar
  52. 52.
    Chen Q, Reis SE, Kammerer CM, McNamara DM, Holubkov R, Sharaf BL, Sopko G, Pauly DF, Merz CN, Kamboh MI, WISE Study Group (2003) Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Am J Hum Genet 72:13–22PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Amir Karban
    • 1
  • Corina Hartman
    • 2
    • 4
    Email author
  • Rami Eliakim
    • 1
  • Matti Waterman
    • 1
  • Shula Nesher
    • 1
  • Ofra Barnett-Griness
    • 3
  • Raanan Shamir
    • 2
  1. 1.Department of GastroenterologyRambam Health Care CampusHaifaIsrael
  2. 2.Pediatric Gastroenterology and Nutrition Unit, Meyer Children’s Hospital, Rambam Health Care CampusHaifaIsrael
  3. 3.Department of Community Medicine and EpidemiologyCarmel Medical CenterHaifaIsrael
  4. 4.Division of Pediatric Gastroenterology and NutritionMeyer Children’s Hospital of Haifa, Rambam Health Care CenterHaifaIsrael

Personalised recommendations