The narcolepsy-associated DRw15,DQw6,Dw2 haplotype has no unique HLA-DQA or -DQB restriction fragments and does not extend to the HLA-DP subregion

Abstract

Almost all patients with cataplectic narcolepsy are DR2-positive. It has been suggested that the non-DR2 allele/haplotype might not be neutral with respect to disease susceptibility. It has also been reported that Taq I DQA and Bam HI, Eco RI, Eco RV, and Pst I DQB restriction fragments might differentiate between narcoleptic and healthy DR2-positive individuals. In the present study, HLA class II gene polymorphisms were investigated by restriction fragment length polymorphism (RFLP) analysis in 47 Swedish patients with cataplectic narcolepsy, 100 random controls, and DR2-associated homozygous cell lines. All patients had Taq I DRB-DQA-DQB patterns corresponding to the DRw15,DQw6,Dw2 haplotype. The non-DR2 haplotype was found to be neutral. This genotyped group of patients allows firm rejection of a recessive mode of inheritance and supports a dominant or additive model. No DQA or DQB RFLPs were found that could differentiate between DR2-positive narcoleptics, DRw15,DQw6,Dw2-positive controls, or Dw2-homozygous cell lines. No significant Msp I HLA-DP association was found. No linkage disequilibrium was observed between the DRw15,DQw6,Dw2 haplotype and alleles of the DP subregion in patients or controls. Thus, the HLA-D region-associated narcolepsy susceptibility gene may be located telomeric to the HLA-DP subregion. No RFLPs have been observed that can locate the narcolepsy susceptibility gene closer to the DQ than to the DR subregion.