Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.

Giovanni Savettieri, Bruce C.A. Cree, Sergio E. Baranzini, Pablo Villoslada, Stephen Sawcer, Antonio Uccelli, Ann B. Begovich, Jorge R. Oksenberg, Robin R. Lincoln, Xavier Montalban, Stephen L. Hauser, Glenys Thomson, Carolyn Deloa, Patricia P. Ramsay, Lisa F. Barcellos, Farren Briggs, Alastair Compston, Jonathan L. Haines, Margaret A. Pericak-Vance

    Risultato della ricerca: Article

    232 Citazioni (Scopus)

    Abstract

    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=7.8x10(-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=5.7x10(-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.
    Lingua originaleEnglish
    pagine (da-a)2813-2824
    Numero di pagine12
    RivistaHuman Molecular Genetics
    Volume15
    Stato di pubblicazionePublished - 2006

    Fingerprint

    HLA-DRB1 Chains
    Multiple Sclerosis
    Genotype
    HLA-DR2 Antigen
    Chronic Progressive Multiple Sclerosis
    Phenotype
    Relapsing-Remitting Multiple Sclerosis
    HLA Antigens
    Major Histocompatibility Complex
    Age of Onset
    Sample Size
    Haplotypes
    Chromosomes
    Genes

    All Science Journal Classification (ASJC) codes

    • Molecular Biology
    • Genetics(clinical)
    • Genetics

    Cita questo

    Savettieri, G., Cree, B. C. A., Baranzini, S. E., Villoslada, P., Sawcer, S., Uccelli, A., ... Pericak-Vance, M. A. (2006). Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Human Molecular Genetics, 15, 2813-2824.

    Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. / Savettieri, Giovanni; Cree, Bruce C.A.; Baranzini, Sergio E.; Villoslada, Pablo; Sawcer, Stephen; Uccelli, Antonio; Begovich, Ann B.; Oksenberg, Jorge R.; Lincoln, Robin R.; Montalban, Xavier; Hauser, Stephen L.; Thomson, Glenys; Deloa, Carolyn; Ramsay, Patricia P.; Barcellos, Lisa F.; Briggs, Farren; Compston, Alastair; Haines, Jonathan L.; Pericak-Vance, Margaret A.

    In: Human Molecular Genetics, Vol. 15, 2006, pag. 2813-2824.

    Risultato della ricerca: Article

    Savettieri, G, Cree, BCA, Baranzini, SE, Villoslada, P, Sawcer, S, Uccelli, A, Begovich, AB, Oksenberg, JR, Lincoln, RR, Montalban, X, Hauser, SL, Thomson, G, Deloa, C, Ramsay, PP, Barcellos, LF, Briggs, F, Compston, A, Haines, JL & Pericak-Vance, MA 2006, 'Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.', Human Molecular Genetics, vol. 15, pagg. 2813-2824.
    Savettieri G, Cree BCA, Baranzini SE, Villoslada P, Sawcer S, Uccelli A e altri. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Human Molecular Genetics. 2006;15:2813-2824.
    Savettieri, Giovanni ; Cree, Bruce C.A. ; Baranzini, Sergio E. ; Villoslada, Pablo ; Sawcer, Stephen ; Uccelli, Antonio ; Begovich, Ann B. ; Oksenberg, Jorge R. ; Lincoln, Robin R. ; Montalban, Xavier ; Hauser, Stephen L. ; Thomson, Glenys ; Deloa, Carolyn ; Ramsay, Patricia P. ; Barcellos, Lisa F. ; Briggs, Farren ; Compston, Alastair ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. / Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. In: Human Molecular Genetics. 2006 ; Vol. 15. pagg. 2813-2824.
    @article{b685462bd7e84586b1a43d0b80870041,
    title = "Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.",
    abstract = "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=7.8x10(-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=5.7x10(-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.",
    author = "Giovanni Savettieri and Cree, {Bruce C.A.} and Baranzini, {Sergio E.} and Pablo Villoslada and Stephen Sawcer and Antonio Uccelli and Begovich, {Ann B.} and Oksenberg, {Jorge R.} and Lincoln, {Robin R.} and Xavier Montalban and Hauser, {Stephen L.} and Glenys Thomson and Carolyn Deloa and Ramsay, {Patricia P.} and Barcellos, {Lisa F.} and Farren Briggs and Alastair Compston and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.}",
    year = "2006",
    language = "English",
    volume = "15",
    pages = "2813--2824",
    journal = "Human Molecular Genetics",
    issn = "0964-6906",
    publisher = "Oxford University Press",

    }

    TY - JOUR

    T1 - Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.

    AU - Savettieri, Giovanni

    AU - Cree, Bruce C.A.

    AU - Baranzini, Sergio E.

    AU - Villoslada, Pablo

    AU - Sawcer, Stephen

    AU - Uccelli, Antonio

    AU - Begovich, Ann B.

    AU - Oksenberg, Jorge R.

    AU - Lincoln, Robin R.

    AU - Montalban, Xavier

    AU - Hauser, Stephen L.

    AU - Thomson, Glenys

    AU - Deloa, Carolyn

    AU - Ramsay, Patricia P.

    AU - Barcellos, Lisa F.

    AU - Briggs, Farren

    AU - Compston, Alastair

    AU - Haines, Jonathan L.

    AU - Pericak-Vance, Margaret A.

    PY - 2006

    Y1 - 2006

    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=7.8x10(-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=5.7x10(-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=7.8x10(-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=5.7x10(-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.

    UR - http://hdl.handle.net/10447/27361

    UR - https://academic.oup.com/hmg/article/15/18/2813/643845?searchresult=1

    M3 - Article

    VL - 15

    SP - 2813

    EP - 2824

    JO - Human Molecular Genetics

    JF - Human Molecular Genetics

    SN - 0964-6906

    ER -