RESUMEN
Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.
Asunto(s)
Cromosomas Humanos Par 6/genética , Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Esclerosis Múltiple/genética , Adolescente , Adulto , Anciano , Alelos , Niño , Femenino , Efecto Fundador , Variación Genética , Cadenas beta de HLA-DP , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Italia , Desequilibrio de Ligamiento , Masculino , Repeticiones de Microsatélite , Persona de Mediana EdadRESUMEN
A minisatellite polymorphism located in the 3' flanking region of the interleukin-6 (IL-6) gene was analysed in 192 Sardinian simplex families with multiple sclerosis (MS). By applying a high-resolution sizing approach, 9 alleles were identified. None of these were associated with in globo susceptibility to MS as shown by transmission disequilibrium testing. Analysis of clinically different groups showed that the A5 allele was associated with a benign (P = 0.007) but not with a malignant (P = 0.45) course of disease. In particular, the frequency of the A5/A5 genotype was significantly higher in patients with benign MS (P = 0.002). In addition, carriage of any of the larger alleles (A6-->A9) was associated with accelerated onset of disease (P = 0.025). Our results suggest that allelic variations in the IL-6 gene may predispose to alterations in the course and initial onset of MS.