Catechol-O-methyltransferase association with hemoglobin A1c.

AIMS: Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. METHODS: We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women's Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. RESULTS: COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (ß=-0.032% [0.012], p=0.008) and borderline significant in MAGIC (ß=-0.006% [0.003], p=0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR=0.98 [0.96-0.998], p=0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR=0.81 [0.65-1.00], p=0.05). CONCLUSIONS: COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD.

Conscientiousness is modified by genetic variation in catechol-O-methyltransferase to reduce symptom complaints in IBS patients.

BACKGROUND: Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions or genes associated with cognitive function or sympathetic tone can influence complaints. Genetic variation in catechol-O-methyltransferase (COMT) is associated with anxiety, personality, pain, and response to placebo treatment. We hypothesized that the association of complaint reporting with personality might be modified by variation in the COMT val158met genotype. METHODS: We administered a standard 25-item complaint survey weekly over 3-weeks to a convenience sample of 187 irritable bowel syndrome patients enrolled in a placebo intervention trial and conducted a repeated measures analysis. RESULTS: We found that complaint severity rating, our primary outcome, was negatively associated with the personality measures of conscientiousness (ß = -0.31 SE 0.11, P = 0.003) and agreeableness (ß = -0.38 SE 0.12, P = 0.002) and was positively associated with neuroticism (ß = 0.24 SE 0.09, P = 0.005) and anxiety (ß = 0.48 SE 0.09, P < 0.0001). We also found a significant interaction effect of COMT met alleles (ß = -32.5 SE 14.1, P = 0.021). in patients genotyped for COMT val158met (N  = 87) specifically COMT × conscientiousness (ß = 0.73 SE 0.26, P = 0.0042) and COMT × anxiety (ß = -0.42 SE 0.16, P = 0.0078) interaction effects. CONCLUSION: These findings potentially broaden our understanding of the factors underlying clinical complaints to include the personality dimension of conscientiousness and its modification by COMT.