HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis.
A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS). In parallel, a linkage disequilibrium analysis using 650 single nucleotide polymorphisms (SNP) markers of the HLA complex mapped the entire genetic effect to the HLA-DR-DQ subregion, reflected by the well-established risk haplotype HLA-DRB1*15,DQB1*06. Contrary to this, in a cohort of 1,084 MS patients and 1,347 controls, we show that the HLA-A gene confers an HLA-DRB1 independent influence on the risk of MS (P = 8.4x10(-10)). This supports the opposing view, that genes in the HLA class I region indeed exert an additional influence on the risk of MS, and confirms that the class I allele HLA-A*02 is negatively associated with the risk of MS (OR = 0.63, P = 7x10(-12)) not explained by linkage disequilibrium with class II. The combination of HLA-A and HLA-DRB1 alleles, as represented by HLA-A*02 and HLA-DRB1*15, was found to influence the risk of MS 23-fold. These findings imply complex autoimmune mechanisms involving both the regulatory and the effector arms of the immune system in the triggering of MS.
Brynedal
Boel
B
Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. boel.brynedal@ki.se
Duvefelt
Kristina
K
Jonasdottir
Gudrun
G
Roos
Izaura M
IM
Akesson
Eva
E
Palmgren
Juni
J
Hillert
Jan
J
D017931:DNA Primers / Q000235:genetics; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D012044:Regression Analysis; D012307:Risk Factors; D013548:Sweden
D017931:DNA Primers; D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains