Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia Paulo Caleb Junior Lima Santos a, * , Aline Cruz Morgan a , Cintia Elin Jannes a , Luciana Turolla a , Jose Eduardo Krieger a , Raul D. Santos b , Alexandre Costa Pereira a, * a Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, SP, Brazil b Lipid Clinic, Heart Institute (InCor), University of Sao Paulo Medical School, SP, Brazil article info Article history: Received 25 August 2013 Received in revised form 4 December 2013 Accepted 5 December 2013 Available online 4 January 2014 Keywords: LDLR gene Lipid-lowering therapy Familial hypercholesterolemia Type of mutation abstract Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Methods: For 14  3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. Results: The frequencies of the types of LDLR mutations were: null-mutation (n ¼ 40, 25.6%), defective- mutation (n ¼ 59, 37.8%), and without an identified mutation (n ¼ 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9  1.9 mmol/L, 7.9  1.7 mmol/L), compared to those with a defective (8.9  2.2 mmol/L, 7.0  2.0 mmol/L), or no mutation (7.9  1.9 mmol/L, 5.8  1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective(27.1%), and without mutations (47.4%) (p ¼ 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41 e58.16, p ¼ 0.02). Conclusions: Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation. Ó 2014 Published by Elsevier Ireland Ltd. 1. Introduction Familial hypercholesterolemia (FH; OMIM 143890) is an auto- somal dominant disease mainly caused by mutations in the low- density lipoprotein receptor (LDLR) gene. This common disorder is characterized by severely elevated LDL-C (low-density lipopro- tein cholesterol), xanthomas, and the development of premature cardiovascular disease (CVD). To date, more than 1000 mutations in the gene that encodes LDL receptors have been described world- wide [1e3]. The LDLR gene (606945) consists of 18 exons, with correlation between exons and the functional domains of the LDL receptor protein. Regarding the type of LDLR mutations, five classes based on phenotypic effects have been proposed. Class I mutations usually are nonsense mutations, large deletions and promoter mutations resulting in no detectable LDL receptor protein. Class II mutations (transport defective alleles) cause either complete (class II a) or partial (class II b) block of the transport of the LDL receptor from the endoplasmic reticulum to the Golgi apparatus. Class III mutations result in defective LDL binding; class IV mutations cause a defi- ciency in the internalization of LDL and class V mutations fail to recycle effectively [3e6]. * Corresponding authors. Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo Medical School, Av. Dr. Enéas de Carvalho Aguiar, 44 Cerqueira César, São Paulo, SP CEP 05403-000, Brazil. Tel.: þ55 11 2661 5929; fax: þ55 11 2661 5022. E-mail addresses: pacaleb@usp.br (P.C.JuniorL. Santos), alexandre.pereira@incor. usp.br (A.C. Pereira). Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis 0021-9150/$ e see front matter Ó 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.028 Atherosclerosis 233 (2014) 206e210