The Risk of Coronary Heart Disease Associated With Glycosylated Hemoglobin of 6.5% or Greater Is Pronounced in the Haptoglobin 2-2 Genotype.
BACKGROUND
Research targeting glycosylated hemoglobin A1c (HbA1c) to <6.5% to prevent coronary heart disease (CHD) events has conflicting results. We previously observed the haptoglobin (Hp) Hp2-2 genotype is associated with a ∼10-fold increased CHD risk among individuals with HbA1c ≥6.5%, and thus might be useful in identifying those at high risk of CHD who would benefit from maintaining HbA1c <6.5%.


OBJECTIVE
This study sought to model whether HbA1c ≥ 6.5% in the Hp2-2 genotype is associated with CHD in a prospective case-control study nested within the Health Professionals Follow-Up Study (HPFS).


METHODS
HbA1c concentration and Hp genotype were determined for 695 incident cases of CHD from 1994 to 2010 and matched control participants. Logistic regression models calculated relative risk (RR) and 95% CI, for the first and second halves of follow-up, adjusting for confounding variables. A dataset from the Nurses' Health Study served as a replication cohort.


RESULTS
The prevalence of the Hp2-2 genotype in HPFS was 39%. Compared with HbA1c <6.5%, the RR of CHD for HbA1c ≥6.5% for the Hp2-2 genotype over full follow-up was 3.07 (95% CI: 1.37 to 6.86) to 3.88 (95% CI: 1.31 to 11.52) during the first half of follow-up and 2.16 (95% CI: 0.61 to 7.61) in the second half. The corresponding RRs for the Hp1-1 + Hp2-1 genotypes were: full follow-up, 2.19 (95% CI: 1.14 to 4.24); first half, 1.60 (95% CI: 0.73 to 3.53); and second half, 4.72 (95% CI: 1.26 to 17.65).


CONCLUSIONS
In 2 independent cohorts, the risk of CHD associated with HbA1c ≥6.5% is pronounced in the Hp2-2 genotype, particularly in early cases. The Hp2-2 genotype may identify individuals at greatest CHD risk from hyperglycemia.
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Electronic address: lcahill@hsph.harvard.edu.
Leah E
LE
Cahill
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Majken K
MK
Jensen
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Stephanie E
SE
Chiuve
Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
Hadar
H
Shalom
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Jennifer K
JK
Pai
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Alan J
AJ
Flint
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Kenneth J
KJ
Mukamal
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
Kathryn M
KM
Rexrode
Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
Andrew P
AP
Levy
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Eric B
EB
Rimm
D000368:Aged; D015415:Biomarkers; D016022:Case-Control Studies; D003327:Coronary Disease / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis*; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment
D015415:Biomarkers; D006442:Glycated Hemoglobin; D006242:Haptoglobins; C485359:HP protein, human
acute myocardial infarction; coronary disease; epidemiology; genetic association; glycoproteins