TY - JOUR
T1 - Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis
AU - Barcellos, Lisa F.
AU - Sawcer, Stephen
AU - Ramsay, Patricia P.
AU - Baranzini, Sergio E.
AU - Thomson, Glenys
AU - Briggs, Farren
AU - Cree, Bruce C.A.
AU - Begovich, Ann B.
AU - Villoslada, Pablo
AU - Montalban, Xavier
AU - Uccelli, Antonio
AU - Savettieri, Giovanni
AU - Lincoln, Robin R.
AU - DeLoa, Carolyn
AU - Haines, Jonathan L.
AU - Pericak-Vance, Margaret A.
AU - Compston, Alastair
AU - Hauser, Stephen L.
AU - Oksenberg, Jorge R.
N1 - Funding Information:
The authors are grateful to the individuals with MS and their families for making this study possible. They thank the International MS Genetics Consortium for providing some of the HLA-DRB1 genotype data. They thank R. Gomez and C. Tong for recruitment of US cases to the study and W. Chin, H. Mousavi and R. Guerrero for sample preparation and repository management. They also thank G. Artim and J. Penko for technical support. This work was funded by grants of the National Institutes of Health, National Multiple Sclerosis Society and Nancy Davis Foundation.
PY - 2006/9/15
Y1 - 2006/9/15
N2 - Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1* 1501-DQB1* 0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1* 15 was strongly associated in families (P=7.8 × 10-31), and a dominant DRB1* 15 dose effect was confirmed (OR = 7.5, 95% CI = 4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P = 0.03). Strong evidence for under-transmission of DRB1* 14 (P =5.7×10-6) even after accounting for DRB1* 15 (P = 0.03) was present, confirming a protective effect. In addition, a high risk DRB1* 15 genotype bearing DRB1* 08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1* 15 association observed in primary progressive MS families (P = 0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1* 15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype phenotype relationships.
AB - Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1* 1501-DQB1* 0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1* 15 was strongly associated in families (P=7.8 × 10-31), and a dominant DRB1* 15 dose effect was confirmed (OR = 7.5, 95% CI = 4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P = 0.03). Strong evidence for under-transmission of DRB1* 14 (P =5.7×10-6) even after accounting for DRB1* 15 (P = 0.03) was present, confirming a protective effect. In addition, a high risk DRB1* 15 genotype bearing DRB1* 08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1* 15 association observed in primary progressive MS families (P = 0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1* 15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype phenotype relationships.
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U2 - 10.1093/hmg/ddl223
DO - 10.1093/hmg/ddl223
M3 - Article
C2 - 16905561
AN - SCOPUS:33748740746
VL - 15
SP - 2813
EP - 2824
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 18
ER -