It is noteworthy that epidemiological studies have demonstra
It is noteworthy that epidemiological studies have demonstrated that some GAD patients have experienced anxiety symptoms in childhood and young adulthood, whereas others have developed their disorder at a later age (especially persons ≥ 50 years of age) (Hoehn-Saric et al., 1993; Le Roux et al., 2005). Therefore, our results that COMT Val158Met polymorphism is associated with the risk of GAD via decreased resting vagal control in an age-specific way may help to explain, at least partly, the underlying neural and genetic mechanisms of a bimodal distribution for age of onset of GAD that peaked in early life and late adulthood (Hoehn-Saric et al., 1993; Le Roux et al., 2005). However, since the ages of our study subjects range only from 20 to 65 years, further studies in adolescents and those aged over 65 years are warranted.
Prior studies have shown that several variables, such as gender, BMI, smoking status, physical exercise, stress levels, medications, and medical and/or psychological morbidities may influence the vagal control of HRV (Cohen et al., 1999). However, our study had a highly-controlled protocol for adjusting the potential effects of the above-mentioned non-genetic confounders. Indeed, even when further analyzing the subsample composed of only drug- and comorbidity-free GAD patients and healthy controls to minimize confounding effects, the results still remained. In addition, HRV patterns may vary in the n-acetyl-l-cysteine mg due to racial stratification (Martin et al., 2010). However, all the subjects in our study were Han Chinese, drawn from northern Taiwan, which has been revealed to have high levels of genetic homogeneity (Chang et al., 2017). Thus, the current findings may precisely show the associations between the COMT gene, resting parasympathetic control and GAD, without the aforementioned biases. Altogether, these facts may suggest that our study results are less likely to be false-positive findings.
This study has some limitations that must be mentioned. We did not control for the respiratory rate, which has been shown to influence HRV measures (Cohen et al., 1999). However, this may not affect our findings since differences in HRV between spontaneous and metronome-guided breathing are relatively small (Bloomfield et al., 2001). Furthermore, it should be cautious when explaining the 5-min changes in the HRV monitoring. However, short-term resting HRV recordings have been demonstrated to be highly reliable (Sandercock et al., 2005). In addition, the studied COMT minor (Met) allele frequency is obviously lower in this Asian sample (˜0.25) than in the Western population (˜0.48) (Smith and Boettiger, 2012). Future studies should be conducted in large, racially diverse samples, with an adequately-controlled method such as ours, to validate the current research findings.
Conclusion In summary, our data suggest that functional Val158Met polymorphism of the COMT gene is correlated with decreased resting vagal control in an age-dependent manner, and this is, in turn, further associated with increased risk for GAD. These findings may show the age-specific parasympathetic pathways underlying the complex associations between COMT Val158Met variant and GAD.
Conflict of interest
Acknowledgements This study was supported by grants MAB-104-074 and MAB-106-108 from Medical Affairs Bureau, Ministry of National Defense, Taipei, Taiwan. We thank Ms. Hsiao-Hsin Hung for her assistance in preparing this manuscript. Preliminary results were presented as a poster at the 2018 45th Annual Military Medicine Symposium, Taipei, Taiwan.
Introduction The main function of the enzyme catechol-O-methyltransferase (COMT) is to inactivate dopamine, norepinephrine, and epinephrine neurotransmitters in the mammalian brain (Tunbridge et al., 2006). A single-nucleotide polymorphism (SNP) of the gene for COMT results in a valine-to-methionine mutation at position 158. The homozygous Val variant metabolizes dopamine up to four times the rate of its methionine (Gogos et al., 1998; Mattay et al., 2003; Slifstein et al., 2008). The influence of the COMT polymorphism is especially prominent in the prefrontal cortex (PFC) due to the lack of dopamine transporter in this region (Mattay et al., 2003; Slifstein et al., 2008). Due to these increased synaptic dopamine levels, Met carriers feature more stress reactivity and pain sensitivity as well as schizophrenia (Meyer-Lindenberg, 2010; Zubieta et al., 2003). Other research has also shown that the COMT Val158Met polymorphism is significantly associated with changes in brain connectivity (Zhang et al., 2015) and that it interacted with both parental warmth and stressful life events to influence affective decision-making (He et al., 2012).