UCLA

Parkinson’s disease (PD) is a common neurodegenerative disorders with a complex and unclear etiology in which both environmental and genetic factors contribute to disease. Over the past decade, gene-environment interaction and DNA methylation association studies have been used to explore the biological mechanisms underlying PD in order to help develop new strategies for prevention and treatment.

Drinking caffeinated coffee has been reported to protect against PD. Caffeine is an adenosine A2A receptor (ADORA2A) antagonist that increases dopaminergic neurotransmission and Cytochrome P450 1A2 (CYP1A2) metabolizes caffeine. In a population-based case control study in Denmark (PASIDA), we estimated statistically significant interactions for ADORA2A rs5760423 and heavy vs. light coffee consumption in incident (OR interaction=0.66 [0.46-0.94], p=0.02) but not prevalent PD. In meta-analyses combining data from a large consortium study (PEGASUS), PD associations with daily coffee consumption were strongest among carriers of variant alleles in both ADORA2A and CYP1A2.

There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We replicate the previously reported inverse association human leukocyte antigen (HLA)-DRB1 rs660895 and the risk of PD in the Danish PASIDA study. Moreover, both in the Danish study and in the pooled analysis combining two French studies (Terre and Partage), sub-multiplicative interactions were observed between rs660895 and smoking (OR interaction=1.54, p=0.001), such that the inverse association of rs660895-G with PD decreased among smokers.

Lastly, we investigated whether epigenetics play a role in health benefits of drinking coffee. We associate epigenome-wide DNA methylation levels to habitual coffee consumption from two studies with blood (Parkinson’s Environment and Gene (PEG wave 1) and Women’s Health Initiative), and one with saliva samples (PEG wave 2) using bi-weighted mid-correlation and meta-analysis. Adjusting for age, gender, and blood cell composition, one CpG (cg21566642 near ALPPL2) surpassed genome-wide significance (p = 3.7x10-10) and from among ten additional CpGs significant at p≤5.0x10-6. These CpGs are found in or near genes related to lipid metabolism and immune response. Interestingly, when we stratified by menopausal hormone therapy, methylation differences with coffee consumption were observed only in women who never used MHT. We did not replicate any of the associations found in blood in our saliva samples.

Overall, my dissertation provides epidemiologic and biological evidence supporting the hypotheses that caffeine plays a biological role in reducing PD risk and may have beneficial effects in chronic disease or other neurodegenerative disorders. More importantly, neuroinflammation is an important contributor to the pathogenesis of PD.