Parkinson's Diseases Susceptibility Genes and Pesticides

While many pathophysiologic pathways may be involved in the neurodegeneration responsible
for PD, genetic factors are likely to determine a general susceptibility to
neurodegeneration. There are a number of genetic polymorphisms of genes such as those coding
for the cytochrome p450 super-family of genes referred to as 'susceptibility genes'.
However, they are generally not sufficient to cause disease unless a person encounters
exposure to an environmental toxin: the disease is caused by a gene-environment interaction.
Thus, it is imperative to assess genetic susceptibility in individuals exposed to a toxin.
We will test the gene-environment interaction hypothesis by conducting an epidemiologic
population-based case-control study of newly diagnosed PD patients from three rural
California counties: Kern, Fresno, and Tulare. Over a four year period, we expect to collect
400 cases referred to us by local neurologists, farm worker clinics, and Parkinson's
foundations. For each case, one population control will be selected at random from
residential parcel maps and Medicare databases and, in addition, one unaffected sibling
control and - when possible - affected siblings to avoid potential biases and inefficiencies
inherent in the use of each type of control. For each study subject, an environmental and
occupational pesticide exposure estimate will be derived using California pesticide-use
reporting (PUR) data and information about pesticide application on crops in combination
with crop patterns shown in satellite images and aerial photographs; in addition, extensive
exposure interviews will be conducted with all study subjects. In a three-tiered approach to
examine the effects of gene-environment interactions we will: 1) test for association (and
linkage) of PD to selected loci associated with PD in earlier studies using multiallelic
repeat markers and genotyping; 2) test for association using intragenic single nucleotide
polymorphisms (SNPs) of 50 candidate genes arrayed to create "the PD array"; and 3) use
future technical possibilities to screen for genome wide associations using array technology
to scan 5,000-10,000 SNPs throughout the genome. Data analysis will employ hierarchical
modeling procedures to take into account multiple comparison issues and to incorporate prior
knowledge such as increased neurotoxicity due to the interaction of gene products and
chemicals.

Newly diagnosed patients with idiopathic PD (first PD diagnosis after January 1998 who are
currently living in one of the three target counties (Kern, Tulare, Fresno) and have lived
in California for at least 5 years are eligible for participation. For each patient, one
or more unaffected sibling controls and one population control will be recruited. The
population control are being selected randomly from Medicare records (95% of all controls)
and residential parcel listings (for those patients younger than 65 years of age only; the
same inclusion criteria will be applied as to the cases. The controls are being marginally
matched to cases according to 5-year age categories (e.g. 50-54, 55-59, 60-64, etc.), race
(white, African-American, Asian, Hispanic, other), and sex.

All study cases by definition will be patients who elicited care from health care
providers.

We are aiming to enroll every newly diagnosed PD patient into our study and expect patient
population participating in our study that is as diverse as the rural population.