Furthermore haplotypes formed by rs rs rs and rs of

Furthermore, haplotypes formed by rs6269, rs4633, rs4818, and rs4680 of the COMT gene constitute a central COMT locus haploblock that is associated with the enzymatic activity of COMT [8]. The SNPs rs6269 and rs4818, which are located in the central COMT locus haploblock, have been observed to be associated with pain sensitivity in patients with chronic pain syndrome [8,19]. Therefore, we focused our analyses on this central haploblock, covering the order of occurrence from 5′ to 3′ in the COMT gene as rs6269, rs4633, rs4818, and rs4680 (Fig. 2). Six haplotypes out of a possible 16, which had a frequency >0.5%, were detected from these four variants, with the most frequent haplotype (Haplotype 1, 24.6%) being composed of the most frequent TMP269 for the SNPs rs4633 and rs4680 and the least frequent alleles for the SNPs rs6269 and rs4818 (G_C_G_G for SNPs rs6269, rs4633, rs4818, and rs4680, respectively, Fig. 2). The second major haplotype (Haplotype 2, 24.3%) was composed of the most frequent alleles for the SNPs rs6269 and rs4818 and the least frequent alleles for the SNPs rs4633 and rs4680 (A_T_C_A). The third haplotype (Haplotype 3, 16.1%) was composed of a combination of the most frequent alleles for all SNPs (A_C_C_G). The fourth major haplotype (Haplotype 4, 14.3%) was composed of the least frequent alleles for all markers (G_T_G_A). The fifth major haplotype (Haplotype 5, 11.9%) was composed of the described alleles of the four markers (A_C_G_G), and the sixth haplotype (Haplotype 6, 1.1%) was composed of the described alleles of the four markers (G_C_C_G). These six haplotypes accounted for 92.3% of all detected haplotypes in our study population. We found that patients carrying Haplotype 4 (log-rank test, P = 0.02) and Haplotype 6 (log-rank test, P < 0.01) had a significantly increased probability of developing dementia (Fig. 3A and B). Consistently, the common genetic variant in these two susceptible haplotypes was the “G” allele of COMT rs6269, which was shown to increase the risk of dementia during the follow-up period (Fig. 1B). The Cox regression analysis results are presented in Table 1. We found that the development of dementia was influenced by the Haplotype 6 of COMT (HR = 3.24; P = 0.02). Because some evidence has shown doses of levodopa in patients with PD can be influenced by specific COMT haplotypes [20] and doses of levodopa itself might also affect the rate of cognitive decline, although the results were inconsistent [21,22], we therefore examined the mean LEDD per day in patients with different COMT haplotype. In our study population, we did not find significant differences of LEDD among PD patients with different COMT haplotype (P = 0.97, Supplementary Figure 2A). Consistently, there was no significant correlation between LEDD and changes of MMSE scores at the end of the follow-up period (P = 0.34, Supplementary Figure 2A).
Discussion Our study showed that the G allele of COMT rs6269 and COMT Haplotype 6 (G_C_C_G for rs6269, rs4633, rs4818, and rs4680) were significantly associated with cognitive decline in patients with PD after a mean follow-up period of 2 years. We did not discover any significant association between the exonic nonsynonymous rs4680 variant (Val158Met) or other COMT genetic variants and susceptibility for dementia in our PD population. Our findings suggest that in addition to single genetic variants, haplotypes of COMT constituting rs6269, rs4633, rs4818, and rs4680 can have a more prominent effect on cognitive decline in patients with PD. There were no significant correlations between motor symptom severity and LEDD with changes of MMSE during the follow-up period. Relevant studies have addressed the possible association between SNPs in the COMT gene and the risk of PDD; however, these studies have reported inconsistent results [11,12,[23], [24], [25]], particularly for rs4680, which primarily determines COMT activity and influences synaptic dopamine concentration. The Val allele confers higher enzymatic activity than the Met allele, resulting in a dose-dependent decrease in synaptic dopamine availability. Studies of healthy volunteers have suggested that the COMT genotype influences cognitive, reward-related, and emotion processing [26]. A longitudinal follow-up study found that the Val allele of the COMT rs4680 genotype is associated with the change in global and executive cognitive function over an 8-year period in a biracial cohort of elderly men and women [11]. However, in this study, we did not discover any association between the genotypes of rs4680 and either cognitive status or cognitive decline to dementia during the follow-up period. Consistently, several cross-sectional studies of European PD patients also failed to identify the association between rs4680 and the risk of dementia [23,25]. A 5-year longitudinal follow-up study of a population-representative cohort of newly diagnosed patients with PD in the United Kingdom (CamPaIGN study) showed that the COMT genotype had no effect on dementia, although it had a significant effect on the performance in the Tower of London test (a frontostriatal task) [12]. Instead, we identified that the COMT haplotype (G_C_C_G for rs6269, rs4633, rs4818, and rs4680) significantly influenced the risk of dementia in our PD cohort. This functional haplotype conferred 4.8 times higher COMT activity than other haplotypes in the in vitro cell culture system [8]. These findings are in agreement with the previously reported theory that the collective grouping of SNPs in haplotypes has a stronger association with the assessed phenotype than individual SNPs [27,28].