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    • Several genetic loci have been proposed

    2020-08-06

    Several genetic loci have been proposed as risk factors for cognitive decline in the elderly population [[4], [5], [6]]. Among them, catechol-O-methyltransferase (COMT) encodes a key enzyme that degrades dopamine, which is deficient in patients with PD. A common polymorphism at codon 158 (Val158Met, called rs4680) affects the activity of this enzyme, and Met/Met carriers exhibit low enzyme activity compared with Val/Val carriers [7]. Haplotypes composed of combinations of the favipiravir of rs6269, rs4633, rs4818, and rs4680 of the COMT gene also affect COMT activity [8]. The genotypes and haplotypes of COMT therefore modulate dopamine levels in the frontostriatal circuits, which in turn affect executive cognitive performance [9,10]. Thus, examination of the role of COMT genetic variants and haplotypes in cognitive function is of considerable importance for patients with PD. To date, few studies have prospectively investigated the association between COMT and the trajectory of cognitive decline over time [11,12]. Therefore, in this study, we explored the contribution of the genetic variants and haplotypes of COMT to the risk and progression of cognition decline in a regularly followed up cohort of PD patients without dementia.
    Methods
    Results Patient characteristics including age at disease onset, disease duration, sex, education years, UPDRS part III scores, LEDD, MMSE scores at baseline and at least 1 year after enrolment were depicted in supplementary Table 1. Age was significantly correlated with MMSE scores at the end of the follow-up period (P < 0.01, Supplementary Figure 1A). However, the severity of motor symptoms, defined as UPDRS part III scores, had only a modest correlation with MMSE scores (P = 0.21, Supplementary Figure 1B). Of the 409 patients, 185 (45.2%) progressed to dementia after a mean follow-up period of 647.3 ± 327.1 days. We found that the initial cognitive status could influence the development of dementia. Patients with initial low MMSE scores (26–28) had a significantly higher probability of developing dementia than participants with a MMSE score greater than 28 (29–30) (log-rank test, P = 0.005, Fig. 1A). The baseline and follow-up MMSE scores stratified by different COMT genotypes were shown in supplementary Table 2. The MMSE scores of patients carrying the GG genotype of the COMT rs6269 variant were lower than those of patients carrying the GA and AA genotypes. The survival curve of patients carrying different genotypes of COMT rs6269 showed that patients with the GG genotype of COMT rs6269 had a significantly higher risk of PDD than patients carrying the GA and AA genotypes (log-rank test, P < 0.01, Fig. 1B). The changes in MMSE scores during the follow-up period did not differ among patients carrying individual genotypes of other COMT variants (Supplementary Fig. 3A–D). 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 alleles 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).