Abstract 15011: Genetic Variants in ABCG5/G8 Are Associated With Primary Hypercholesterolemia

Introduction: A large proportion of subjects with primary hypercholesterolemia do not have a causative mutation in LDLR, APOB, or PCSK9. GWAs have identified ABCG5 and ABCG8 associated with LDL cholesterol (LDLc) levels. ABCG5/G8 encode for transporters that play an important role in decreasing sterols intestinal absorption and promoting its biliary excretion. The downexpression in ABCG5/G8 produce an increase of cholesterol into the VLDL and LDL leading to hypercholesterolemia. Hypothesis: ABCG5/G8 genetic variants are associated with primary hypercholesterolemia. Methods: We have sequenced ABCG5 and ABCG8 promoters, coding regions, and intron-exon boundaries in 191unrelated subjects with LDLc >95th percentile, triglycerides <200 mg/dl and body mass index (BMI) <27.5 kg/m2 and no mutation in PCSK9, LDLR and APOB. Bioinformatical analysis were carried out with MutationTaster, PolyPhen-2 and SIFT and statistical analysis were performed using SPSS software v.20. Results: We have identified 21 and 25 previously identified variants in ABCG5 and ABCG8 respectively. In addition, we have found a new ABCG5 variant p.(Asn285Ser). By comparing the allelic frequencies of those variants with the reported by 1000 Genomes Project we have found differences with statistical significance in 10 and 7 SNPs in ABCG5 and ABCG8 respectively. Three of these changes have been predicted as damaging or disease causing by Bioinformatical analysis: p.Arg50Cys, p.Asn440Lys and p.Val151Val. Multivariate lineal regression using LDLc as dependent variable has shown that c.502-273A>G in ABCG5, BMI and c.*380T>G in ABCG5 explain independently of age and gender the 13,1% of the LDLc variability (p=0.002). Conclusions: Common and rare genetic variants in ABCG5/G8 are associated with primary hypercholesterolemia. Common ABCG5 variants explain a substantial proportion of LDLc in primary hypercholesterolemia, suggesting a polygenic background in some cases with this phenotype. ![][1] [1]: /embed/graphic-1.gif