The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish

Abstract

Objective: To determine whether long-term exposure to moderate elevations in plasma plant sterol levels increases risk for atherosclerosis.

Methods and results: In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Carriers of a single 574R allele had increased plant sterol levels (eg, 35%-37% higher plasma levels of sitosterol, campesterol, and stigmasterol) and increased plant sterol/cholesterol ratios (P<0.001 for all). 574R carriers had significantly decreased levels of lathosterol and lanosterol, precursors in a pathway for endogenous cholesterol synthesis, suggesting that plant sterols may alter regulation of genes involved in cholesterol synthesis. The G574R variant was not associated with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol levels. Compared with noncarriers, 574R carriers had decreased carotid intima-media wall thickness (0.62 versus 0.66 mm; age- and sex-adjusted P=0.03). Adjustment for body weight, blood pressure, and standard lipid measures (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) did not alter this association.

Conclusions: Although the G574R variant is associated with moderately elevated plant sterol levels, carriers of the 574R allele had modestly lower levels of carotid wall thickness compared with noncarriers.

Figure 1

Mean sitosterol levels by age and genotype.

Figure 2

Mean (and SD) values of intima-media wall thickness (IMT, in mm) between ABCG8 G574R heterozygotes and G574G (noncarriers) (A) and carotid IMT values in heterozygotes and noncarriers by age (B).

Figure 3

Alternations in cholesterol synthetic pathway through changes in plasma plant sterol levels.