The cohort of 9,328 Caucasian ARIC participants had a mean age of 54 years at baseline, and 53% were female (). At baseline in 1987–89, mean (SD) levels of HDL-C, LDL-C, triglycerides and total cholesterol were 50.3 (16.8) mg/dL, 139 (39) mg/dL, 139 (94) mg/dL, and 216 (42) mg/dL respectively. 3.4% were taking pharmacologic agents to improve their lipid levels.
Characteristics, lipid levels, and pharmacologic use of lipid-lowering treatments across study visits: ARIC Caucasians, 1987–1998
Over 9 years of follow-up, overall HDL-C levels remained fairly stable, while LDL-C levels decreased and triglyceride levels increased (). The prevalence of hypercholesterolemia and use of medications to lower lipid levels increased greatly over the course of follow-up.
Cross-sectional relation of lipid gene scores to lipid levels
In cross-sectional analyses all four lipid gene scores were significantly related to their corresponding phenotypes (p<5 × 10−34 for all) (). After adjusting for age, sex, and center, the HDL-C gene score explained 1.6% of the variance in baseline HDL-C levels, and each standard deviation increase in the HDL-C gene score was associated with 1.89 mg/dL lower HDL-C levels. Sex modified the relation of the HDL-C gene score to HDL-C levels (p = 0.05). In stratified analyses, the association per 1 standard deviation higher HDL-C gene score was stronger among women (−2.16 mg/dL) than men (−1.56 mg/dL). For LDL, the LDL-C gene score explained 6.0% of the variation in LDL-C levels, and each standard deviation higher LDL-C gene score was associated with 9.5 mg/dL higher LDL-C levels. There was no evidence of sex-interactions in the relation of the LDL-C gene score to LDL-C levels. Similarly, the triglyceride gene score explained 6.0% of the variation in triglyceride levels, and levels were 22.8 mg/dL higher for each standard deviation higher triglyceride gene score. There was an interaction by sex (p < 0.0001), with each standard deviation higher triglyceride gene score having a greater association among men (26.5 mg/dL) then women (19.2 mg/dL). For total cholesterol, the gene score explained 6.8% of the variation, and each standard deviation higher total cholesterol gene score was associated with 10.7 mg/dL higher levels. No significant sex-interactions were present in the relation of the total cholesterol gene scores to levels of total cholesterol.
Longitudinal relation of lipid gene scores to lipid levels
Using linear mixed models regression ( and Supplemental Tables 2–5
), each standard deviation higher triglyceride gene score was associated with an increase in triglyceride levels of 0.3 mg/dL (p = 0.003) for each 3-year time-period. This result remained significant even after adjusting for BMI (p = 0.002). There was a three-way interaction (p=0.01; age*gene score*time) in that the greater increase in triglyceride levels at higher triglyceride gene scores was stronger among younger participants (age: 45–54; time*gene score interaction beta: 0.52; p-value: 0.0003) than older participants (age: 55–64; beta: 0.07; p-value: 0.62). The HDL-C gene score, LDL-C gene score and total cholesterol gene score were not significantly related to change in levels of their respective phenotypes.
Time trends in lipid levels according to phenotype-specific lipid gene scores: ARIC Caucasians, 1987–1998
In sensitivity analyses, we explored omitting people upon starting use of lipid lowering medications, and including only people in the analysis with lipid levels for all 4 visits. Results of these sensitivity analyses were similar to those of the primary analyses (data not shown).
Incidence of abnormal lipid levels
Lipid gene scores were positively related to incidence of abnormal lipid levels (). The HR (95% CI) for developing abnormal HDL-C levels per each standard deviation higher HDL-C gene score was 1.15 (1.10, 1.20). For LDL-C the comparable HR was 1.41 (1.32, 1.50), while for triglycerides it was 1.49 (1.41, 1.56), and for total cholesterol 1.36 (1.29, 1.45). Lipid gene scores for LDL-C, triglycerides, and total cholesterol also predicted incidence of lipid-lowering medication use, regardless of actual lipid levels. There was no evidence to suggest that sex or age significantly modified the relations of lipid gene scores to incidence of abnormal lipid levels or use of lipid lowering medications.
Hazard ratio (95% CI) of abnormal lipid levels and use of lipid-lowering medications per 1 standard deviation in lipid gene scores*: ARIC Caucasians, 1987–1998
Notably, for all traits, participants with higher gene scores had mean baseline lipid values closer to “abnormal” thresholds used to define incidence than did participants with lower lipid gene scores. For example, the cut-point for HDL-C was 40 mg/dL; the mean (SD) of HDL-C for those in the highest quartile of HDL-C gene score was 48.3 (16.0) mg/dL versus 53.4 (17.4) mg/dL for those in the lowest quintile. Similarly, those in the top quartile of LDL-C gene scores had mean LDL-C values closer to the abnormal cut-point (160 mg/dL) than those in the lowest quartile [149.3 (38.0) vs. 125.7 (36.8)]. The same held true for triglycerides [cutpoint: 200 mg/dL, mean among upper gene score quartile = 166.7 (117.0) mg/dL, mean among lower gene score quartile = 112.0 (63.8) mg/dL] and total cholesterol [cutpoint: 240 mg/dL, mean among upper gene score quartile = 227.7 (40.8) mg/dL, mean among lower gene score quartile = 201.8 (39.1) mg/dL].