A genetic variant in the catechol-O-methyl transferase (COMT) gene is related to age-dependent differences in the therapeutic effect of calcium-channel blockers

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  Figure 1. Flow chart illustrating study design and objectives tested. Initially, statistical analyses were performed in the whole population testing for differences in BP levels in relation to genetic variants in genes involved in estrogen metabolism. In addition, the influence of these SNPs on BP under the treatment of antihypertensive drugs was tested. Both unadjusted and adjusted analyses were performed. Adjusted analyses were conducted correcting for age, sex, BMI (kg/m2), smoking habits, diabetes, antihypertensive polymedication, and menopausal state (included as covariate in analyses investigating specifically pre- and postmenopausal women). In multiple comparisons, statistically significant values were evaluated based on Bonferroni corrected P values. Statistical outcomes reaching Bonferroni corrected P value thresholds (P < .01) were further investigated in sex- and age-related interaction and stratification analyses (age cutoff: 70 years). ACEIs = angiotensin-converting-enzyme inhibitors, ARBs = angiotensin-receptor blockers, BMI = body mass index, CCBs = calcium-channel blockers, LD = linkage disequilibrium, N = number of subjects, SNP = single nucleotide polymorphism.

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  Figure 2. The association of COMT variant rs4680 with blood pressure under the treatment of calcium-channel blockers (CCBs) in elderly individuals (age ≥ 70). (A, B) Elderly individuals treated with CCBs and carrying the G allele of rs4680 showed significantly lower SBP levels than wildtype carriers. This observation was strongly pronounced in homozygous rs4680 variant carriers. (C) DBP was lower in elderly rs4680 carriers treated with CCBs compared with elderly wildtype carriers. ∗P < .05, ∗∗P < .01, ∗∗∗P < .005. P values were obtained using the unpaired Student t test (2-sided) or general linear model (univariate) analysis. DBP = diastolic blood pressure, SBP = systolic blood pressure.

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  Figure 3. Hypothesized functional pathway causing the age-related impact of COMT SNP rs4680 on blood pressure regulation. COMT mRNA expression, COMT protein levels, and enzyme activity are influenced by age and genetic variants. The polymorphism rs4680 in COMT is associated with major individual differences in COMT activity. The Val (G) allele is associated with significantly higher COMT activity. Age is associated with increased COMT expression and, thus, activity across different genotypes of the coding SNP rs4680. Since COMT catalyzes the breakdown of catecholamines into methylated metabolites with lower activity, higher COMT expression and activity causes a decrease of circulating catecholamine and blood pressure levels. Furthermore, fluid volume and vessel stiffness impact blood pressure levels as well. The estrogen-dependent regulation of COMT expression induces a sexually dimorphic effect of rs4680 on COMT activity, leading to the observation that specifically elderly male variant carriers profited from a BP lowering effect of CCBs. However, this observed association was made in a very small sample and is therefore shown with a dashed arrow. BP = blood pressure, SNP = single…