Linkage analysis of HLA class II Genes in Swedish multiplex families with multiple sclerosis

Abstract

We assessed the influence of human leukocyte antigen (HLA) class II as susceptibility genes in multiple sclerosis (MS) by linkage analysis. Other research groups, who have shown negative results in studies on affected sibling pairs, have questioned the influence of the HLA class II genes, although they confirmed the association of the DR15,DQ6,Dw2 haplotype to MS. In this report, we find a significant lod score (>3) when using a 2-point linkage analysis of 49 small Swedish nuclear MS families with at least two affected family members, typed for HLA class II alleles by PCR amplification with sequence-specific primers. We obtained maximum lod scores when we used dominant or intermediate models with low penetrance. We found that the positive effect on the total lod score was not confined to those families carrying the presumed susceptibility HLA-haplotype Dw2. This observation supports the notion of a functional role of the HLA class II molecules themselves in MS. In addition, we observed significant transmission distortion and an intrafamilial association of the MS-associated class II haplotype HLA-Dw2. These results indicate that the HLA class II genes are of clear importance for MS in the studied population.

Inheritance mode of multiple sclerosis: the effect of HLA class II alleles is stronger than additive

“…Using different parametric and nonparametric methods, many studies aimed to investigate the presence of linkage between MS and loci in the HLA region or association with specific alleles (Clerget-Darpoux et al 1984;Eoli et al 1995;Epplen et al 1997;Fogdell et al 1997;Haile et al 1981;Haines et al1998;Ho et al 1982;Kellar-Wood et al 1995;Oturai et al 1999;Payami et al 1986;Risch 1986;Sherman et al 1986;Stewart et al 1981;Thomson 1983;Tienari et al 1994;Tiwari et al 1980). These investigators applied dominant, intermediate and recessive models, based on former studies or theoretical arguments.…”

Multiple sclerosis complexity in selected populations: the challenge of Sardinia, insular Italy1

“…Whole genome screen (Ebers et al ., 1996; Sawcer et al ., 1996; The Multiple Sclerosis Genetics Group, 1996) and linkage analysis in multiplex families (Fodgell et al ., 1997; Kuokkanen et al ., 1997; The Multiple Sclerosis Genetics Group, 1998) confirmed a susceptibility role of the human leucocyte antigen (HLA) genes. All studies are concordant with the conclusion that HLA haplotypes contribute, although modestly, to overall susceptibility and that a relatively large number of other major human histocompatibility complex (MHC) or non‐MHC genes with individually small effect may be responsible for predisposition to MS.…”

Incidence of multiple sclerosis among European Economic Area populations, 1985-2009: the framework for monitoring

“…Despite intensive research over decades and early identification of susceptibility genes [1], its aetiology remains poorly known, with more than 50 susceptibility alleles identified and a considerable proportion of these regulated by Vitamin D [2,3]. Environmental factors, probably acting before adulthood, also appear to be implicated, as reflected by birth-cohort and season-of-birth effects [4,5], selected results of twin studies [6] and changing incidence among populations migrating to environments with different risk [7].…”