Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis

Abstract

Background: We aimed to investigate the association of serum pentadecanoic acid (15:0), a biomarker of dairy fat intake, with incident cardiovascular disease (CVD) and all-cause mortality in a Swedish cohort study. We also systematically reviewed studies of the association of dairy fat biomarkers (circulating or adipose tissue levels of 15:0, heptadecanoic acid [17:0], and trans-palmitoleic acid [t16:1n-7]) with CVD outcomes or all-cause mortality.

Methods and findings: We measured 15:0 in serum cholesterol esters at baseline in 4,150 Swedish adults (51% female, median age 60.5 years). During a median follow-up of 16.6 years, 578 incident CVD events and 676 deaths were identified using Swedish registers. In multivariable-adjusted models, higher 15:0 was associated with lower incident CVD risk in a linear dose-response manner (hazard ratio 0.75 per interquintile range; 95% confidence interval 0.61, 0.93, P = 0.009) and nonlinearly with all-cause mortality (P for nonlinearity = 0.03), with a nadir of mortality risk around median 15:0. In meta-analyses including our Swedish cohort and 17 cohort, case-cohort, or nested case-control studies, higher 15:0 and 17:0 but not t16:1n-7 were inversely associated with total CVD, with the relative risk of highest versus lowest tertile being 0.88 (0.78, 0.99), 0.86 (0.79, 0.93), and 1.01 (0.91, 1.12), respectively. Dairy fat biomarkers were not associated with all-cause mortality in meta-analyses, although there were ≤3 studies for each biomarker. Study limitations include the inability of the biomarkers to distinguish different types of dairy foods and that most studies in the meta-analyses (including our novel cohort study) only assessed biomarkers at baseline, which may increase the risk of misclassification of exposure levels.

Conclusions: In a meta-analysis of 18 observational studies including our new cohort study, higher levels of 15:0 and 17:0 were associated with lower CVD risk. Our findings support the need for clinical and experimental studies to elucidate the causality of these relationships and relevant biological mechanisms.

Fig 1. HRs of incident CVD as a function of serum pentadecanoic acid (15:0) in the 60YO study.

Data were fitted using Cox regression models adjusted for baseline age, sex, BMI, alcohol intake, smoking habits, physical activity, education, and prevalent hypertension, hyperlipidaemia, and type 2 diabetes. Dashed lines represent 95% confidence limits. The reference value of serum 15:0 is the 10th percentile (i.e., 0.17% of total fatty acids). The histogram shows the distribution of serum 15:0 in the cohort, and the tick marks under the histogram indicate serum 15:0 levels of individuals who experienced an incident CVD event during follow-up. CVD, cardiovascular disease; HR, hazard ratio.

Fig 2. HRs of all-cause mortality as a function of serum pentadecanoic acid (15:0) in the 60YO study.

Data were fitted using Cox regression models adjusted for baseline age, sex, BMI, alcohol intake, smoking habits, physical activity, education, and prevalent hypertension, hyperlipidaemia, type 2 diabetes, and CVD. Dashed lines represent 95% confidence limits. The reference value of serum 15:0 is the 10th percentile (i.e., 0.17% of total fatty acids). The histogram shows the distribution of serum 15:0 in the cohort and the tick marks under the histogram indicate serum 15:0 levels of individuals who died during follow-up. CVD, cardiovascular disease; HR, hazard ratio.

Fig 3. Flow chart of systematic review and selection process.

Fig 4. Risk estimates for CVD incidence and all-cause mortality in the top tertile of pentadecanoic acid (15:0) relative to the bottom tertile.

AT, adipose tissue; CE, cholesterol ester; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HF, heart failure; PP, plasma phospholipids; RBC, red blood cell (erythrocyte); RR, relative risk.

Fig 5. Risk estimates for CVD incidence and all-cause mortality in the top tertile of heptadecanoic acid (17:0) relative to the bottom tertile.

AT, adipose tissue; CE, cholesterol ester; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HF, heart failure; PP, plasma phospholipids; RBC, red blood cell (erythrocyte); RR, relative risk.