Exploring gene-environment interactions in Parkinson’s disease

Abstract

The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson's disease (PD) risk; namely, alpha-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the NeuroGenetics Research Consortium, with complete data on all six factors, were studied. Uniform protocols were used for diagnosis, recruitment, data collection and genotyping. A logistic regression model which included gene-exposure interactions was applied. Likelihood ratio tests (LRTs) were used for significance testing and Bayesian inference was used to estimate odds ratios (ORs). MAPT (P = 0.007), SNCA REP1 (P = 0.012), smoking (P = 0.001), and coffee (P = 0.011) were associated with PD risk. Two novel interactions were detected: APOE with coffee (P = 0.005), and REP1 with smoking (P = 0.021). While the individual main effects were modest, each yielding OR < 1.6, the effects were cumulative, with some combinations reaching OR = 12.6 (95% CI: 5.9-26.8). This study provides evidence for the long-held notion that PD risk is modulated by cumulative and interactive effects of genes and exposures. Furthermore, the study demonstrates that while interaction studies are useful for exploring risk relationships that might otherwise go undetected, results should be interpreted with caution because of the inherent loss of power due to multiple testing. The novel findings of this study that warrant replication are the evidence for interaction of coffee with APOE, and of smoking with REP1 on PD risk.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Both GWAS mentioned above [262,263] as well as a replication study of a Chinese sample [264] reported strong associations with α-Synuclein. Two studies reported an interaction between the α-Synuclein Rep1 polymorphism and smoking [270,271]. One study reported an interaction between the α-Synuclein Rep1 polymorphism and pesticides, more prominent in early-onset cases [271], but another study [272] reported no such interaction.…”

“…Meta-analysis of 40 studies showed a slightly increased PD risk for the epsilon 2 versus 3 allele (OR 1.14, 95% CI 1.03-1.27), but no association for the epsilon 4 allele implicated in Alzheimer's disease [265]. One study reported an interaction between APOE and coffee intake; the inverse association with coffee was stronger among carriers of the epsilon 2 allele, however, the main effect of APOE was not significant [270].…”

“…One study [270] assessed possible gene-environment interactions for this variant; no evidence for interactions with smoking or coffee intake was found. The GWAS including individuals of European descent [263] reported a strong association with MAPT, but this finding was not replicated in the Japanese GWAS [262], indicating genetic heterogeneity specific to populations.…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…While the symptomatic anti-parkinsonian and antidyskinetic benefits of the drugs (see below) have generated most interest, the targeting of adenosine transmission as PD therapy is reinforced by epidemiological data suggesting that caffeine (a non-selective adenosine receptor antagonist) may protect nigral dopaminergic neurons against degeneration in PD (Jiménez-Jiménez et al, 1992;Ross et al, 2000;Ascherio et al, 2001;Hernan et al, 2002;Powers et al, 2008;McCulloch et al, 2008).…”

Population genetic and Alzheimer’s disease related gene-interaction studies on 17q21.31 genomic inversion

“…As tauopathies are multifactorial disorders, the role of environmental factors and epigenetic effects on the genome are also considerable (McCulloch et al, 2008). These can influence gene expression (Caffrey et al, 2006), alternative splicing (Andreadis, 2005) or both and may lead to enhanced tangle formation and disease development.…”