Sex-dependent associations of plasma high-density lipoprotein cholesterol and mortality risk in healthy older men and women: two prospective cohort studies

The relationship between high plasma high-density lipoprotein cholesterol (HDL-C) and cause and mortality are not well established in healthy older people. This study examined the associations between HDL-C levels and mortality in initially healthy older men and women. This analysis included participants from the Aspirin in Reducing Events in the Elderly (ASPREE; n=18,668) trial and a matched cohort from the UK Biobank (UKB; n=62,849 ≥65 years). Cox regression was used to examine hazard ratios between HDL-C categories <1.03 mmol/L, 1.03–1.55 mmol/L (referent category), 1.55–2.07 mmol/L, and >2.07 mmol/L and all-cause, cancer, cardiovascular disease (CVD), and “non-cancer non-CVD” mortality. Genetic contributions were assessed using a polygenic score for HDL-C. Among ASPREE participants (aged 75±5 years), 1836 deaths occurred over a mean follow-up of 6.3±1.8 years. In men, the highest category of HDL-C levels was associated with increased risk of all-cause (HR 1.60, 95% CI 1.26–2.03), cancer (HR 1.37, 95% CI 0.96–2.00), and “non-cancer non-CVD” mortality (HR 2.35, 95% CI 1.41–3.42) but not CVD mortality (HR 1.08, 95% CI 0.60–1.94). The associations were replicated among UKB participants (aged 66.9±1.5 years), including 8739 deaths over a mean follow-up of 12.7±0.8 years. There was a non-linear association between HDL-C levels and all-cause and cause-specific mortality. The association between HDL-C levels and mortality was unrelated to variations in the HDL-C polygenic score. No significant association was found between HDL-C levels and mortality in women. Higher HDL-C levels are associated with increased risk from cancer and “non-cancer non-CVD” mortality in healthy older men but no such relationship was observed in women. Supplementary Information The online version contains supplementary material available at 10.1007/s11357-023-00904-4.


Association of Plasma High-Density Lipoprotein Cholesterol and Mortality in Healthy Older Adults
Table S1: Information of 309 variants used in the polygenic risk score for HDL-C.
Table S2: Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality ASPREE: Excluding the US population, participants reporting high physical activity and adjustment for weight change from baseline to annual visit 2 (HR, 95% CI) Table S3: Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality excluding those with a history of prostate cancer and testosterone supplements ASPREE (HR, 95% CI), only males Table S4: Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality excluding those who were taking hormone replacement therapy ASPREE (HR, 95% CI), only females Table S5: Baseline characteristics of participants: Overall, and high-density lipoprotein cholesterol (HDL-C) category in the UK Biobank cohort Table S6: Association between baseline HDL and mortality in the UK Biobank: Caucasians only, Excluding those reporting high physical activity (HR, 95% CI) Table S7: Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality adjusted for HDL-C-PRS in the Aspirin in Reducing Events in the Elderly (ASPREE) and the UK Biobank (UKB) cohort (HR, 95% CI) Table S8: Death endpoint subtype for non-cancer non-cardiovascular cause Table S9: Comparison of associations between elevated high-density lipoprotein cholesterol (HDL-C) and cause and sex-specific mortality events observed in ASPREE, UKB and other previously published studies.

Fig S1 .
Fig S1.Distribution of HDL polygenic risk score: A. Aspirin in Reducing Events in the Elderly B. UK biobank Fig S2.Distribution of HDL cholesterol concentrations in the Aspirin in Reducing Events in the Elderly (ASPREE): A. Males B. Females Fig S3.Distribution of high-density lipoprotein cholesterol (HDL-C) concentrations in the UK Biobank (UKB): A. Males B. Females Fig S4.Nonlinear association between high-density lipoprotein (HDL) cholesterol levels in men in the UK Biobank (UKB): A. all-cause mortality, B. Cancer mortality, C. CVD mortality and D. noncancer-non-CVD mortality

Figure S5 .
Figure S5.Nonlinear association between high-density lipoprotein (HDL) cholesterol levels in women in the UK Biobank (UKB): A. all-cause mortality, B. Cancer mortality, C. CVD mortality and D. noncancer-non-CVD mortality

Table S1 :
Information of 309 variants used in the polygenic risk score for HDL-C.

Table S2 :
Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality ASPREE: Excluding the US population, participants reporting high physical activity and adjustment for weight change from baseline to annual visit 2 (HR, 95% CI)

Table S3 :
Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality excluding those with a history of prostate cancer and testosterone supplements ASPREE (HR, 95% CI), only males

Table S4 :
Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality excluding those who were taking hormone replacement therapy ASPREE (HR, 95% CI), only females

Table S5 :
Baseline characteristics of participants: Overall, and high-density lipoprotein cholesterol (HDL-C) category in the UK Biobank cohort

Table S6 :
Association between baseline HDL and mortality in the UK Biobank: Caucasians only, Excluding those reporting high physical activity (HR, 95% CI) a ethnic background not adjusted b physical activity not adjusted

Table S7 :
Association between baseline high-density lipoprotein cholesterol (HDL-C) and mortality adjusted for HDL-C-PRS in the Aspirin in Reducing Events in the Elderly (ASPREE) and the UK Biobank (UKB) cohort (HR, 95% CI) adjusted for age, country of birth, BMI, physical activity, alcohol use, smoking status, level of education, 100mg Aspirin, nonHDL-C, hypertension, diabetes, chronic kidney disease, and HDL PRS z score and principal components for population structure b adjusted for age, ethnic background, BMI, physical activity, alcohol use, smoking status, level of education, nonHDL-C, hypertension, diabetes, chronic kidney disease, and HDL PRS z score a

Table S8 :
Death endpoint subtype for non-cancer non-cardiovascular cause

Table S9 :
Comparison of associations between elevated high-density lipoprotein cholesterol (HDL-C) and cause and sex-specific mortality events observed in ASPREE, UKB and other previously published studies.Fig S2.Distribution of HDL cholesterol concentrations in the Aspirin in Reducing Events in the Elderly (ASPREE): A. Males B. Females A.