Extensive HLA class II studies in 58 non‐DRB1*15 (DR2) narcoleptic patients with cataplexy

Abstract

Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narcolepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0102 and DQB1*0602, a DQ1 subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.

Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis

“…PCR primers and conditions were comparable to those of the previous papers, for D6S276 [28,29], MIB [30], TNFa [31,32], TNFd [32], D6S273 [33], DQ-CARII [34], T16CAR [34], D6S2443 [35], D6S2444 [35], TAP1 [36], and D6S439 [27]. PCR-amplified products were denatured for 5 min.…”

Diretrizes brasileiras para o diagnóstico de narcolepsia

“…7 There is a significant association of narcolepsy with the DQB1*0602 allele of the major histocompatibility complex (HLA). The prevalence rate of HLA-DQB1*0602 is 88% to 98% in the narcoleptic population with cataplexy, 40% to 60% in the narcoleptic population without cataplexy, and 12% to 34% in the general population [8][9][10][11][12][13] (Table 1). In the southeastern population of Brazil, the prevalence of HLA-DQB1*0602 is 13.6% among Caucasians 14 and 14.30% in Mulattos.…”

Genetic Studies in the Sleep Disorder Narcolepsy

“…More than 90% of narcolepsy-cataplexy patients across all ethnic groups carry a specific allele of HLA DQB1, DQB1*0602 (Matsuki et al 1992;Mignot et al 1994); this allele is present in 12%-38% of the general population across many ethnic groups (Matsuki et al 1992;Mignot et al 1994; Lin et al 1997). DQB1*0602 is associated almost exclusively with DR2 in Japanese (Lin et al 1997) and Caucasians (Begovich et al 1992), whereas it is observed frequently in association with DR2, DR5, or other DR subtypes in African-Americans (Mignot et al 1994(Mignot et al , 1997a. The increased DR-DQ haplotypic diversity in African-Americans explains the low DR2 association observed in this population.…”

“…DQB1*0602 is associated almost exclusively with DR2 in Japanese (Lin et al 1997) and Caucasians (Begovich et al 1992), whereas it is observed frequently in association with DR2, DR5, or other DR subtypes in African-Americans (Mignot et al 1994(Mignot et al , 1997a. The increased DR-DQ haplotypic diversity in African-Americans explains the low DR2 association observed in this population.To further characterize the DQB1 region in narcoleptic subjects, novel polymorphic markers were isolated and characterized (Mignot et al 1997a). The markers tested included six novel microsatellite markers (DQCAR, DQCARII, G51152, DQRIV, T16CAR, and G411624R).…”

“…Other haplotypes with DQA1*0102 but not DQB1*0602, such as DQA1*0102 and DQB1*0604, are frequent in control populations in all ethnic groups and do not predispose to narcolepsy. DQA1*0102 alone is thus not likely to confer susceptibility but may be involved in addition to DQB1*0602 for the development of narcolepsy (Mignot et al 1994(Mignot et al , 1997a.Microsatellite analysis in the HLA DQ region revealed that only the area surrounding the coding regions of DQB1 and DQA1 is well conserved across all susceptibility haplotypes. Polymorphism can be observed in microsatellite and/or in the promoter regions flanking the DQB1*0602 and DQA1*0102 alleles and in the region between these two genes (Mignot et al 1997a).…”