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-Synuclein, pesticides, and Parkinson disease

A case–control study

From the Department of Neurology (L.B., R.F., W.A.R., D.M.M.), the Division of Epidemiology (W.A.R.) and the Division of Biostatistics (N.K.S., T.G.L., M.A.), Department of Health Sciences Research, and the Department of Laboratory Medicine (J.M.C.), Mayo Clinic College of Medicine, Rochester, MN; the Department of Neuroscience (S.J.L., M.J.F.), Mayo Clinic College of Medicine, Jacksonville, FL; and the Department of Environmental and Occupational Sciences (H.C.), University of Washington, Seattle, WA. Dr. Brighina was on leave from the Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy, at the time of the study.

Address correspondence and reprint requests to Dr Maraganore, Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905

Background: Aggregation and fibrillization of the -synuclein protein (encoded by the SNCA gene) may represent key events in the pathogenesis of Parkinson disease (PD). Variability in the length of a dinucleotide repeat sequence (REP1) within the SNCA promoter confers susceptibility to sporadic PD. Pesticide exposures may also confer susceptibility to PD. Our objective was to test possible joint effects of SNCA REP1 genotypes and pesticide exposures on the risk of PD.

Methods: This was a case–control study. Cases were recruited prospectively from the Department of Neurology of the Mayo Clinic, Rochester, MN, after June 1, 1996. The control subjects included unaffected siblings of cases and unrelated population control subjects. We assessed pesticide exposures by telephone interview and genotyped SNCA REP1. Odds ratios (ORs) and 95% CIs were determined using conditional logistic regression models.

Results: There were 833 case–control pairs. We observed an increased risk of PD with increasing SNCA REP1 bp length (OR, 1.18 for each score unit; 95% CI, 1.02–1.37; p = 0.03). Pesticide exposures were associated with PD in younger subjects only (lowest quartile of age at study, 59.8 years; OR, 1.80; 95% CI, 1.12–2.87; p = 0.01 for all pesticides; OR, 2.46; 95% CI, 1.34–4.52; p = 0.004 for herbicides). In multivariate analyses, both SNCA REP1 score and pesticide exposures were significantly associated with PD in younger subjects, but there were no pairwise interactions.

Conclusions: Our findings suggest that SNCA REP1 genotype and herbicides have independent effects on risk of Parkinson disease, primarily in younger subjects.

dmaraganore{at}mayo.edu

e-Pub ahead of print on March 5, 2008, at www.neurology.org.

Supported by grants NS 33978 and ES 10751 (National Institutes of Health).

Disclosure: Dr. Maraganore is the co-inventor of a US provisional patent application entitled "Method of treating neurodegenerative disease." It has been licensed to Alnylam Pharmaceuticals, Inc. and he has received less than $10,000 in royalty payments. Dr. Maraganore has consulted for Alnylam Pharmaceutical, Inc., Pfizer, Inc., and Merck and Co., Inc. during the last 5 years but received no personal compensation. Dr. Farrer is the co-inventor of a US provisional patent application entitled "Method of treating neurodegenerative disease." It has been licensed to Alnylam Pharmaceuticals, Inc. and he has received royalty payments in excess of $10,000. Dr. Farrer has a consulting relationship with Amgen, Inc. for which no payments have been made to date. Mayo Clinic has received royalty payments in excess of $10,000 from Alnylam Pharmaceuticals, Inc., in relation to the US provisional patent application entitled "Method of treating neurodegenerative disease."

Received June 23, 2007. Accepted in final form November 1, 2007.