Catechol-O-methyltransferase association with hemoglobin A1c

Abstract

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 (β = −0.032% [0.012], p = 0.008) and borderline significant in MAGIC (β = −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.

The influence of dopamine-beta-hydroxylase and catechol O-methyltransferase gene polymorphism on the efficacy of insulin detemir therapy in patients with type 2 diabetes mellitus

“…They achieved significantly better HbA1c values after the 52-week treatment compared to patients carrying the GG genotype, pointing to the fact that presence of one or two A allele of the COMT Val108/158Met could be associated with a better response to insulin detemir therapy. This finding differs from the data from a recent study that reported an association of the G allele with lower values of HbA1c [ 50 ], but is partly consistent with the results from a male obesity study in Denmark in which the GG genotype was associated with impaired glucose tolerance and high fat BMI [ 29 , 50 ].…”

Systems Pharmacogenomics – Gene, Disease, Drug and Placebo Interactions: A Case Study in COMT

“…The COMT val-allele was modestly protective from risk of Type II diabetes [ [50][51] Cardiovascular disease The val-allele was protective from risk of cardiovascular disease in several studies [48,52,53] † The COMT rs4680 val-allele encodes a form of the enzyme which is 3-4× more active than the met-allele form.…”

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

“…Experimental and clinical data link reduced COMT activity and 2ME levels to the development of obesity and insulin resistance [99,100]. Moreover, a low-activity variant of COMT (val/met 158) may contribute to MS [99], whereas the high-activity form of COMT (rs4680) is associated with lower HbA1c and protection from type 2 diabetes [101]. Also, both genetic and pharmacologically-induced deficiency of COMT exacerbates high-fat diet (HFD)-induced insulin resistance in mice [100].…”