Research Article For reprint orders, please contact: reprints@futuremedicine.com Multivariate analysis for coronary heart disease in heterozygote familial hypercholesterolemia patients Juan Francisco S ´ anchez Mu ˜ noz-Torrero* , ‡ ,1 , Maria D Rivas ‡ ,2 , Jose Zamorano 2 , Pedro Pablo Joya-V ´ azquez 3 , Leopoldo Perez de Isla 4 , Teresa Padro 5 , Pedro Mata 6 & the SAFEHEART Investigators † 1 Department of Internal Medicine, Hospital San Pedro de Alcantara, Caceres, Spain 2 Research Unit, Hospital San Pedro de Alcantara, Caceres, Spain 3 Digestive Unit, Hospital General de Llerena, Llerena, Spain 4 Department of Cardiology, Hospital Clinico San Carlos, Madrid, Spain 5 Centro de Investigacion Cardiovascular CSIC-ICCC, Hospital Sant Pau & IIB-Sant Pau, & CIBEROBN, ISC III, Barcelona, Spain 6 Fundacion Hipercolesterolemia Familial, Madrid, Spain * Author for correspondence: Tel.: +34 6 5625 9939; juanf.sanchezm@gmail.com † A full list of SAFEHEART investigators is given in the supplementary material ‡ Authors contributed equally Aim: rs599839 polymorphism has been related with low levels of cholesterol and reduced coronary heart disease (CHD). Methods: We investigated the frequency of this polymorphism in patients with heterozy- gous familial hypercholesterolemia (HeFH) in the Spanish familial hypercholesterolemia cohort, 230 with and 202 without CHD. Results & discussion: A lower G-allele prevalence was observed in HeFH patients with CHD with respect to controls, 35 versus 45%, respectively (p = 0.029), suggesting a protective effect. However, it was found that there was no association between rs599839 alleles and CHD in the multivariate analysis. Conclusion: The frequency of the protective G-allele of the rs599839 polymorphism was lower in HeFH patients with CHD compared with those HeFH patients without CHD. However, its role in HeFH may be masked by very high levels of cholesterol. First draft submitted: 20 September 2017; Accepted for publication: 24 November 2017; Published online: 31 January 2018 Keywords: coronary heart disease • familial hypercholesterolemia • rs599839 polymorphism Familial hypercholesterolemia (FH) is an autosomal disorder characterized by high concentrations of low-density lipoprotein (LDL) cholesterol and a greater risk of premature atherosclerotic cardiovascular disease [1,2]. High concentrations of LDL cholesterol are associated with worse prognosis in individuals with FH [3]. However, the levels of cholesterol in these patients are influenced by factors other than mutations within the APOB, LDLR, PCSK9 genes since patients carrying identical heterozygous mutations can present variable LDL cholesterol concentrations. It is very probable that in addition to the genetic and environmental factors, there are other factors that may explain the great phenotypic heterogeneity among individuals with the same FH genotype [4,5]. Recent genome-wide SNP association studies have identified a number of SNPs associated with cardiovascular disease and myocardial infarction [6,7]. Among them, the SNP rs599839 located in the 3 ′ UTR of the PSRC1 gene near the SORT1 gene on chromosome 1p13.1 has been reported to be associated with LDL cholesterol levels [8,9]. The minor G-allele has been associated with increased expression of SORT1 mRNA leading to an increase in LDL cholesterol uptake into cells [10]. This effect decreases total plasma cholesterol and LDL cholesterol levels that may lower the risk of coronary heart disease (CHD) [11]. However, the impact of SNP rs599839 on patients diagnosed with FH has not yet been defined. The aim of this case–control study was to investigate the frequency of the SNP rs599839 in patients with genetically confirmed diagnosis of heterozygous familial hypercholesterolemia (HeFH) and its possible association with CHD. Per. Med. (2018) 15(2), 87–92 ISSN 1741-0541 87 10.2217/pme-2017-0075 C  2018 Future Medicine Ltd