Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Identification of Human LRG1 Polymorphisms and Their Genetic Association with Rheumatoid Arthritis

  • Jin, Eun-Heui (Genome Research Center for Immune Disorders, Wonkwang University School of Medicine) ;
  • Chae, Soo-Cheon (Department of Pathology, Wonkwang University School of Medicine) ;
  • Shim, Seung-Cheol (Division of Rheumatology, Department of Internal Medicine, Eulji University School of Medicine) ;
  • Kim, Hwan-Gyu (Division of Biological Sciences, Research Center of Bioactive Materials, Chonbuk National University) ;
  • Chung, Hun-Taeg (Genome Research Center for Immune Disorders, Wonkwang University School of Medicine)
  • Published : 2008.06.30
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Abstract

Human leucine-rich alpha-2-glycoprotein 1 (LRG1) was first identified as a trace protein in human serum. The primary sequence of LRG1 includes repeated leucine residues and putative membrane-binding domains. But, there is no published information on the genetic variation of this gene. In this study, LRG1 was identified as one of several upregulated genes in RA patients. We examined the expression levels of LRG1 between an RA patient and a healthy control by RT-PCR and validated that LRG1 was highly expressed in RA patients compared with controls. We identified the possible variation sites and single nucleotide polymorphisms (SNPs) in the human LRG1 gene by direct sequencing and analyzed the association of genotype and allele frequencies between RA patients and a control group without RA. We further investigated the relationship between these polymorphisms and the level of RF or anti-CCP in RA patients. We identified a total of three SNPs(g.-678A>G, g.-404C>T and g.1427T>C) and two variation sites (g.-1198delA and g.-893delA) in the LRG1 gene. Our results suggest that polymorphisms of the LRG1 gene are not associated with the susceptibility of RA in the Korean population.

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References

  1. Baechler, E.C., Batliwalla, F.M., Karypis, G., Gaffney, P.M., Ortmann, W.A., Espe, K.J., Shark, K.B., Grande, W.J., Hughes, K.M., Kapur, V., Gregersen, P.K., and Behrens, T.W. (2003). Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. USA. 100, 2610-2615 https://doi.org/10.1073/pnas.0337679100
  2. Batliwalla, F.M., Baechler, E.C., Xiao, X., Li, W., Balasubramanian, S., Khalili, H., Damle, A., Ortmann, W.A., Perrone, A., Kantor, A.B., Gulko, P.S., Kern, M., Furie, R., Behrens, T.W., and Gregersen, P.K. (2005). Peripheral blood gene expression profiling in rheumatoid arthritis. Genes. Immunol. 6, 388-397. https://doi.org/10.1038/sj.gene.6364209
  3. Blass, S., Engel, J.M., and Burmester, G.R. (1999). The immunologic homunculus in rheumatoid arthritis. Arthritis Rheum. 42, 2499-2506. https://doi.org/10.1002/1529-0131(199912)42:12<2499::AID-ANR1>3.0.CO;2-R
  4. Blass, S., Union, A., Raymackers, J., Schumann, F., Ungethum, U., Muller-Steinbach, S., De Keyser, F., Engel, J.M., and Burmester, G.R. (2001). The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis Rheum. 44, 761-771. https://doi.org/10.1002/1529-0131(200104)44:4<761::AID-ANR132>3.0.CO;2-S
  5. Bomprezzi, R., Ringner, M., Kim, S., Bittner, M.L., Khan, J., Chen, Y., Elkahloun, A., Yu, A., Bielekova, B., Meltzer, P.S., Martin, R., McFarland, H.F., and Trent, J.M. (2003). Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Mol. Genet. 12, 2191-2199. https://doi.org/10.1093/hmg/ddg221
  6. Buchanan, S.G., and Gay, N.J. (1996). Structural and functional diversity in the leucine-rich repeat family of proteins. Prog. Bioohys. Mol. Biol. 65, 1-44.
  7. Gregerin, P.K. (1999). Genetics of rheumatoid arthritis : confronting complexity. Arthritis Res. 1, 37-44. https://doi.org/10.1186/ar9
  8. Haupt, H., and Baudner, S. (1977). Isolation and characterization of an unknown, leucine-rich 3.1-S-alpha2-glycoprotein from human serum. Hoppe Seylers Z. Phisiol. Chem. (article in German). 358, 639-646. https://doi.org/10.1515/bchm2.1977.358.1.639
  9. Heller, R.A., Schena, M., Chai, A., Shalon, D., Bedilion, T., Gilmore, J., Woolley, D.E., and Davis, R.W. (1997). Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc. Natl. Acad. Sci. USA. 94, 2150-2155. https://doi.org/10.1073/pnas.94.6.2150
  10. Kakisaka, T., Kondo, T., Okano, T., Fujii, K., Honda, K., Endo, M., Tsuchida, A., Aoki, T., Itoi, T., Moriyasu, F., Yamada, T., Kato, H., Nishimura, T., Todo, S., and Hirohashi, S. (2007). Plasma proteomics of pancreatic cancer patients by multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis (2D-DIGE) : Up-regulation of leucine-rich alpha-2-glycoprotein in pancreatic cancer. J. Chroma. B. 852, 257-267. https://doi.org/10.1016/j.jchromb.2007.01.029
  11. Kawakami, T., Hoshida, Y., Kanai, F., Tanaka, Y., Tateishi, K., Ikenoue, T., Obi, S., Sato, S., Teratani, T., Shiina, S., Kawabe, T., Suzuki, T., Hatano, N., Taniguchi, H., and Omata, M. (2005). Proteomic analysis of sera from hepatocellular carcinoma patients after radiofrequency ablation treatment. Proteomics 5, 4287-4295. https://doi.org/10.1002/pmic.200401287
  12. Kobe, B., and Deisenhofer, J. (1994). The leucine-rich repeat : a versatile binding motif. TIBS. 19, 415-421. https://doi.org/10.1016/0968-0004(94)90090-6
  13. Li, X., Miyajima, M., Jiang, C., and Arai, H. (2007). Expression of $TGF-{\beta}s$ and $TGF-{\beta}$ type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neuro. Letters 413, 141-144. https://doi.org/10.1016/j.neulet.2006.11.039
  14. Li, X., Miyajima, M., Mineki, R., Taka, H., Murayama, K., and Arai, H. (2006). Analysis of potential diagnostic biomarkers in cerebrospinal fluid of idiopathic normal pressure hydrocephalus by proteomics. Acta. Neurochir. (Wien) 148, 859-864. https://doi.org/10.1007/s00701-006-0787-4
  15. Newmeyer, D.D., and Ferguson-Miller, S. (2003). Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481-490. https://doi.org/10.1016/S0092-8674(03)00116-8
  16. Okano, T., Kondo, T., Kakisaka, T., Fujii, K., Yamada, M., Kato, H., Nishimura, T., Gemma, A., Kudoh, S., and Hirohashi, S. (2006). Plasma proteomics of lung cancer by a linkage of mlti-dimensional liquid chromatography and two-dimensional difference gel electrophoresis. Proteomics. 6, 3938-3948. https://doi.org/10.1002/pmic.200500883
  17. Pullerits, R., Bokarewa, M., Jonsson, I.M., Verdrengh, M., and Tarkowski, A. (2005). Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology 44, 32-39. https://doi.org/10.1093/rheumatology/keh406
  18. Schellekens, G.A., Visser, H., de Jong, B.A., van den Hoogen, F.H., Hazes, J.M., Breedveld, F.C., and van Venrooij, W.J. (2000). The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155-163. https://doi.org/10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3
  19. Schena, M., Shalon, D., Davis, R.W., and Brown, P.O. (1995). Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467-470. https://doi.org/10.1126/science.270.5235.467
  20. Shalon, D., Smith, S., and Brown, P.O. (1996). A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res. 6, 639-645. https://doi.org/10.1101/gr.6.7.639
  21. Shukaili, A., and Jabri, A. (2006). Rheumatoid arthritis, cytokines and hypoxia. What is the link? Saudi Med. J. 27, 1642-1649.
  22. Suzuki, A., Yamada, R., Chang, X., Tokuhiro, S., Sawada, T., Suzuki, M., Nagasaki, M., Nakayama-Hamada, M., Kawaida, R., Ono, M., Ohtsuki, M., Furukawa, H., Yoshino, S., Yukioka, M., Tohma, S., Matsubara, T., Wakitani, S., Teshima, R., Nishioka, Y., Sekine, A., Iida, A., Takahashi, A., Tsunoda, T., Nakamura, Y., and Yamamoto, K. (2003). Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395-402. https://doi.org/10.1038/ng1206
  23. Takahashi, N., Takahashi, Y., and Putnam, F.W. (1985). Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich ${\alpha}2-glycoprotein$ of human serum. Proc. Natl. Acad. Sci. USA 82, 1906-1910 https://doi.org/10.1073/pnas.82.7.1906
  24. Tighe, H., and Carson, D.A. (2001). Rheumatoid factor. In Kelley's Textbook of Rheumatology, Ruddy, S., Harris, E. D., Sledge, C., eds. (Philadelphia: W.B. Saunders Company), pp.151-161.
  25. Tokuhiro, S., Yamada, R., Chang, X., Suzuki, A., Kochi, Y., Sawada, T., Suzuki, M., Nagasaki, M., Ohtsuki, M., Ono, M., Furukawa, H., Nagashima, M., Yoshino, S., Mabuchi, A., Sekine, A., Saito, S., Takahashi, A., Tsunoda, T., Nakamura, Y., and Yamamoto, K. (2003). An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat. Genet. 35, 341-348. https://doi.org/10.1038/ng1267
  26. Waaler, E. (1940). On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. Acta. Pathol. Microbiol. Scand. 17, 172. https://doi.org/10.1111/j.1699-0463.1940.tb01475.x