Gene Found in Sudden Sleep Disorder Implicates the Immune System

Neil Risch

Narcolepsy, a sleep disorder that causes alert individuals to suddenly nod off, now has been traced to a specific gene that helps guide targeted attacks by cells of the immune system. According to a report by UCSF and Stanford researchers that was published online this month in the scientific journal Nature Genetics, the evidence points to an autoimmune cause for narcolepsy. An autoimmune disease is one in which the immune system attacks the body’s own tissues. The seemingly strange link to this peculiar disorder – those afflicted nearly instantaneously lose muscle tone and enter a dream state from which they may be difficult to arouse — has been suspected for several years. However, nobody previously had convincingly demonstrated a link between narcolepsy and the possible trigger of an autoimmune response. The discovery may lead to new insights into other autoimmune diseases, the list of which has grown and includes some fairly common diseases. Years ago, researchers identified an association between narcolepsy and DNA in a region of human chromosome number 6. The location on the chromosome is home to the same HLA genes used to match organ donors and recipients to prevent transplant rejection. “This is a collection of loci that modulates immune responses,” says Neil Risch, PhD, a senior scientist on the Nature Genetics study and head of the Institute for Human Genetics at UCSF. “Many of these genes are associated with a large array of autoimmune diseases, including type 1 diabetes, lupus, multiple sclerosis and rheumatoid arthritis.” But that association was not proof of an autoimmune cause for narcolepsy, such as has been shown in type 1 diabetes. In type 1 diabetes, antibody proteins made and secreted by cells of the immune system target beta cells of the pancreas. This latest narcolepsy genetics study was launched by Risch and Stanford collaborators Joachim Hallmayer, MD, and Emmanuel Mignot, MD, PhD, to identify additional genes that could play a role in autoimmune responses in narcolepsy. Risch, along with UCSF colleague Pui-Yan Kwok, MD, PhD, and his lab group, analyzed DNA, comparing study subjects with and without narcolepsy.

T Cells of the Immune System Are Implicated

The new evidence that narcolepsy is an autoimmune disease is the finding that the disorder is associated with particular inherited variations in a gene that encodes a protein found on a type of immune cell. This cell type, called a T cell, play a crucial role in targeting immune responses. The researchers initially studied more than 1,800 Caucasians. All had the previously identified HLA gene variant. More than 800 had narcolepsy, but the rest did not. The researchers identified a nearly twofold elevated risk for narcolepsy associated with variations in a gene that encodes a protein called T-cell receptor alpha. They confirmed their initial findings in additional studies of Caucasians, Asians and African Americans. Researchers had previously suspected a role for T-cell receptor variants in autoimmune diseases, and had searched for associations, but this is the first time one has emerged from such a study. “This is a disease that nobody suspected was autoimmune until a very strong association with HLA was identified,” Risch says. “That was shocking — as is this new finding. People have previously scoured T-cell receptor genes, searching for an association with disease, and until now nobody had found any. “It could be that variations in T-cell receptors are associated with other autoimmune diseases, but the associations may be weaker and harder to define.” Mignot first discovered a decade ago that dogs with narcolepsy have defects in the gene that encodes hypocretin, a hormone that helps dogs — and humans — stay awake. Researchers expected to find a similar genetic cause in humans, but never did. The hypocretin gene is normal in humans with narcolepsy, even though they are indeed deficient in hypocretin. That led Mignot to speculate that an autoimmune response might be destroying specialized cells that secrete the hormone. Japanese researchers initially identified the HLA association. Soon afterward, Mignot pinpointed its chromosomal location, as well as the genetic variant responsible. Nearly everyone with the disorder has inherited this particular HLA genetic variant. However, few who inherit the variation are ever afflicted with the disorder. Inheritance of certain T-cell receptor variants, along with the HLA variant, greatly increases that risk. However, this is not necessarily information that individuals at risk can immediately take advantage of. “On an individual level, it may not be that meaningful if, say, your risk increases from 1 percent to 2 percent,” Risch says. “But if you are talking about the disease burden for an entire population, it becomes more significant.” According to the research team’s estimates of “attributable risk,” if the most significant T-cell receptor variant identified were absent in humans, Caucasian populations would have roughly 20 percent fewer cases of narcolepsy, and Asian populations would have about 42 percent fewer cases, because the associated variant is more common in Asians.

Genome-wide Association Studies

Risch first proposed doing genome-wide association studies to search for disease-risk genes in an open-ended way more than a decade ago. Since then, this type of global gene scan has not only become a reality, but has also become very popular. The cost has plummeted, as Risch had foreseen. Still, the value of these genome-wide studies has recently been called into question because the individual contribution to disease risk for the genes identified tends to be small. The roughly twofold increased risk identified for the most strongly associated of three T-cell receptor alpha variants identified in the current study actually is large for a genetic variant identified through a genome-wide association study, Risch says. But the primary value of these studies may be to increase what is known about how and why diseases arise, rather than to serve as preliminary work for developing new disease screening or diagnostics tests, according to Risch, who played a central role in designing the Nature Genetics study. “I think the significance of what we find in these studies is that they provide insights into how to think about disease mechanisms, and ultimately can lead to new disease prevention and treatment strategies. “For instance, in narcolepsy, I don’t think one could have gathered evidence in any other way to demonstrate that this is, in fact, an autoimmune disease.”

Narcolepsy Is Strongly Associated with the T-Cell Receptor Alpha Locus

Joachim Hallmayer, Juliette Faraco, Ling Lin, Stephanie Hesselson, Juliane Winkelmann, Minae Kawashima, Geert Mayer, Giuseppe Plazzi, Sona Nevsimalova, Patrice Bourgin, Sheng Seung-Chul Hong, Yutaka Honda, Makoto Honda, Birgit Hög, William T. Longstreth Jr., Jacques Montplaisir, David Kemlink, Mali Einen, Justin Chen, Stacy L. Musone, Matthew Akana, Taku Miyagawa, Jubao Duan, Alex Desautels, Christine Erhardt, Per Egil Hesl, Francesca Poli, Birgit Frauscher, Jong-Hyun Jeong, Sung-Pil Lee, Thanh G. N. Ton, Mark Kvale, Libor Kolesar, Marie Dobrovolná, Gerald T. Nepom, Dan Salomon, H-Erich Wichmann, Guy A. Rouleau, Christian Gieger, Douglas F Levinson, Pablo V. Gejman, Thomas Meitinger, Terry Young, Paul Peppard, Katsushi Tokunaga, Pui-Yan Kwok, Neil Risch and Emmanuel Mignot

Nature Genetics (Published online May 3, 2009)

Abstract | Full Text

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