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HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis.

Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, Hillert J - PLoS ONE (2007)

Bottom Line: A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. boel.brynedal@ki.se

ABSTRACT
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.

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Related in: MedlinePlus

Empirical odds ratios (ORs) for combinations of the HLA-DRB1*15 and HLA-A*02 alleles.A genotype of two HLA-A*02 alleles but no HLA-DRB1*15 allele was used as baseline in the calculation of ORs. P values are reported above the bars.
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pone-0000664-g001: Empirical odds ratios (ORs) for combinations of the HLA-DRB1*15 and HLA-A*02 alleles.A genotype of two HLA-A*02 alleles but no HLA-DRB1*15 allele was used as baseline in the calculation of ORs. P values are reported above the bars.

Mentions: It has previously been reported that HLA-DRB1*15 exerts an allele dose effect on the risk of MS [16], [17]. Figure 1 illustrates how the genotypes of HLA-DRB1 and HLA-A jointly modified the empirical OR's of MS, the most susceptible genotypes (homozygosity for DRB1*15 but no A*02) and most resistant (homozygosity for A*02 but no DRB1*15) genotypes differed 23 fold in the risk of MS. The magnitude of the risk jointly conferred by these loci greatly exceeds the relative risk of 3.5 typically seen for carriage of HLA-DRB1*15. This indicates that genes in the HLA region may confer a larger fraction of the genetic aetiology of MS than previously thought. This notion is further supported by the results of recent MS linkage analyses; in these studies, with increasing power of the analysis, the HLA locus has gradually obtained higher LOD scores, eventually exceeding 11, while all other candidate loci have remained insignificant[18], [19]. Recently, Yeo and co-workers reported an association with several alleles of HLA-DRB1, together with a negative association with the HLA class I allele HLA-C*05 in patients lacking DRB1 risk alleles, a finding which supports the importance of HLA class I genes in MS [9]. However, it remains to be studied whether the HLA-C locus contributes to MS susceptibility in our population, and, if so, whether there may be a confounding effect of LD between HLA-A*02 and HLA-C*05.


HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis.

Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, Hillert J - PLoS ONE (2007)

Empirical odds ratios (ORs) for combinations of the HLA-DRB1*15 and HLA-A*02 alleles.A genotype of two HLA-A*02 alleles but no HLA-DRB1*15 allele was used as baseline in the calculation of ORs. P values are reported above the bars.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1919434&req=5

pone-0000664-g001: Empirical odds ratios (ORs) for combinations of the HLA-DRB1*15 and HLA-A*02 alleles.A genotype of two HLA-A*02 alleles but no HLA-DRB1*15 allele was used as baseline in the calculation of ORs. P values are reported above the bars.
Mentions: It has previously been reported that HLA-DRB1*15 exerts an allele dose effect on the risk of MS [16], [17]. Figure 1 illustrates how the genotypes of HLA-DRB1 and HLA-A jointly modified the empirical OR's of MS, the most susceptible genotypes (homozygosity for DRB1*15 but no A*02) and most resistant (homozygosity for A*02 but no DRB1*15) genotypes differed 23 fold in the risk of MS. The magnitude of the risk jointly conferred by these loci greatly exceeds the relative risk of 3.5 typically seen for carriage of HLA-DRB1*15. This indicates that genes in the HLA region may confer a larger fraction of the genetic aetiology of MS than previously thought. This notion is further supported by the results of recent MS linkage analyses; in these studies, with increasing power of the analysis, the HLA locus has gradually obtained higher LOD scores, eventually exceeding 11, while all other candidate loci have remained insignificant[18], [19]. Recently, Yeo and co-workers reported an association with several alleles of HLA-DRB1, together with a negative association with the HLA class I allele HLA-C*05 in patients lacking DRB1 risk alleles, a finding which supports the importance of HLA class I genes in MS [9]. However, it remains to be studied whether the HLA-C locus contributes to MS susceptibility in our population, and, if so, whether there may be a confounding effect of LD between HLA-A*02 and HLA-C*05.

Bottom Line: A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. boel.brynedal@ki.se

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus