The overall objective of this study is to clarify the association of genes within the major histocompatibility complex (MHC) with narcolepsy and idiopathic central nervous system (CNS) hypersomnia in white and black individuals from the southeastern region of the United States. There are two hypothesis to be tested. Firstly, it is hypothesized that by use of genetic and clinical variables narcolepsy can be divided into additional disease subgroups than has heretofore been defined. Secondly, it is hypothesized that a gene tightly linked to the HLA-D region, is more closely associated with narcolepsy than serologically defined DR2 or DQwl. The finding of DR2, DQwl negative narcoleptics as well as the difference in the frequency of these genes in black as opposed to white narcoleptic subjects support this latter contention. In order to test these hypotheses white and black subjects who present with clinically well--defined narcolepsy or idiopathic CNS hypersomnia will be identified and assessed with regard to their clinical features and family history of disease. The frequency of HLA-DR and DQ phenotypes in cases will be compared with the frequency in healthy age, race, and sex matched controls selected from the same geographic region. Utilizing DNA probes that recognize nucleotide sequences within the D region of the MHC the frequency of restriction fragment length polymorphisms (RFLPS) between cases and controls will also be compared. Families where one or more additional members other than the proband are affected with narcolepsy, or one of the various forms of idiopathic CNS hypersomnia will be selected and the members HLA phenotyped. These families will be utilized to conduct a formal segregation and linkage analysis in an attempt to determine the mode of inheritance of narcolepsy and/or idiopathic CNS hypersomnia. The RFLPs found associated with these disorders in the population study will be evaluated with regard to their segregation in multiply affected families. Lastly, the HLA-D region genes that are found to be associated in population studies with narcolepsy and/or idiopathic CNS hypersomia and which segregate with the disease in family studies will be sequenced. These genomic sequences will be compared with their counterparts in matched controls in order to determine if there are genetic variants unique to narcolepsy and/or idiopathic CNS hypersomnia. This study is an opportunity to more clearly define the role of MHC genes in the etiology of these disorders which might suggest possible strategies for prevention or control.
| Acton, R T; Harman, L; Go, R C et al. (1993) Comparison of HLA phenotypes among African Americans from Alabama, Maryland, and North Carolina. Transplant Proc 25:2404-7 |
