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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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A schematic view of the association results and LD structure of the human MBP gene locus at chromosome 18q23.SNPs located between rs470131 and rs2717096 are plotted in −log10 scale according to their chromosomal positions and p-values calculated with Cochran-Mantel-Haenszel test. Red circle indicates mhp-value of rs2000811 by meta-analysis using the combined results of collections 1 to 4. Relative locations of the genes in the region are shown with their transcriptional orientations by arrows. LD blocks were generated using the genome scan results.
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pone-0020457-g001: A schematic view of the association results and LD structure of the human MBP gene locus at chromosome 18q23.SNPs located between rs470131 and rs2717096 are plotted in −log10 scale according to their chromosomal positions and p-values calculated with Cochran-Mantel-Haenszel test. Red circle indicates mhp-value of rs2000811 by meta-analysis using the combined results of collections 1 to 4. Relative locations of the genes in the region are shown with their transcriptional orientations by arrows. LD blocks were generated using the genome scan results.

Mentions: The disease associated marker rs2000811 is located in the second intron of the MBP (myelin basic protein) gene at chromosome 18q23 within a 156-kb region that contains the MBP gene (NCBI MapViewer, build 36.3). Linkage disequilibrium (LD) was evaluated using genotyping results obtained in collections 1 and 2; rs2000811 did not show significant LD with other markers from the region (r2<0.14; Figure 1), or elsewhere in the genome. An imputation analysis using the Japanese HapMap data identified a SNP, rs9958028, which was 358-bp apart and in strong LD with rs2000811 (r2 = 0.96), as the second strongest association. However, no other marker was in strong LD with these two markers (r2 = 0.35 or smaller) (Figure S2). To determine if unidentified polymorphisms within MBP were in LD with rs2000811, we performed a sequencing of the exons and the promoter region of the MBP gene in 84 Japanese population control DNAs (Method S1). We identified 66 SNPs, 37 of which were not registered in dbSNP, and three of which were deleterious polymorphisms (Tables S6 and S7). Again, none of these polymorphisms was in strong LD with rs2000811 (r2 = 0.35 or smaller) (Figure S3). An imputation analysis using the genotyping results obtained by sequencing did not discover any other polymorphisms showing stronger association signals (p>0.0070) than that of rs2000811. Taken together, these data suggest that rs2000811 and/or one or more other as yet unidentified non-coding polymorphisms within or near MBP are responsible for the genetic association.


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)

A schematic view of the association results and LD structure of the human MBP gene locus at chromosome 18q23.SNPs located between rs470131 and rs2717096 are plotted in −log10 scale according to their chromosomal positions and p-values calculated with Cochran-Mantel-Haenszel test. Red circle indicates mhp-value of rs2000811 by meta-analysis using the combined results of collections 1 to 4. Relative locations of the genes in the region are shown with their transcriptional orientations by arrows. LD blocks were generated using the genome scan results.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020457-g001: A schematic view of the association results and LD structure of the human MBP gene locus at chromosome 18q23.SNPs located between rs470131 and rs2717096 are plotted in −log10 scale according to their chromosomal positions and p-values calculated with Cochran-Mantel-Haenszel test. Red circle indicates mhp-value of rs2000811 by meta-analysis using the combined results of collections 1 to 4. Relative locations of the genes in the region are shown with their transcriptional orientations by arrows. LD blocks were generated using the genome scan results.
Mentions: The disease associated marker rs2000811 is located in the second intron of the MBP (myelin basic protein) gene at chromosome 18q23 within a 156-kb region that contains the MBP gene (NCBI MapViewer, build 36.3). Linkage disequilibrium (LD) was evaluated using genotyping results obtained in collections 1 and 2; rs2000811 did not show significant LD with other markers from the region (r2<0.14; Figure 1), or elsewhere in the genome. An imputation analysis using the Japanese HapMap data identified a SNP, rs9958028, which was 358-bp apart and in strong LD with rs2000811 (r2 = 0.96), as the second strongest association. However, no other marker was in strong LD with these two markers (r2 = 0.35 or smaller) (Figure S2). To determine if unidentified polymorphisms within MBP were in LD with rs2000811, we performed a sequencing of the exons and the promoter region of the MBP gene in 84 Japanese population control DNAs (Method S1). We identified 66 SNPs, 37 of which were not registered in dbSNP, and three of which were deleterious polymorphisms (Tables S6 and S7). Again, none of these polymorphisms was in strong LD with rs2000811 (r2 = 0.35 or smaller) (Figure S3). An imputation analysis using the genotyping results obtained by sequencing did not discover any other polymorphisms showing stronger association signals (p>0.0070) than that of rs2000811. Taken together, these data suggest that rs2000811 and/or one or more other as yet unidentified non-coding polymorphisms within or near MBP are responsible for the genetic association.

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