Association of Catechol-O-methyltransferase (COMT Val¹⁵⁸Met) with future risk of cardiovascular disease in depressed individuals - a Swedish population-based cohort study

Epidemiological and family studies have repeatedly shown that genetic predisposition accounts for 40–60% of the risk for coronary artery disease. Correspondingly for depression, twin studies suggest a heritability of 40–50%, and family studies indicate a two- to threefold increase in lifetime risk of developing depression among first-degree relatives [1]. Multiple studies have shown that depression is a risk factor for cardiovascular diseases (CVD) including coronary heart disease and stroke [2]. Thus genetic vulnerability is important in both CVD and depression, and some of these genetic underpinnings may be shared between the disorders.

Catechol-O-methyltransferase (COMT) has previously been implicated in both depression and CVD. The enzyme COMT is expressed in several tissues and degrades not only dopamine but also other catecholamines and sex steroids, like catechol estrogens and dietary polyphenols. Animal and human studies have shown that altered levels of dopamine neurotransmission contribute to depressive-like behavior and influence depressive symptoms [3, 4]. Dopamine, [5] catechol amines [6, 7] and estrogens [8] have well-known effects on the cardiovascular system, e.g. blood pressure regulation. The COMT enzymatic activity is dependent on genetic variations in the COMT gene. The Val¹⁵⁸Met has a large effect on the enzymatic activity and the minor allele is quite frequent in many human populations. COMT Val¹⁵⁸Met is a substitution of methionine (Met) for valine (Val) at codon 158 encoded by a single nucleotide polymorphism (SNP), rs4680. The Met allele has a lower enzymatic activity compared to the Val allele. The Val/Val genotype is associated with approximately 40% more effective degradation of dopamine compared to the Met/Met genotype, while those with Val/Met genotype display an intermediate COMT activity [9, 10].

Although COMT Val¹⁵⁸Met has not shown significance in genome-wide association studies (GWAS) on depression, a recent meta-analysis by Wang et al. suggested an effect on major depressive disorder depending on ethnicity, with Val being the vulnerability allele in Europeans [11, 12]. The COMT Val¹⁵⁸Met has also been reported to be associated with cardiovascular disease and metabolic disorder. COMT Val¹⁵⁸Met homozygosity for the low-activity allele (Met/Met), has been associated with myocardial infarction (n_cases = 69, n_controls = 723) [13] and metabolic disorders like abdominal obesity and high blood pressure in men (n = 240) [14]. In contrast, in a larger cohort study in Swedes by Eriksson et al. (n_cases = 174, n_controls = 348), Met/Met was reported to be protective against myocardial infarction [8]. The purpose of this study was to determine the effect of COMT Val¹⁵⁸Met on the risk of CVD among depressed persons. Based on the fact that the Val allele was the risk allele for depression in the meta analysis in Europeans [11], and Met/Met homozygosity had a protective effect on myocardial infarction in the large Swedish cohort [14], we hypothesized that the Val allele might increase the risk for depression leading to CVD. Because of previous gender-specific associations for COMT Val¹⁵⁸Met with depression and CVD [14‐16] we performed gender-stratified analyses.

Out of the 3525 participants with COMT Val¹⁵⁸Met data 1094 (31.0%) had Met/Met genotype, 1720 (48.0%) were Met/Val and 711 (20.2%) were Val/Val (Table 1).

The genotype distribution was in Hardy Weinberg equilibrium (p = 0.31). Those homozygous for Val/Val showed a borderline reduced risk for depression (OR = 0.70 (95% CI: 0.60-1.0), Table 2). However, those who were Val/Val had a point-wise increased risk for future CVD (OR = 1.3 (95% CI: 1.0-1.7)). Stratification on gender showed that the OR point estimate for risk for later CVD was higher among women than men (OR = 1.5 (95% CI: 0.8-2.4) and OR = 1.1 (95% CI: 0.7-1.7), respectively, Table 2).

Also, depression had a main effect increasing the risk for CVD in this cohort (OR = 1.9 (95% CI 1.4-2.5)) [31]. Considering both depression and Val¹⁵⁸Met genotype for future risk of CVD, the OR was 3.6 (95% CI: 2.0-6.6)) for those having both Val/Val and depression and 1.1 (95% CI: 0.8-1.6) for those having Val/Val and no depression (Table 3). The OR (95% CI) for those who were Met carriers and had depression was 1.5 (1.0-2.3). We also stratified the data by gender and found that the point-wise effect on risk of later CVD was higher in women compared to men among those having both Val/Val and depression; OR 7.0 (3.0-14) and 2.1 (1.0-6.8), respectively (Table 3). To explore the possibility of a dilution effect by having Met/Met plus Val/Met in the reference group, we calculated the OR for having Val/Val and depression using the reference group being those having Met/Met and no depression. This OR was 4.2 (95% CI 2.1-8.4) for men and women together, and 8.5 (95% CI 3.4-21.2) for women only. This indicated a slight but no major dilution effect by including both Met/Met and Met/Val in the reference group (corresponding ORs being 3.6 and 7.0, respectively, Table 3).

Indices of additive interaction in the sample demonstrating additive interaction between depression and Val¹⁵⁸Met genotype for later CVD are shown in Table 4. For multiplicative interaction, effect size of the interaction term and the loglikelihood test comparing the main effect model and the model with interaction term are shown in Table 4 and indicate borderline statistical significance.

Depression is a known risk factor for CVD [31‐33]. The COMT Val¹⁵⁸Met genetic variation influencing COMT enzyme activity has previously been associated with risk for depression [12], and risk for CVD [8, 13, 14]. The identity of the at risk allele has varied between studies, although a meta-analysis demonstrated high activity COMT Val allele as risk allele for depression. An influence of gender as well as childhood adversity on the Val¹⁵⁸Met association with depression has previously been reported [15], although a recent meta-analysis found no Val¹⁵⁸Met association to depression in any gender [16]. Using a large population-based Swedish cohort of adults we here show for the first time that the COMT Val¹⁵⁸Met genotype, corresponding to high COMT enzymatic activity, implies an increased risk of CVD especially for those who had depression up to 14 years earlier. Thus, both an additive and a multiplicative interaction between depression and COMT Val¹⁵⁸Met for risk of CVD were detected. Additionally, this risk of CVD by high COMT activity genotype and depression was more pronounced in women compared to men. Both mild and severe depression were considered, scored at two time points for each participant, and the original cohort was randomly selected among Swedish nationals in the Stockholm County.

There are previous reports demonstrating a relationship between COMT Val¹⁵⁸Met and acute coronary events, ischemic stroke and CVD risk factors like hypertension and lipid abnormalities [13, 14, 34]. The results from these studies are however not fully consistent with regard to which allele implies a disease risk and the influence of depression on the relationship was not previously assessed. Hagen and coworkers reported that high COMT activity (Val/Val genotype) is overrepresented in male and female Norwegians with systolic hypertension (≥140 mmHg) (n = 2591) [34]. This finding was confirmed in a Chinese population (n = 3079) showing that high activity COMT (Val/Val) was associated with cardio -metabolic risk factors including hypertension and high triglyceride levels [35]. Accordingly, Eriksson et al. reported a protective effect of low activity COMT (Met/Met or Val/Met) against myocardial infarction in Swedish and Finnish hypertensive men (n = 522) [8]. Contrary to this, low activity COMT (Met/Met or Val/Met) was associated with acute coronary events in Finnish men (n = 792) [13], and with high systolic and diastolic blood pressure and abdominal obesity in Swedish men (n = 1302) [14]. The reason for the discrepancy in risk allele identity between the aforementioned studies is unclear but could in part be related to different ranges of estrogen levels, and thereby different gender and age distributions. Accordingly, we found that high activity COMT (Val/Val)*depression was associated with increased CVD risk in women, but not in men. This sex-based difference might partially be explained by the difference in estrogen activity between men and women. Estrogen plays an important role in the cardiovascular system and COMT is key in the degradation of estrogens. Thus, the association between COMT Val/Val and CVD in females might reflect altered levels of estrogen and its metabolites [8, 36]. Moreover, estrogen signaling influences COMT transcription through estrogen response elements in the COMT promoter [37, 38]. The COMT enzyme metabolizes also dopamine and catecholamines which regulate both mood and cardiovascular functions through wide-spread expression of their receptors. Therefore, our Val/Val-CVD association finding may partly be due to effects of COMT enzyme activity variation on the metabolism of these transmitters. The influence of depression on the Val/Val-CVD association may in part be through increased inflammation and oxidative stress often seen in the depressed state, [39] which could potentiate a high COMT enzyme activity effect on cardiovascular function. Of the individuals in PART 11% had a non-Swedish origin, among those the vast majority had a Nordic origin. The Swedish population at time of sampling had no strong internal genetic borders [40] and especially the southern/middle parts of Sweden (from where the participants of this study are derived) were more genetically homogeneous [41].

The risk for later CVD was increased in depressed persons with high activity COMT Val¹⁵⁸Met genotype (Val/Val), with a synergistic interaction between depression status and COMT genotype. This effect on risk for CVD was higher in women and might in part reflect estrogen signaling. The findings warrant further studies.