A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease

Background: NURR1 plays a key role in mesencephalic dopaminergic neuron development and survival. A homozygous NURR1 polymorphism (a single base-pair insertion in intron 6) (NI6P) has been reported to be associated with Parkinson disease (PD). Objective: To assess the association of the N16P with PD and diffuse Lewy body disease. Design: Case-control study. Setting: Movement disorders clinic and tissue provided by brain banks. Patients: Patients with pathologically proven PD (n=37) or diffuse Lewy body disease (n = 35)., neuropathologically normal control subjects (n = 59), those clinically diagnosed as having PD (n=66), and spousal controls (n = 29). Methods: Determining the frequency of heterozygotes and homozygotes for the NI6P by DNA sequencing and restriction endonuclease analyses. Results: Overall, 41 (39.8%) of the 103 patients with PD were heterozygotes compared with 22 (25.0%) of the 88 controls (P=.03), with a relative risk (estimated from the odds ratio) for PD of 2.03 (95% confidence interval, 1.08-3.81) for heterozygotes vs wild type subjects. Heterozygotes were more frequent in the subgroup of patients with pathologically confirmed PD (18 [48.6%] of 37) vs controls (14 [23.7%] of 59) (P=.01), with a relative risk for PD of 2.84 (95% confidence interval, 1.17-6.88) for heterozygotes vs wild type subjects. In patients clinically diagnosed as having PD, heterozygotes; were more frequent in early-onset cases (onset at less than or equal to 45 years) (10 [55.6%] of 18) compared with late-onset cases (onset at >45 years) (10 [23.8%] of 42) (P=.02) or spousal controls (8 [27.6%] of 29) (P=.06), with a relative risk for early-onset PD of 4.17 (95% confidence interval, 1.13-15.33) for heterozygotes vs subjects with 2 wild type alleles. The homozygous NI6P was not associated with PD, but was present in 6 (17.1%) of the 35 patients with diffuse Lewy body disease compared with 3 (5.1%) of the 59 controls (P=.06). Conclusions: The common heterozygous NI6P is associated with an increased risk of PD. An association of borderline significance was found for the homozygous NI6P and diffuse Lewy body disease.