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 (HbA_1c) 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 HbA_1c <6.5%, and thus might be useful in identifying those at high risk of CHD who would benefit from maintaining HbA_1c <6.5%. Objectives This study sought to model whether HbA_1c < 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 HbA_1c 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 HbA_1c <6.5%, the RR of CHD for HbA_1c <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 HbA_1c <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.