HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Ombrello, M. J., Remmers, E. F., Tachmazidou, I., Grom, A., Foell, D., Haas, J., Martini, A., Gattorno, M., Ozen, S., Prahalad, S., Zeft, A. S., Bohnsack, J. F., Mellins, E. D., Ilowite, N. T., Russo, R., Len, C., Hilario, M. O. E., Oliveira, S., Yeung, R. S. M., Rosenberg, A., Wedderburn, L. R., Anton, J., Schwarz, T., Hinks, A., Bilginer, Y., Park, J., Cobb, J., Satorius, C. L., Han, B., Baskin, E., Signa, S., Duerr, R. H., Achkar, J. P., Kamboh, M. I., Kaufman, K. M., Kottyan, L. C., Pinto, D., Scherer, S. W., Alarcon-Riquelme, M. E., Docampo, E., Estivill, X., Gul, A., de Bakker, P. I. W., Raychaudhuri, S., Langefeld, C. D., Thompson, S., Thomson, W., Kastner, D. L., & Woo, P. Proceedings of the National Academy of Sciences of the United States of America, 112(52):15970–15975, December, 2015.
doi  abstract   bibtex   
Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 x 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 x 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 x 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 x 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.
@article{ombrello_hla-drb111_2015,
	title = {{HLA}-{DRB1}*11 and variants of the {MHC} class {II} locus are strong risk factors for systemic juvenile idiopathic arthritis.},
	volume = {112},
	issn = {1091-6490 0027-8424},
	doi = {10.1073/pnas.1520779112},
	abstract = {Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is  poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 x 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 x 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 x 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 x 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the  relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.},
	language = {eng},
	number = {52},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	author = {Ombrello, Michael J. and Remmers, Elaine F. and Tachmazidou, Ioanna and Grom, Alexei and Foell, Dirk and Haas, Johannes-Peter and Martini, Alberto and Gattorno, Marco and Ozen, Seza and Prahalad, Sampath and Zeft, Andrew S. and Bohnsack, John F. and Mellins, Elizabeth D. and Ilowite, Norman T. and Russo, Ricardo and Len, Claudio and Hilario, Maria Odete E. and Oliveira, Sheila and Yeung, Rae S. M. and Rosenberg, Alan and Wedderburn, Lucy R. and Anton, Jordi and Schwarz, Tobias and Hinks, Anne and Bilginer, Yelda and Park, Jane and Cobb, Joanna and Satorius, Colleen L. and Han, Buhm and Baskin, Elizabeth and Signa, Sara and Duerr, Richard H. and Achkar, J. P. and Kamboh, M. Ilyas and Kaufman, Kenneth M. and Kottyan, Leah C. and Pinto, Dalila and Scherer, Stephen W. and Alarcon-Riquelme, Marta E. and Docampo, Elisa and Estivill, Xavier and Gul, Ahmet and de Bakker, Paul I. W. and Raychaudhuri, Soumya and Langefeld, Carl D. and Thompson, Susan and Thomson, Wendy and Kastner, Daniel L. and Woo, Patricia},
	month = dec,
	year = {2015},
	pmid = {26598658},
	pmcid = {PMC4702958},
	keywords = {*Polymorphism, Single Nucleotide, Arthritis, Juvenile/*genetics, Child, Gene Frequency, Genetic Predisposition to Disease/*genetics, Genotype, HLA-DRB1 Chains/*genetics, Haplotypes, Histocompatibility Antigens Class II/*genetics, Humans, Linkage Disequilibrium, Meta-Analysis as Topic, Odds Ratio, Risk Factors, Still's disease, autoinflammation, human leukocyte antigen, systemic juvenile idiopathic arthritis},
	pages = {15970--15975},
}
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