Role of polymorphisms in dopamine synthesis and metabolism genes and association of DBH haplotypes with Parkinson's disease among North Indians.
OBJECTIVE
Genetic and non-genetic components are believed to govern the etiology of common complex traits such as Parkinson's disease (PD). In view of the biochemical evidence of depleted dopamine levels in the affected brains and also the most common and effective therapeutic modality of administration of levodopa in PD, genes from the dopaminergic pathway emerge as major determinants. We have earlier shown the role of DRD4-120 bp duplication marker in PD susceptibility. In this study, contribution of six genes involved in dopamine synthesis and metabolism to PD susceptibility and disease severity was assessed in a North Indian PD cohort.


METHODS
339 patients diagnosed using UKPD brain bank criteria and 344 matched controls were recruited and disease severity was assessed using the Hoehn and Yahr scale and Unified Parkinson Disease Rating Scale III scores. Allelic, genotypic and haplotypic associations with PD were computed; severity was compared among the genotypic categories of markers; gene-gene interactions were assessed using multiple logistic regression.


RESULTS
A highly significant association of dopamine beta-hydroxylase (DBH) haplotypes (rs1611115T>C - rs1108580A>G - rs5320A>G - rs129882C>T) with PD was observed; haplotypes C-A-G-C [P=0.000005, Odds ratio (95% confidence interval): OR (95% CI)=1.76 (1.38-2.25)] and C-A-G-T [P=0.000001, OR (95% CI)=0.49 (0.37-0.65)] retaining significance after Bonferroni correction. rs129882, a 3'UTR SNP in DBH showed significant association with disease severity [Hoehn and Yahr (P=0.005) and Unified Parkinson Disease Rating Scale (P=0.006)].


CONCLUSIONS
Observed association of DBH SNP/SNP haplotypes with PD susceptibility and its role in modulating disease severity reiterates the importance of dopamine pathway in sporadic PD etiology in general and potential therapeutic implications of DBH in particular.
Punia
Sohan
S
Department of Genetics, University of Delhi South Campus, All India Institute of Medical Sciences, New Delhi, India.
Das
Mitashree
M
Behari
Madhuri
M
Mishra
Bikash K
BK
Sahani
Asish K
AK
Govindappa
Shyla T
ST
Jayaram
Sachi
S
Muthane
Uday B
UB
K
Thelma B
TB
Juyal
Ramesh C
RC
D003710:Demography; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007194:India; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D004299:Dopamine beta-Hydroxylase; D004298:Dopamine