Association between Parkinson%26apos;s disease and the HLA-DRB1 locus

作者：Ahmed Ismail^*; Tamouza Ryad; Delord Marc; Krishnamoorthy Rajagopal; Tzourio Christophe; Mulot Claire; Nacfer Magali; Lambert Jean Charles; Beaune Philippe; Laurent Puig Pierre; Loriot Marie Anne; Charron Dominique; Elbaz Alexis

来源：Movement Disorders, 2012, 27(9): 1104-1110.

DOI：10.1002/mds.25035

• Parkinson%26apos
• s disease
• case-control
• genetics
• major histocompatibility complex

Two genome-wide association studies (GWASs) recently highlighted the HLA-DRA and HLA-DRB5 genes as associated with Parkinson disease (PD). However, because HLA-DRA displays a low level of polymorphisms and HLA-DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA-DR region; (2) to identify PD-associated HLA alleles; and (3) to perform a meta-analysis of our top finding. As part of 2 French population-based casecontrol studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single-nucleotide polymorphisms (SNPs) in the HLA-DR region. HLA-DRB1 alleles were imputed using the HLA*IMP software. HLA typing was performed in a subsample of the participants. We performed a meta-analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.570.87) within the HLA-DRB1 gene, which encodes the most polymorphic HLA-DR chain (DR beta). A meta-analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.820.91; P %26lt; .0001). SNP-based imputation of HLA alleles showed an inverse association between PD and the HLA-DRB1*04 allele. We replicated an association between PD and the HLA-DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA-DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology.