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.

Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's disease patients.

Recent discovery of pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene in Parkinson's disease (PD) patients in different ethnic groups have raised a hope of diagnostic screening and genetic counseling. We investigated the six most commonly reported mutations in LRRK2 gene among Indian PD patients, using PCR-RFLP method. Mutations G2019S, R1441C, R1441G, and R1441H were screened in 1012 individuals (PD, 800; controls, 212) while mutations I2012T and I2020T were screened in 748 PD patients. We did not observe any of these six mutations in this study sample except in a single female young onset PD patient who showed a heterozygous G2019S mutation. The absence of mutations was reconfirmed by sequencing of probands from several autosomal dominant PD families. Our observations suggest that these mutations may be a rare cause of PD among Indians and therefore of little help for diagnostic screening and genetic counseling for Indian PD patients.

Genetic susceptibility to Parkinson's disease among South and North Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120-bp duplication marker.

The depletion of dopamine levels in the brain due to degeneration of dopaminergic neurons of substantia nigra pars compacta is a hallmark of Parkinson's disease (PD). The cumulative contribution of genetic variations in genes from the dopaminergic pathway has been widely implicated to confer susceptibility to idiopathic PD. We present in this paper an extensive association analysis of a total of 20 markers including single nucleotide polymorphism/short tandem repeat/variable number tandem repeat/duplication markers from five candidate genes (namely, dopamine receptors DRD1, DRD2, DRD3, and DRD4, and dopamine transporter) with PD among two independent sample sets. The allelic, genotypic, and haplotypic association of these markers with PD was tested in South Indian (SI) samples (147 cases, 130 controls) and replicated in a larger North Indian (NI) sample set (340 cases, 344 controls). Of the several markers analyzed, 120 bp duplication marker of DRD4 gene showed promising results with PD in both of the sample sets. A significant allelic association in SI [odds ratio, OR (95% confidence interval, CI)=0.67 (0.47-0.97) for 120 bp dup; 1.48 (1.03-2.13) for 120 bp WT] and genotypic association in SI [OR (95% CI)= 0.56 (0.35-0.91) for 120 bp dup/dup; 1.62 (0.99-2.64) for 120 bp dup/120 bp WT] and in NI [OR (95% CI)= 1.41 (1.03-1.93) for 120 bp dup/120 bp WT] was observed. This is the first report on the association of dopaminergic gene polymorphisms with PD from the Indian sub-continent.

Parkin mutations in familial and sporadic Parkinson's disease among Indians.

We observed a mutation frequency of 8.5% in Parkin gene among Indian PD patients based on sequencing and gene dosage analysis of its exons. We identified nine point mutations of which seven are novel and hitherto unreported. These mutations accounted for 14.3% familial PD, 6.9% young onset and 5.9% late onset sporadic PD. Of the 20 PD patients with mutations only two had homozygous mutations and one was a compound heterozygote. Homozygous exonic deletions were absent but heterozygous exon rearrangements were observed in 9.2% of patients (19% familial PD and 4.5% young onset sporadic PD).

Association of N-acetyl transferase 2 gene polymorphism and slow acetylator phenotype with young onset and late onset Parkinson's disease among Indians.

OBJECTIVES: To investigate the association of (i) seven SNPs and SNP haplotypes in the phase II conjugating enzyme N-acetyl transferase 2 gene; and (ii) slow acetylator phenotype, with the development of young onset (YO) and late onset (LO) Parkinson's disease (PD) among Indians. METHODS: A total of 267 cases (132 YOPD, age at onset < or =40 years; 135 LOPD, age at onset >40 years) and 324 age and sex matched controls (132 for YOPD and 192 for LOPD) were genotyped for NAT2 SNPs. Allelic, genotypic and haplotypic association was tested by chi2 using a case-control approach. Chi2 test of association of acetylation phenotype (by genotype) with PD was also carried out. RESULTS: Of the seven SNPs genotyped, SNP191 was monomorphic and therefore, not included for analysis. With SNPs 590 and 857 a significant allelic [OR (95% CI) 4.147 (2.28-7.54) for A allele and 2.565 (1.34-4.92) for A allele, respectively] and genotypic [OR (95% CI) 0.27 (0.14-0.52) for GG and 0.35 (0.174-0.712) for GG, respectively] association with YOPD was observed. There was a significant allelic and genotypic association of SNP 282 with LOPD [chi2 = 8.92, P = 0.003 and chi2 = 10.2, P = 0.006, respectively]. There was also a significant association of protective and predisposing haplotypes TCGG and TCAG [OR (95% CI) 0.446 (0.31-0.63) and 3.742 (2.0-6.99), respectively] with YOPD and predisposing haplotype TCGA [OR (95% CI) 3.214 (1.43-7.22)] with LOPD. Slow acetylator phenotype was significantly associated with YOPD [OR (95% CI) 2.32 (1.2-4.48)]. CONCLUSION: Specific SNPs and SNP haplotypes in NAT2 and slow acetylator phenotype are significantly associated with YOPD and to a lesser extent with LOPD among Indians.

Task-specific dystonia in tabla players.

Task-specific dystonia significantly impairs the performance of approximately 8% of musicians [Lederman RJ. Muscle Nerve 2003;27:549-561]. We describe hand dystonia in two professional musicians experienced while playing tabla, a percussion instrument.