Gothelf's Haplotype of COMT in Parkinson's Disease: A Case-Control Study

Background: Catechol-O-methyltransferase (COMT) catalyzes catecholamine O-methylation and contributes to dopamine turnover, potentially influencing levodopa requirements in Parkinson's disease (PD). We evaluated whether the Gothelf COMT haplotype-and its constituent variants rs2075507, rs4680 (Val158Met), and rs165599-differ in frequency between PD cases and controls. We then tested associations between these variants and clinical phenotypes, with a prespecified focus on levodopa equivalent daily dose (LEDD). Finally, we examined whether haplotype structure and allele-specific context (e.g., background-dependent effects) help explain observed genotype-phenotype relationships in the PD cohort. Aim: Analysis of the rs2075507, rs4680 and rs165599 at individual and haplotype level between control and diseased groups. Furthermore, analysis of association of individual SNPs or haplotype level with clinical outcomes. Subjects and methods: Fifty-five individuals with Parkinson's disease (PD) and fifty-three neurologically healthy controls were enrolled at a single center. Genomic DNA was isolated from peripheral blood, and three COMT variants-rs2075507 (promoter), rs4680/Val158Met (coding), and rs165599 (3'UTR)-were genotyped by Sanger sequencing. Allele, genotype, and tri-marker haplotype frequencies were estimated, and case-control differences were evaluated. Within the PD cohort, associations with clinical outcomes-primarily levodopa equivalent daily dose (LEDD)-were analyzed using multivariable linear models. Statistical tests were two-sided, with multiplicity control as specified in the corresponding tables. Results: The rs2075507 polymorphism showed a robust additive association with LEDD; each A allele predicted higher dose (LEDD ≈ +1331 mg/day, p = 0.001) after adjusting for age and sex. The tri-haplotype test did not show significant association with LEDD. Nevertheless, rs2075507 SNP strongly marked downstream backgrounds: in AA carriers, rs4680-rs165599 haplotypes were enriched for Val (G) and rs165599-G; in GG carriers, for rs165599-A with mixed Val/Met; and GA was A-loaded at both loci. Exact tests confirmed that AA and GG differed in rs4680-rs165599 composition, whereas GA vs. GG was not significant. Conclusions: The promoter variation at rs2075507 may represent the genetic contributor to levodopa dose requirements when modeled with SNP-SNP interactions, with its effect is modified mostly by rs165599 polymorphism. Tri-haplotypes do not independently predict LEDD. The rs4680 (coding) and rs165599 (3'UTR) context appears to fine-tune rather than determine dosing needs, mainly via interaction with rs2075507 SNP.