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. 2003 Feb;40(2):104–108. doi: 10.1136/jmg.40.2.104

Association of the CD14 gene –159C polymorphism with progression of IgA nephropathy

H Yoon 1, J Shin 1, S Yang 1, D Chae 1, H Kim 1, D Lee 1, H Kim 1, S Kim 1, J Lee 1, Y Kim 1
PMCID: PMC1735366  PMID: 12566518

Abstract

The risk factors associated with the progression of IgA nephropathy (IgAN), the most common form of glomerulonephritis, are unclear. It has been suggested that CD14 signalling in response to various microbes affects the natural history of chronic inflammatory conditions. It has been hypothesised that variants in the promoter region of the CD14 gene might alter the expression of CD14, and this in turn could influence the progressive nature of IgAN.

PCR-RFLP was used to determine the polymorphism at the -159 site (T to C). The distribution of the CD14/-159 polymorphism was no different in patients with IgAN (n=216) compared to 171 healthy controls. After follow up for 86 months, it was found that an excess of the C genotype occurred in patients with progressive disease (p=0.03) and the risk of disease progression increased as the number of C alleles increased (p for trend = 0.002). The hazard ratio for progression in the patients with the CC genotype was 3.2 (p=0.025) compared with the patients possessing the TT genotype. After LPS stimulation, sCD14 was released more abundantly from the PBMCs of the TT subjects than from that of the CC subjects (p=0.006), even though mCD14 expression level was no different. In addition, the TT subjects released less IL-6 than the CC subjects after stimulation (p=0.0003). These results suggest that the CD14/-159 polymorphism is an important marker for the progression of IgAN and may modulate the level of the inflammatory responses.

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Selected References

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  1. Alamartine E., Sabatier J. C., Guerin C., Berliet J. M., Berthoux F. Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses. Am J Kidney Dis. 1991 Jul;18(1):12–19. doi: 10.1016/s0272-6386(12)80284-8. [DOI] [PubMed] [Google Scholar]
  2. Baldini M., Lohman I. C., Halonen M., Erickson R. P., Holt P. G., Martinez F. D. A Polymorphism* in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol. 1999 May;20(5):976–983. doi: 10.1165/ajrcmb.20.5.3494. [DOI] [PubMed] [Google Scholar]
  3. Collins F. S., Guyer M. S., Charkravarti A. Variations on a theme: cataloging human DNA sequence variation. Science. 1997 Nov 28;278(5343):1580–1581. doi: 10.1126/science.278.5343.1580. [DOI] [PubMed] [Google Scholar]
  4. D'Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis. 2000 Aug;36(2):227–237. doi: 10.1053/ajkd.2000.8966. [DOI] [PubMed] [Google Scholar]
  5. Floege J., Feehally J. IgA nephropathy: recent developments. J Am Soc Nephrol. 2000 Dec;11(12):2395–2403. doi: 10.1681/ASN.V11122395. [DOI] [PubMed] [Google Scholar]
  6. Fujieda S., Suzuki S., Sunaga H., Yamamoto H., Seki M., Sugimoto H., Saito H. Induction of IgA against Haemophilus parainfluenzae antigens in tonsillar mononuclear cells from patients with IgA nephropathy. Clin Immunol. 2000 Jun;95(3):235–243. doi: 10.1006/clim.2000.4864. [DOI] [PubMed] [Google Scholar]
  7. Galla J. H. IgA nephropathy. Kidney Int. 1995 Feb;47(2):377–387. doi: 10.1038/ki.1995.50. [DOI] [PubMed] [Google Scholar]
  8. Gharavi A. G., Yan Y., Scolari F., Schena F. P., Frasca G. M., Ghiggeri G. M., Cooper K., Amoroso A., Viola B. F., Battini G. IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet. 2000 Nov;26(3):354–357. doi: 10.1038/81677. [DOI] [PubMed] [Google Scholar]
  9. Gibot Sébastien, Cariou Alain, Drouet Ludovic, Rossignol Mathias, Ripoll Laurent. Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate. Crit Care Med. 2002 May;30(5):969–973. doi: 10.1097/00003246-200205000-00003. [DOI] [PubMed] [Google Scholar]
  10. Haziot A., Chen S., Ferrero E., Low M. G., Silber R., Goyert S. M. The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J Immunol. 1988 Jul 15;141(2):547–552. [PubMed] [Google Scholar]
  11. Holt P. G., Sly P. D., Björkstén B. Atopic versus infectious diseases in childhood: a question of balance? Pediatr Allergy Immunol. 1997 May;8(2):53–58. doi: 10.1111/j.1399-3038.1997.tb00145.x. [DOI] [PubMed] [Google Scholar]
  12. Hsu S. I., Ramirez S. B., Winn M. P., Bonventre J. V., Owen W. F. Evidence for genetic factors in the development and progression of IgA nephropathy. Kidney Int. 2000 May;57(5):1818–1835. doi: 10.1046/j.1523-1755.2000.00032.x. [DOI] [PubMed] [Google Scholar]
  13. Kim Y. S., Kang D., Kwon D. Y., Park W. Y., Kim H., Lee D. S., Lim C. S., Han J. S., Kim S., Lee J. S. Uteroglobin gene polymorphisms affect the progression of immunoglobulin A nephropathy by modulating the level of uteroglobin expression. Pharmacogenetics. 2001 Jun;11(4):299–305. doi: 10.1097/00008571-200106000-00004. [DOI] [PubMed] [Google Scholar]
  14. Kitchens R. L., Thompson P. A., Viriyakosol S., O'Keefe G. E., Munford R. S. Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. J Clin Invest. 2001 Aug;108(3):485–493. doi: 10.1172/JCI13139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Koppelman G. H., Reijmerink N. E., Colin Stine O., Howard T. D., Whittaker P. A., Meyers D. A., Postma D. S., Bleecker E. R. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med. 2001 Mar;163(4):965–969. doi: 10.1164/ajrccm.163.4.2004164. [DOI] [PubMed] [Google Scholar]
  16. Kurt-Jones E. A., Popova L., Kwinn L., Haynes L. M., Jones L. P., Tripp R. A., Walsh E. E., Freeman M. W., Golenbock D. T., Anderson L. J. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000 Nov;1(5):398–401. doi: 10.1038/80833. [DOI] [PubMed] [Google Scholar]
  17. Means T. K., Wang S., Lien E., Yoshimura A., Golenbock D. T., Fenton M. J. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol. 1999 Oct 1;163(7):3920–3927. [PubMed] [Google Scholar]
  18. Obana N., Takahashi S., Kinouchi Y., Negoro K., Takagi S., Hiwatashi N., Shimosegawa T. Ulcerative colitis is associated with a promoter polymorphism of lipopolysaccharide receptor gene, CD14. Scand J Gastroenterol. 2002 Jun;37(6):699–704. doi: 10.1080/00365520212504. [DOI] [PubMed] [Google Scholar]
  19. Pei Y., Scholey J., Thai K., Suzuki M., Cattran D. Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients. J Clin Invest. 1997 Aug 15;100(4):814–820. doi: 10.1172/JCI119596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pugin J., Heumann I. D., Tomasz A., Kravchenko V. V., Akamatsu Y., Nishijima M., Glauser M. P., Tobias P. S., Ulevitch R. J. CD14 is a pattern recognition receptor. Immunity. 1994 Sep;1(6):509–516. doi: 10.1016/1074-7613(94)90093-0. [DOI] [PubMed] [Google Scholar]
  21. Ross R., Jonuleit H., Bros M., Ross X. L., Yamashiro S., Matsumura F., Enk A. H., Knop J., Reske-Kunz A. B. Expression of the actin-bundling protein fascin in cultured human dendritic cells correlates with dendritic morphology and cell differentiation. J Invest Dermatol. 2000 Oct;115(4):658–663. doi: 10.1046/j.1523-1747.2000.00112.x. [DOI] [PubMed] [Google Scholar]
  22. Schwandner R., Dziarski R., Wesche H., Rothe M., Kirschning C. J. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 1999 Jun 18;274(25):17406–17409. doi: 10.1074/jbc.274.25.17406. [DOI] [PubMed] [Google Scholar]
  23. Ulevitch R. J., Tobias P. S. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol. 1995;13:437–457. doi: 10.1146/annurev.iy.13.040195.002253. [DOI] [PubMed] [Google Scholar]
  24. Vesy C. J., Kitchens R. L., Wolfbauer G., Albers J. J., Munford R. S. Lipopolysaccharide-binding protein and phospholipid transfer protein release lipopolysaccharides from gram-negative bacterial membranes. Infect Immun. 2000 May;68(5):2410–2417. doi: 10.1128/iai.68.5.2410-2417.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wolf G. Molecular mechanisms of angiotensin II in the kidney: emerging role in the progression of renal disease: beyond haemodynamics. Nephrol Dial Transplant. 1998 May;13(5):1131–1142. doi: 10.1093/ndt/13.5.1131. [DOI] [PubMed] [Google Scholar]
  26. Wurfel M. M., Kunitake S. T., Lichenstein H., Kane J. P., Wright S. D. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med. 1994 Sep 1;180(3):1025–1035. doi: 10.1084/jem.180.3.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zhang D. E., Hetherington C. J., Tan S., Dziennis S. E., Gonzalez D. A., Chen H. M., Tenen D. G. Sp1 is a critical factor for the monocytic specific expression of human CD14. J Biol Chem. 1994 Apr 15;269(15):11425–11434. [PubMed] [Google Scholar]
  28. da Silva Correia J., Soldau K., Christen U., Tobias P. S., Ulevitch R. J. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem. 2001 Mar 26;276(24):21129–21135. doi: 10.1074/jbc.M009164200. [DOI] [PubMed] [Google Scholar]

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