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Original Investigation
January 20, 2021

Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women

Author Affiliations
  • 1Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Division of Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota
  • 3Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 4College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
  • 5Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Cardiol. 2021;6(4):437-447. doi:10.1001/jamacardio.2020.7073
Key Points

Question  Do risk profiles for coronary heart disease differ by age at onset?

Findings  In this cohort study including 28 024 women, associations of most risk factors with coronary heart disease attenuated with increasing age at onset. Of more than 50 clinical and biomarker risk factors examined, diabetes and lipoprotein insulin resistance had the highest relative risk, particularly for premature coronary heart disease; some risk factors (eg, inactivity, lipoprotein[a]) had similar associations by age at onset, and others had no association with coronary heart disease onset at any age.

Meaning  Risk profiles appear to differ by age at coronary heart disease onset in women, with the greatest risk for premature events associated with diabetes and insulin resistance.


Importance  Risk profiles for premature coronary heart disease (CHD) are unclear.

Objective  To examine baseline risk profiles for incident CHD in women by age at onset.

Design, Setting, and Participants  A prospective cohort of US female health professionals participating in the Women’s Health Study was conducted; median follow-up was 21.4 years. Participants included 28 024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020.

Exposures  More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers.

Main Outcomes and Measures  Four age groups were examined (<55, 55 to <65, 65 to <75, and ≥75 years) for CHD onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time.

Results  Of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95% CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non–high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)—all attenuating with age. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset.

Conclusions and Relevance  In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.