BACKGROUND: Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.
BACKGROUND:Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.
Authors: Cory Teuscher; Janice Y Bunn; Parley D Fillmore; Russell J Butterfield; James F Zachary; Elizabeth P Blankenhorn Journal: Am J Pathol Date: 2004-11 Impact factor: 4.307
Authors: Jorge R Oksenberg; Lisa F Barcellos; Bruce A C Cree; Sergio E Baranzini; Teodorica L Bugawan; Omar Khan; Robin R Lincoln; Amy Swerdlin; Emmanuel Mignot; Ling Lin; Douglas Goodin; Henry A Erlich; Silke Schmidt; Glenys Thomson; David E Reich; Margaret A Pericak-Vance; Jonathan L Haines; Stephen L Hauser Journal: Am J Hum Genet Date: 2003-12-10 Impact factor: 11.025
Authors: Tai Wai Yeo; Philip L De Jager; Simon G Gregory; Lisa F Barcellos; Amie Walton; An Goris; Chiara Fenoglio; Maria Ban; Craig J Taylor; Reyna S Goodman; Emily Walsh; Cara S Wolfish; Roger Horton; James Traherne; Stephan Beck; John Trowsdale; Stacy J Caillier; Adrian J Ivinson; Todd Green; Susan Pobywajlo; Eric S Lander; Margaret A Pericak-Vance; Jonathan L Haines; Mark J Daly; Jorge R Oksenberg; Stephen L Hauser; Alastair Compston; David A Hafler; John D Rioux; Stephen Sawcer Journal: Ann Neurol Date: 2007-03 Impact factor: 10.422
Authors: Bruce A C Cree; David E Reich; Omar Khan; Philip L De Jager; Ichiro Nakashima; Toshiyuki Takahashi; Amit Bar-Or; Christine Tong; Stephen L Hauser; Jorge R Oksenberg Journal: Arch Neurol Date: 2009-02