Leah E Cahill1, Majken K Jensen2, Stephanie E Chiuve3, Hadar Shalom4, Jennifer K Pai5, Alan J Flint6, Kenneth J Mukamal7, Kathryn M Rexrode8, Andrew P Levy4, Eric B Rimm9. 1. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Electronic address: lcahill@hsph.harvard.edu. 2. 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. 3. 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. 4. Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel. 5. 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. 6. 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. 7. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 8. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. 9. 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.
Abstract
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%. OBJECTIVES: 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.
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%. OBJECTIVES: 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.
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