Role of polymorphisms in dopamine synthesis and metabolism genes and association of DBH haplotypes with Parkinson's disease among North Indians.

OBJECTIVES: 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)]. CONCLUSION: 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.

Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians.

OBJECTIVE: Inter-individual variations to methotrexate (MTX) response among rheumatoid arthritis (RA) patients have been attributed to clinical heterogeneity and genetic variations influencing MTX pharmacology. In this study, we analyzed the association of polymorphisms in ATIC, AMPD1, ADA, and ADORA2A from the purine biosynthetic pathway with MTX response in RA patients from north India. We also assessed the cumulative contribution of these polymorphisms together with those from the receptor-metabolizer-transporter and folate pathway genes that we have previously investigated. METHODS: RA patients recruited using the American College of Rheumatology criteria were grouped into good (n = 213) and poor (n = 68) responders to MTX, based on Disease Activity Score 28-3. Individual single nucleotide polymorphism association was tested using (chi)2 test, and cumulative contribution of all the single-nucleotide polymorphisms and cumulative contribution of all the SNPs and clinico-demographic factors were assessed using linear and logistic regression. RESULTS: G allele of ADA rs244076 [P = 0.02, odds ratio (95% confidence interval): OR (95% CI) = 1.66 (1.01-2.75)]; and T allele of ADORA2A rs5751876 [P = 0.04, OR (95% CI) = 1.55 (1.01-2.37)] were associated with poor response, but did not stand Bonferroni correction. On regression analyses, FPGS rs1544105, TYMS rs2853539, DHFR rs7387, and ADA rs244076 were identified as putative predictors for MTX response. Carriers of the FPGS rs1544105 AA and AG genotypes [OR (95% CI) = 3.47 (1.19-10.12)] and TYMS rs2853539 AA genotype [OR (95% CI) = 2.76 (1.50-5.07)] were predictors of poor response in our patient population. CONCLUSION: Genes from all the three pathways seem to contribute to MTX response in the Indian population. However, these observations need to be replicated in an independent sample set.