Causal Role Found for Common Genetic Variant in Narcolepsy

An extraordinary association has been found between a specific gene variant related to the human leukocyte antigen immune system and narcolepsy.

Narcolepsy may be caused by an autoimmune response to an environmental trigger such as an infection and in people who are genetically susceptible to narcolepsy, the immune system may respond to the trigger by mistakenly attacking and destroying brain cells that make hypocretin, a hormone that helps promote alertness.


A large team of European scientists led by those at the University of Lausanne (Switzerland) performed a modified genome-wide association study involved 1,261 people with narcolepsy. This represented nearly 90% of European patients suffering from narcolepsy with cataplexy who have complete diagnostic work-up and DNA available. They were matched with 1,422 controls. High-resolution genotyping identified genetic variants including those in the human leukocyte antigen (HLA) system, which contains genes related to immune system function. Analysis was performed by logistic regression.

The investigators found that participants with the major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) allele DQB1*06:02 were 251 times more likely to have narcolepsy with cataplexy than participants without the gene variant. This gene variant had a remarkably high negative predictive value of 99.32%, which means that nearly 100% of narcolepsy with cataplexy patients are DQB1*06:02 positive. Four other DQB1 alleles provided protection against narcolepsy, strongly supporting a causal role for DQB1 in narcolepsy. They suggested that high-resolution genotyping could play a valuable role in diagnosing patients suspected of having narcolepsy and evaluating at-risk populations.

Mehdi Tafti, PhD, the lead author and a professor in the Center for Integrative Genomics, said, “For the first time we have tested the HLA association all over Europe. This almost 100% association with HLA is somehow unique to narcolepsy and suggests a causal implication.” People with narcolepsy experience repeated daily episodes of an irrepressible need to sleep or lapses into sleep, which may occur as sudden, irresistible sleep "attacks." Another common symptom of narcolepsy is cataplexy, which involves sudden muscle weakness caused by strong emotions such as laughter. The study was published in January 2014 issue of the journal SLEEP.

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