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Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses.

Terao C, Ohmura K, Katayama M, Takahashi M, Kokubo M, Diop G, Toda Y, Yamamoto N, Human Disease Genomics Working GroupRheumatoid Arthritis (RA) Clinical and Genetic Study ConsortiumShinkura R, Shimizu M, Gut I, Heath S, Melchers I, Manabe T, Lathrop M, Mimori T, Yamada R, Matsuda F - PLoS ONE (2011)

Bottom Line: The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001).We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease.This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

ABSTRACT
Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8), OR 1.23, 95% CI: 1.14-1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

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Immunohistochemistry of the MBP protein in human synovial tissues stained by monoclonal anti-MBP antibody.Synovial tissue of RA patients, in particular, along the synovial lining layer strongly expressed MBP (A), whereas that of non-inflammatory osteoarthritis patients was much weaker (B). The expression of MBP in the synovial lining layer was weaker near follicules of infiltrated lymphocytes (C). Localized expression of MBP was observed at the plasma membrane of synoviocytes (D).
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pone-0020457-g003: Immunohistochemistry of the MBP protein in human synovial tissues stained by monoclonal anti-MBP antibody.Synovial tissue of RA patients, in particular, along the synovial lining layer strongly expressed MBP (A), whereas that of non-inflammatory osteoarthritis patients was much weaker (B). The expression of MBP in the synovial lining layer was weaker near follicules of infiltrated lymphocytes (C). Localized expression of MBP was observed at the plasma membrane of synoviocytes (D).

Mentions: Next we investigated the expression of the MBP protein in synovial tissue, as this is the main target of inflammation in RA. Microscopic observation revealed that MBP was highly expressed along the lining layer of synovial tissues in 20 out of 23 RA patients tested, while the expression of MBP was observed in only one out of five controls (p = 0.0017), and then generally at a weaker level (Figure 3A, B). In synovial tissue from RA patients, the detected MBP expression was weaker in synovial lining layer adjacent to the follicules of infiltrated lymphocytes (Figure 3C). In synoviocytes, the expression of MBP was mainly observed in the plasma membrane (Figure 3D).


Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses.

Terao C, Ohmura K, Katayama M, Takahashi M, Kokubo M, Diop G, Toda Y, Yamamoto N, Human Disease Genomics Working GroupRheumatoid Arthritis (RA) Clinical and Genetic Study ConsortiumShinkura R, Shimizu M, Gut I, Heath S, Melchers I, Manabe T, Lathrop M, Mimori T, Yamada R, Matsuda F - PLoS ONE (2011)

Immunohistochemistry of the MBP protein in human synovial tissues stained by monoclonal anti-MBP antibody.Synovial tissue of RA patients, in particular, along the synovial lining layer strongly expressed MBP (A), whereas that of non-inflammatory osteoarthritis patients was much weaker (B). The expression of MBP in the synovial lining layer was weaker near follicules of infiltrated lymphocytes (C). Localized expression of MBP was observed at the plasma membrane of synoviocytes (D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108877&req=5

pone-0020457-g003: Immunohistochemistry of the MBP protein in human synovial tissues stained by monoclonal anti-MBP antibody.Synovial tissue of RA patients, in particular, along the synovial lining layer strongly expressed MBP (A), whereas that of non-inflammatory osteoarthritis patients was much weaker (B). The expression of MBP in the synovial lining layer was weaker near follicules of infiltrated lymphocytes (C). Localized expression of MBP was observed at the plasma membrane of synoviocytes (D).
Mentions: Next we investigated the expression of the MBP protein in synovial tissue, as this is the main target of inflammation in RA. Microscopic observation revealed that MBP was highly expressed along the lining layer of synovial tissues in 20 out of 23 RA patients tested, while the expression of MBP was observed in only one out of five controls (p = 0.0017), and then generally at a weaker level (Figure 3A, B). In synovial tissue from RA patients, the detected MBP expression was weaker in synovial lining layer adjacent to the follicules of infiltrated lymphocytes (Figure 3C). In synoviocytes, the expression of MBP was mainly observed in the plasma membrane (Figure 3D).

Bottom Line: The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001).We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease.This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

ABSTRACT
Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8), OR 1.23, 95% CI: 1.14-1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

Show MeSH
Related in: MedlinePlus