Catechol-O-methyltransferase association with hemoglobin A1c.
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.



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.



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).



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.
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Kathryn T
KT
Hall
The Biostatistics Center, George Washington University, Rockville, MD, USA.
Kathleen A
KA
Jablonski
Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
Ling
L
Chen
Genomics Platform, Broad Institute, Cambridge, MA, USA.
Maegan
M
Harden
Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Benjamin R
BR
Tolkin
Harvard Medical School, Boston, MA, USA.|Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Ted J
TJ
Kaptchuk
Pennington Biomedical Research Center, Baton Rouge, LA 70808.
George A
GA
Bray
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Paul M
PM
Ridker
Harvard Medical School, Boston, MA, USA.|Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Jose C
JC
Florez
Harvard Medical School, Boston, MA, USA.|Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Kenneth J
KJ
Mukamal
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Daniel I
DI
Chasman
D000483:Alleles; D001786:Blood Glucose / Q000032:analysis; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006442:Glycated Hemoglobin / Q000032:analysis*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide
D001786:Blood Glucose; D002394:Catechol O-Methyltransferase; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human; C588010:COMT protein, human
COMT; Diabetes Prevention Program (DPP); Hemoglobin A1C; Type 2 diabetes; Women's Health Study (WHS)