Abstract
A complex interplay between genetic and environmental factors is thought to be involved in the etiology of Parkinson's disease (PD). A recent genome-wide association and interaction study (GWAIS) identified GRIN2A, which encodes an NMDA-glutamate-receptor subunit involved in brain's excitatory neurotransmission, as a PD genetic modifier in inverse association with caffeine intake. Here in, we attempted to replicate the reported association of a single nucleotide polymorphism, GRIN2A_rs4998386, and its interaction with caffeine intake with PD in patient-control study in an ethnically homogenous population in southeastern Sweden, as consistent and independent genetic association studies are the gold standard for the validation of genome-wide association studies. All the subjects (193 sporadic PD patients and 377 controls) were genotyped, and the caffeine intake data was obtained by questionnaire. We observed an association between rs4998386 and PD with odds ratio (OR) of 0.61, 95% confidence intervals (CI) of 0.39–0.96, p = 0.03, under a model excluding rare TT allele. There was also a strong significance in joint effects of gene and caffeine on PD risk (TC heavy caffeine vs. CC light caffeine: OR = 0.38, 95%CI = [0.20–0.70], p = 0.002) and gene-caffeine interaction (OR = 0.998, 95%CI = [0.991–0.999], p<0.001). Overall, our results are in support of the findings of the GWAIS and provided additional evidence indicating PD protective effects of coffee drinking/caffeine intake as well as the interaction with glutamate receptor genotypes.
Highlights
Recent advances in genetic research in familial form of Parkinson’s disease (PD) have identified several causative genes and shed lights on underlying disease mechanisms
The results from a series of Genome wide association studies (GWAS) added our understanding of the genetic basis of PD by identifying several loci with common genetic variants associated with PD risk
While the NMDA-receptor is involved in synaptic plasticity and learning, its excessive activation results in excitotoxicity leading to neuronal damage, which is thought to be a mechanism underlies several neurologic or neurodegenerative disorders
Summary
Recent advances in genetic research in familial form of Parkinson’s disease (PD) have identified several causative genes and shed lights on underlying disease mechanisms. In vast majority (.85%) of PD is sporadic form and only limited genetic risk factors have been identified far. Sporadic form of PD is thought to be a complex disorder caused by combinations of multiple genetic and environmental factors. It is likely that specific variants of a gene cannot alone explain disease status in a given individual, but instead, they confer an increased risk. Genome wide association studies (GWAS) are capable of capturing such weak genetic effects and was hoped to become a powerful tool to identify susceptibility loci of PD. Despite the expectation, over 20 GWAS related studies, including original GWAS, reanalysis, and meta-analysis, conducted on PD population to date have identified only a few candidate genes. The most consistently replicated main effects detected are for SNCA and MAPT, but others are less consistent [1], [2]
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