Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.
Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.
复制标题
作者：
帕金森病 (PD) 是一种导致运动和认知障碍的常见疾病。我们对来自 NeuroGenetics Research Consortium 的 2000 名 PD 受试者和 1986 名对照白种人受试者进行了一项全基因组关联研究 (GWAS)。我们确认了SNCA和MAPT；复制 GAK (PPankratz+NGRC=3.2×10−9)；并检测到与 HLA (PNGRC=2.9×10−8) 的新关联，该关联在两个数据集中复制 (PMeta-analysis=1.9×10−10)。我们将新的 PD 基因命名为 PARK17 (GAK) 和 PARK18 (HLA)。 PD-HLA 关联在遗传和环境风险层中是一致的，并且在散发性 (P=5.5×10−10) 和迟发性 (P=2.4×10−8) PD 中很强。关联峰位于 rs3129882，这是 HLA-DRA 中的非编码变体。两项研究表明 rs3129882 影响 HLA-DR 和 HLA-DQ 的表达。 PD 大脑表现出 DR 抗原的上调和 DR 阳性反应性小胶质细胞的存在。此外，非甾体类抗炎药（NSAID）可降低帕金森病风险。与 HLA 的遗传关联整合了免疫系统参与的证据，并为药物开发和药物遗传学提供了新的目标。
Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and 1986 control Caucasian subjects from NeuroGenetics Research Consortium. We confirmed SNCA and MAPT; replicated GAK (PPankratz+NGRC=3.2×10−9); and detected a novel association with HLA (PNGRC=2.9×10−8) which replicated in two datasets (PMeta-analysis=1.9×10−10). We designate the new PD genes PARK17 (GAK) and PARK18 (HLA). PD-HLA association was uniform across genetic and environmental risk strata, and strong in sporadic (P=5.5×10−10) and late-onset (P=2.4×10−8) PD. The association peak was at rs3129882, a non-coding variant in HLA-DRA. Two studies suggested rs3129882 influences expression of HLA-DR and HLA-DQ. PD brains exhibit up-regulation of DR antigens and presence of DR-positive reactive microglia. Moreover, non-steroidal anti-inflammatory drugs (NSAID) reduce PD risk. The genetic association with HLA coalesces the evidence for involvement of the immune system and offers new targets for drug development and pharmacogenetics.
登录
查看更多内容
影响因子：
11.2
作者：
Hernán, MA;Takkouche, B;Gestal-Otero, JJ
通讯作者：
Gestal-Otero, JJ
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.5
作者：
通讯作者：
--
影响因子：
9.9
作者：
MCGEER, PL;ITAGAKI, S;MCGEER, EG
通讯作者：
MCGEER, EG
影响因子：
9.8
作者：
Maraganore, DM;de Andrade, M;Ballinger, DG
通讯作者：
Ballinger, DG