Lipoprotein lipase variants genetically associated with hypertension and metabolic syndrome – Abstract

Wen-Harn Pan

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Background: Metabolic syndrome is characterized by a clustering of insulin-resistance related disorders that include hypertension, hypertriglyceridemia, low HDL-C, hyperglycemia, and obesity. Little is known of the hierarchical origin of the disease. Here we report a series of studies designed to unravel further the genetic connections and genetic variants with respect to lipid metabolism, involving the lipoprotein lipase (LPL) gene, hypertension and metabolic syndrome.

Methods and Results: In the initial linkage study, nonparametric linkage analysis and transmission disequilibrium tests (TDT) showed significant linkage and association of the LPL marker on intron 6 with hypertension. Furthermore, linkage disequilibrium analysis, haplotypes construction, family-based association study, and finally re-sequencing the homozygotes with risk and protective alleles were performed, we identified two LPL genetic variants (or haplotypes) associated with elevated risk. A genetic variant ACATT, starting near the exon 6-intron 6 junction and spanning 1422 bp, was significantly associated with hypertension (p=0.04), with hypertension combined with elevated triglyceride (TG) (p<0.0001), and with metabolic syndrome (p=0.0047), according to the TDT. Another genetic variant C-AA-T, composed of three intron SNPs on introns 3 and 4, was also significantly associated with elevated triglyceride (p=0.005), with hypertension combined with elevated TG (p<0.0001), and with metabolic syndrome (p=0.033). The strongest association between LPL haplotypes and metabolic syndrome-related disorders was detected in subjects that carried both these risk haplotypes, each of which exists in a significant proportion (15-21%) in our studied population.

Conclusions: This finding lends support to the “lipotoxicity” theory for the development of hypertension, and metabolic syndrome and unravel the culprit variants associated with increased risk of these metabolic disorders.