Narcolepsy-cataplexy affects 0.05% of the US population. The cause of the disorder is a loss of hypocretin/orexin neurons in the hypothalamus, of likely autoimmune origin. The disease is uniquely tightly associated with Human Leukocyte Antigen (HLA) DQB1*0602, and may serve as a model to the study of other autoimmune diseases affecting the brain. A weaker association with the T-Cell receptor (TCR) loci is also found. The focus of this application is to sequence the HLA-DQA1 and DQB1 exons and promoter region in 4,000 controls and 3,500 patients with DQB1*0602 like haplotypes. Patients and controls will include Asians, Caucasians and African Americans. The ultimate goal of this project is to determine which DQA1 and DQB1 amino acids are involved in disease susceptibility, and to model the DQ heterodimer binding site involved. Together with work ongoing in the TCR arena, this project offers the opportunity to model the HLA-peptide-TCR trimolecular complex involved in narcolepsy susceptibility. It will also make use of the newly developed FLX 454 titanium sequencing technique to generate and analyze high throughput, low cost full HLA DQA1 and DQB1 sequence, and to develop and perfect new statistical analytic tools, such as the Sequence Variant Type Analysis (SFVT), for disease association studies.

Public Health Relevance

(provided by applicant): Narcolepsy affects 1/2000 Americans and is a common neurological disorder. The proposed study may lead to new therapeutic avenues for the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS073581-03
Application #
8259851
Study Section
Special Emphasis Panel (ZAI1-MFH-I (M3))
Program Officer
Utz, Ursula
Project Start
2010-08-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$380,734
Indirect Cost
$142,775
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Han, Fang; Lin, Ling; Schormair, Barbara et al. (2014) HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep 37:1601-8