LRRK2 外显子变异与多系统萎缩风险。
LRRK2 exonic variants and risk of multiple system atrophy.
机构信息
From the Section of Biostatistics (M.G.H., N.N.D.) and Departments of Neuroscience (A.I.S.-O., S.R., K.O., M.E.M., D.W.D., O.A.R.) and Neurology (S.F., W.P.C., R.J.U., Z.K.W.), Mayo Clinic, Jacksonville, FL; Department of Molecular Neuroscience (L.S., A.S., H.H.), Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Medical Genetics (M.J.F.), University of British Columbia, Vancouver, Canada; Laboratory of Neurogenetics (A.B.S.), National Institute on Aging, Bethesda, MD; Institute of Genetic Medicine (P.F.C., M.J.K.), Newcastle University, Central Parkway, Newcastle upon Tyne; Neuropathology Unit (S.M.G.), Department of Medicine, Imperial College London; Queen Square Brain Bank for Neurological Disorders (J.L.H., K.A.), Department of Molecular Neuroscience, UCL Institute of Neurology, University College London; Clinical and Cognitive Sciences Research Group (D.M.A.M.), Institute of Brain, Behavior and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford; and MRC London Neurodegenerative Diseases Brain Bank (S.A.-S., C.T.), King's College London, UK.
出版信息
Neurology. 2014 Dec 9;83(24):2256-61. doi: 10.1212/WNL.0000000000001078. Epub 2014 Nov 5.
OBJECTIVE
The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA).
METHODS
One series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association with MSA.
RESULTS
In the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio [OR] = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest single-variant association was again observed for p.M2397T (OR = 0.59, p = 0.0005).
CONCLUSIONS
These findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important.
目的
本研究旨在评估富含亮氨酸重复激酶 2（LRRK2）基因常见外显子变异与多系统萎缩（MSA）风险之间的关联。
方法
本病例对照研究纳入了一个来自美国的系列（92 例经病理证实的 MSA 患者，416 例对照）和另一个来自英国的系列（85 例经病理证实的 MSA 患者，352 例对照）。我们补充了来自美国的 53 例临床可能或确诊 MSA 患者的数据。对 17 种常见的 LRRK2 外显子变异进行基因分型，并评估其与 MSA 的关联。
结果
在 177 例经病理证实的 MSA 患者和 768 例对照的联合系列中，LRRK2 p.M2397T 与 MSA 之间存在显著关联（比值比 [OR] = 0.60，p = 0.002）。这种保护作用在美国系列中更为显著（OR = 0.46，p = 0.0008），而在英国系列中则不显著（OR = 0.82，p = 0.41）。我们还观察到其他与 MSA 相关的显著关联，包括 p.G1624G（OR = 0.63，p = 0.006）和 p.N2081D（OR = 0.15，p = 0.010）。p.G1624G-M2397T 单体型在美国系列（p < 0.0001）和联合系列（p = 0.003）中与 MSA 显著相关，但在英国系列中则不相关（p = 0.67）。当额外纳入美国的临床 MSA 患者时，结果仍然一致，其中 p.M2397T 再次表现出最强的单变量关联（OR = 0.59，p = 0.0005）。
结论
这些发现提供了证据表明 LRRK2 外显子变异可能导致 MSA 的易感性。在其他系列和荟萃分析研究中的验证将是重要的。
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