T Cells of the Immune System Are ImplicatedThe 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 StudiesRisch 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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UCSF Today, June 12, 2006
- UCSF Sleep Disorders Center