The TREM2 variant p.R47H is a risk factor for sporadic amyotrophic lateral sclerosis

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作者：

M Harms，J Cady，E Koval，B Benitez，C Zaidman，J Jockelbalsarotti，P Allred，R Baloh，J Ravits，E Simpson

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摘要：

To determine if p.R47H (rs75932628) in is a risk factor for ALS and assess whether expression is dysregulated in disease.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating gene was found to increase the risk of several neurodegenerative diseases, including Alzheimer's disease. Whether the p.R47H variant is a risk factor for ALS is not currently known.923 sporadic ALS subjects and 1854 normal controls self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in . Clinical data was obtained on ALS subjects for genotype/phenotype correlations. Expression of was measured by quantitative PCR and compared in spinal cord from 18 ALS subjects, 12 neurologically normal controls, as well as from wildtype and transgenic SOD1mice.The variant p. R47H was more common in subject with ALS than in controls and is therefore a significant risk factor for ALS (OR=2.40; 95%CI=1.29-4.15; p=4.1x10). Furthermore, expression was increased in spinal cords from ALS patients and SOD1mice (p=2.8x10, p=2.8x10respectively), confirming dysregulated TREM2 in disease. expression in human spinal cord was negatively correlated with survival (p=0.04), but not other phenotypic aspects of disease.The p.R47H variant is a potent risk factor for sporadic amyotrophic lateral sclerosis. These findings identify the first genetic influence on neuro-inflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases.National Institutes of Health (NIH) grants K08-NS075094 (M.B.H.), R01-AG044546 (C.C.), R01-NS078398-02 (T.M.M.), R01-NS069669 (R.H.B.), 5 T32 HL 83822-5 (J.C.), UL1 RR024992, and the Hope Center for Neurological Disorders at Washington University.

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DOI：

10.1001/jamaneurol.2013.6237

被引量：

226

年份：

2014