Caffeine Interaction with Glutamate Receptor Gene GRIN2A: Parkinson's Disease in Swedish Population

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.

Caffeine, creatine, GRIN2A and Parkinson's disease progression

“…Caffeine intake has been associated with a lower risk of developing PD 1, 2 , and an interaction of this association with GRIN2A genotype has been reported in two prior studies 11, 12 , although this was not replicated in a third study 13 . Two prior studies indicated a deleterious interaction between caffeine and creatine, with higher rates of progression of PD among subjects taking creatine who also had high caffeine intake 7, 8 .…”

“…Adenosine A2a receptors enhance NMDA-induced calcium influx, and caffeine is an A2a receptor antagonist, providing a potential mechanistic link between caffeine and GRIN2A . Two studies have found that the T-allele of the GRIN2A single nucleotide polymorphism (SNP) rs4998386 strongly influences the association of caffeine with the risk of PD 11, 12 , although this association was not replicated in a third study 13 . In the initial paper by Hamza et al 11 , among heavy coffee drinkers, carriers of a GRIN2A T allele had a 59% lower risk of PD compared to light coffee drinkers.…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…Early genome-wide associational studies suggested that GRIN2A, but not GRIN2B, was a modifier gene for Parkinson's disease (Hamza et al, 2011;Lee et al, 2011;Yamada-Fowler et al, 2014). Although a large genome-wide associational study did not correlate epilepsy to any of the NMDA receptor genes (International League Against against Epilepsy Consortium on Complex Epilepsies, 2014), the first potential disease-causing mutations in NMDA receptors were described by Endele et al (2010) in GRIN2A, the gene encoding the GluN2A subunit of the NMDA receptor.…”

Cutaneous malignant melanoma and Parkinson disease: Common pathways?

“…This could induce decreased Ca2 1 influx through the cation channel, potentially leading to increased survival through suppression of cell death via apoptosis (excitotoxicity). 117,118 This result was replicated in a Swedish study, 119 but not in a pooled analysis of independent studies targeting populations from Denmark, Sweden, and the USA. 115 CMM patients with nonsynonymous GRIN2A mutations have a more aggressive course with fast progression and shorter survival compared with noncarriers.…”