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This study reports extensive genomic data for both human leukocyte antigen (HLA) class I and II loci in Norwegian Sami, a native population living in the northwest of Europe. The Sami have a distinct culture and their own languages, which belong to the Uralic linguistic family. Norwegian Sami (n = 200) were typed at the DNA level for the HLA-A, -C, -B, -DRB1 and -DQB1 loci, and compared with a non-Sami Norwegian population (n = 576). The two populations exhibited some common genetic features but also differed significantly at all HLA loci. The most significantly deviating allele frequencies were an increase of HLA-A*03, -B*27, -DRB1*08 and -DQB1*04 and a decrease of HLA-A*01, C*01, -DRB1*04 and -DQB1*02 among Sami compared with non-Sami Norwegians. The Sami showed no deviation from Hardy-Weinberg equilibrium. The hypothesis of selective neutrality was rejected at all loci except for the A- and C- loci for the Sami. HLA haplotype frequencies also differed between the two populations. The most common extended HLA haplotypes were A*02-B*27-C*01-DR*08-DQB1*04 in the Sami and A*01-B*08-C*07-DR*03-DQB1*02 in the other Norwegians. Genetic distance analyses indicated that the Norwegian Sami were highly differentiated from other Europeans and were most closely related to Finns whose language also belongs to the Uralic linguistic family. In conclusion, the Norwegian Sami and the non-Sami Norwegians were significantly different at all HLA loci. Our results can be explained by the fact that the two populations have different origins and that the Sami population has remained smaller and more isolated than its neighbors.

This study confirms a low frequency of multiple sclerosis (MS) among Sami. Only 12 Sami with a diagnosis of MS were identified in the Norwegian Sami population, which represents a significantly lower prevalence of MS in Sami (30/10(5)) compared with other Norwegians (73-164/10(5)). The clinical characteristics as well as the results of human leukocyte antigen (HLA)-DRB1 and -DQB1 typing of the Sami MS patients are reported, showing that three (27%) of the Sami MS patients carried the MS-associated HLA-DRB1*15-DQB1*06 haplotype. Interestingly, the DRB1*15-DQB1*06 haplotype had a significantly reduced frequency among Sami controls (0.086) compared with non-Sami Norwegian controls (0.163) (P(corrected) = 0.015). The low frequency of the disease-associated DRB1*15-DQB1*06 haplotype in the Sami population may contribute to the low prevalence of MS in Sami, in addition to other yet unidentified genetic and environmental factors.

In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS.