Deep brain stimulation and cognition in Parkinson's disease: An eight‐year follow‐up study

Neuroinflammation might be involved in the pathogenesis of most if not all neurodegenerative disorders. Polymorphisms in 2 immune system genes (HLA-DRB5, BST1) are firmly associated with Parkinson’s disease (PD) (http:// www.pdgene.org). Alpha-synuclein (a-Syn) activates microglia. The receptors mediating microglial activation by a-Syn are unknown. Pattern recognition receptors like nucleotidebinding oligomerization domain containing 2 (NOD2) are good candidates. We analyzed 3 single-nucleotide-polymorphisms (SNPs) in the NOD2 gene (R702W [rs2066844], G908R [rs2066845], and 3020insC [rs5743293]) using TaqMan genotyping in 3 large German case–control samples that have been described previously (Supporting Table 1). The study was approved by the local ethics committees, and written informed consent was obtained from all participants. Statistical analysis was performed using PLINK. All cross-tabulated data were assessed using Fisher’s exact statistics. All 3 SNPs had a call rate > 98% and were in Hardy– Weinberg equilibrium (P > .01). Power calculations showed that because of the low minor-allele frequencies, a large sample size of 1755 patients and 1450 controls is necessary to reliably detect odds ratios in the range of 1.5–2.0 (Supporting Figure 1). We did not find any evidence for association either in the combined sample (Table 1) or in the 3 subsamples (results not shown) under the dominant model or in the allelic model. The association statistics for the combination of all 3 SNPs also showed no significant difference between patients and controls (Table 1, Supporting Table 2). NOD2 belongs to the family of PRRs that not only recognize pathogen-associated molecular patterns (PAMPs) but also endogenous danger-associated molecular patterns (DAMPs). In Alzheimer’s disease NOD2 and TLR2 (toll-like receptor 2) receptors cooperate in the regulation of a receptor involved in amyloid beta 1–42 (ab1–42) recognition by microglia. PD and Alzheimer’s disease have many pathogenetic features including neuroinflammation in common. Both, a-synuclein and ab1–42 form fibrillar protein aggregates via oligomeric intermediates. The oligomeric intermediates share structural features. These findings led us to the hypothesis that NOD2 might also be involved in neuroinflammation related to PD. SNP selection was governed by (1) a previous study showing association with PD, (2) the finding that these SNPs account for more than 80% of all variant alleles in Crohn disease, and (3) the prior knowledge that these SNPs have a functional impact on NOD2. These 3 SNPs capture only a small part of the common genetic variability in the NOD2 gene. However, analysis of SNPs rs2111234, rs805734, rs11647841, rs2066843, rs10521209, rs5743289, rs207675, rs574329, and rs3135499, which did cover common variations in the whole NOD2 gene in a large GWAS sample of PD, also did not yield any significant disease associations in allelic, dominant, or recessive models (all P > .1; ref. 7 and personal communication T. Gasser). Our findings render it unlikely that genetic variation in NOD2 plays a major role in PD in German patients but does not preclude a functional role for NOD2 in the pathogenesis of PD.