PREVALENCE OF ANGPTL3 AND APOB GENE MUTATIONS IN SUBJECTS WITH COMBINED HYPOLIPIDEMIA

Abstract

Introduction. Mutations of the ANGPTL3 gene have been found responsible for a novel form of primary hypobetalipoproteinemia (pHBL), the combined hypolipidemia, characterized by low total cholesterol (TC) and low HDL-cholesterol (HDL-C) levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in two large cohorts of 913 American and Italian subjects with primary hypobetalipoproteinemia (TC <5th percentile). Materials and Methods. The cut-offs adopted to define the combined hypolipidemia phenotype were chosen taking into account the TC and HDL-C levels reported in the ANGPTL3 kindred described to date and are as follows: TC levels <2nd percentile and HDL-C levels <20th percentile. We selected seventy-eight subjects with the combined hypolipidemia and analyzed the ANGPTL3 and the APOB genes. Results. We identified nonsense and/or missense mutations in ANGPTL3 gene in eight subjects; no mutations of the APOB gene were found in the seventy-eight subjects with the combined hypolipidemia phenotype ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3-negative subjects with combined hypolipidemia. Lipid profile of ANGPTL3 heterozyotes did not differ from ANGPTL3-negative subjects. Conclusion. These results demonstrated that in a cohort of subjects with severe pHBL the prevalence of ANGPTL3 gene mutations responsible of a combined hypolipidemia phenotype is high (about 10%) while mutations of APOB gene are absent.