Association of Parkinson disease age of onset with DRD2, DRD3 and GRIN2B polymorphisms

Abstract

Introduction Dopamine and glutamate are crucial neurotransmitters in Parkinson disease (PD). While recent large meta-analyses reported that genetic variation of dopamine (DRD2, DRD3) and glutamine (NMDA, GRIN2B) neurotransmitter receptors was not associated with PD risk, they could conceivably influence PD phenotype. We studied the association of these receptor polymorphisms relating to PD age of onset. Methods There were 664 PD patients and 718 controls, all Caucasian, with stored DNA at Mayo Clinic, Jacksonville, Florida. Genotyping was performed for DRD2 (Taq 1A, rs1800497), DRD3 (rs6280), and NMDA (GRIN2B, rs7301328) polymorphisms with ABI Taqman assays. Single nucleotide polymorphism associations with age of onset were evaluated using dominant, recessive, and additive genotypic models. Results DRD3 variant carriers had an approximate 4.4-year decrease in mean age of onset when both copies of the minor allele were present (P = 0.0034) and an approximate 1.5-year decrease in mean age at onset for every additional minor allele (P = 0.023) (recessive and additive models, respectively). There was no association with age of onset for DRD2 or GRIN2B under any statistical model (all P ≥ 0.22). Conclusions The DRD3 (rs6280) polymorphism, but not DRD2 (Taq1A) or GRIN2B, influences younger PD age of onset in the US Caucasian population. Validation of these findings in larger studies with other ethnic groups is indicated.

MicroRNAs and Target Genes As Biomarkers for the Diagnosis of Early Onset of Parkinson Disease

“…Importantly, CYP2D6 and NAT2 genes have been shown exclusively to be associated with EOPD (Agúndez et al, 1995 ; Agundez et al, 1998 ), implying that these detoxification genes would have be suitable as EOPD biomarkers. Similar to that, genes that are involved in dopamine metabolism and transport ( DRD3, SLC6A3, MTHFR ), also showed to pose a risk for PD (Wu Y.-L. et al, 2013 ; Zhai et al, 2014 ; Hassan et al, 2016 ), with particularly, dopamine receptor D3 ( DRD3 ) gene that has been implicated in EOPD patients (Hassan et al, 2016 ). Due to heterogeneity of PD, various other genes have also been associated with PD in one or two populations, including saitohin protein (Lu et al, 2014 ), vitamin D receptor (Gatto et al, 2016 ), semaphorin 5A (Yu et al, 2014 ), granulin (Chen Y. et al, 2016 ), histamine N-methyltransferase ( HNMT ) (Jiménez-Jiménez et al, 2016b ), Ras like without CAAX 2 (Lu Y. et al, 2015 ; Foo et al, 2017 ), syntaxin 1B, parkinson disease 16, FGF20 , glycoprotein nmb (International Parkinson's Disease Genomics and Wellcome Trust Case Control, 2011 ), serine/threonine kinase 39 (Foo et al, 2017 ) and huntingtin interacting protein 1 related ( HIP1R ) (Yu et al, 2015 ) genes.…”

“…One such is in the comparison between LOPD patients and normal controls, miR-128 expression in CSF samples was found to be reduced (Burgos et al, 2014 ) and miR-128 can directly bind to CYP2D6 mRNA and suppression its expression (Li et al, 2015 ), which may indicates that CYP2D6 expression was up-regulated in the LOPD patients, consistent with the needs of CYP2D6 to metabolize the neurotoxins in PD. Although Let-7d was no listed in the differentially expressed microRNAs in EOPD and LOPD studies (Table 1 ), Let-7d was shown to directly regulate the expression of DRD3 (Zhang et al, 2016 ), which is also a gene that have been associated with EOPD (Hassan et al, 2016 ). However, no validated and significant microRNA was found to regulate HNMT and HIP1R expression in brain specifically.…”

Critical Review of Pharmacogenomics in Antiparkinsonian Drug Therapy: Impact on Clinical Management of Parkinson’s Disease

“…Maximum investigated polymorphisms consist of Ser9Gly (or MscI or BalI), which may additionally affect DRD3 receptor membrane insertion, and its intracellular reaction [12]. DRD3 (rs6280) polymorphism has also been known to influence the age of onset in ethnic groups [13].…”

Análise de preditores clínicos e genéticos para o surgimento de discinesias induzidas por L-DOPA na doença de Parkinson

“…As buscas foram ampliadas para as referências encontradas nos artigos obtidos. MRAZEK, 2010), e a variação Gly-9 está associada a um início mais precoce da DP (HASSAN et al, 2016). A frequência do alelo variante em uma população de pacientes caucasianos norte-americana com DP foi de 32% (HASSAN et al, 2016), enquanto que em indivíduos saudáveis do Brasil foi de 47% (MESSAS et al, 2005).…”

“…Sua presença tem repercussões clínicas em várias doenças psiquiátricas, como o transtorno obsessivo-compulsivo, esquizofrenia, alcoolismo e RIECK, 2012). A frequência do alelo A1 (Lys) em pacientes caucasianos com DP nos Estados Unidos foi de 22%(HASSAN et al, 2016), enquanto que em pacientes parkinsonianos brasileiros representou 27% da amostra estudada(RIECK et al, 2012).…”