Genetic variation in SULF2 is associated with postprandial clearance of triglyceride-rich remnant particles and triglyceride levels in healthy subjects

Abstract

Context: Nonfasting (postprandial) triglyceride concentrations have emerged as a clinically significant cardiovascular disease risk factor that results from accumulation of remnant triglyceride-rich lipoproteins (TRLs) in the circulation. The remnant TRLs are cleared from the circulation by hepatic uptake, but the specific mechanisms involved are unclear. The syndecan-1 heparan sulfate proteoglycan (HSPG) pathway is important for the hepatic clearance of remnant TRLs in mice, but its relevance in humans is unclear.

Objective: We sought to determine whether polymorphisms of the genes responsible for HSPG assembly and disassembly contribute to atherogenic dyslipoproteinemias in humans.

Patients and design: We performed an oral fat load in 68 healthy subjects. Lipoproteins (chylomicrons and very low density lipoproteins 1 and 2) were isolated from blood, and the area under curve and incremental area under curve for postprandial variables were calculated. Single nucleotide polymorphisms in genes encoding syndecan-1 and enzymes involved in the synthesis or degradation of HSPG were genotyped in the study subjects.

Results: Our results indicate that the genetic variation rs2281279 in SULF2 associates with postprandial clearance of remnant TRLs and triglyceride levels in healthy subjects. Furthermore, the SNP rs2281279 in SULF2 associates with hepatic SULF2 mRNA levels.

Conclusions: In humans, mild but clinically relevant postprandial hyperlipidemia due to reduced hepatic clearance of remnant TRLs may result from genetic polymorphisms that affect hepatic HSPG.

Figure 1. Postprandial TG and apoB48 in plasma and in lipoprotein subclasses stratified by SULF2 rs2281279 genotype.

Carriers of the G allele had lower AUC for plasma TG (A) and TG content of VLDL1 (C) and VLDL2 (D) than AA homozygotes; the chylomicron TG content (B) did not differ between the different genotype carriers. Carriers of the G allele had lower AUC for apoB48 content of chylomicrons (F) and VLDL1 (G) than AA homozygotes; the apoB48 content in plasma (E) and VLDL2 (H) did not differ between the genotype groups. Data are shown as median (interquartile range). P values were calculated by linear regression adjusting for age, gender and body mass index (BMI). All the data is specified in Table S5. The number of subjects is given at the bottom of each column. AA, subjects with two A alleles; AG, heterozygotes; GG, subjects with two G alleles.