Research Article For reprint orders, please contact: reprints@futuremedicine.com Effect of genetic polymorphisms in SREBF-SCAP pathway on therapeutic response to rosuvastatin in Saudi metabolic syndrome patients Misbahuddin Mohd Rafeeq* ,1 , Hamed Said Habib 2 , Hussam Aly Sayed Murad 1,3 , Mamdouh Abdullah Gari 4 & Zohair Jamil Gazzaz 5 1 Department of Pharmacology, Faculty of Medicine, Rabigh Campus, King Abdulaziz University, Jeddah, Saudi Arabia 2 Department of Paediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia 3 Department of Pharmacology, Faculty of Medicine, Rabigh Campus, King Abdulaziz University, Jeddah, Saudi Arabia & Faculty of Medicine, Ainshams University, Cairo, Egypt 4 Department of Laboratory Medicine, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia 5 Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia * Author for correspondence: Tel.: +966 550 309 636; marafeeq@kau.edu.sa Aim: Genetic variants contribute to statins’ therapeutic variability. SREBF-SCAP pathway is a key player in lipid homeostasis. Hence, effect of SREBF-SCAP polymorphisms on therapeutic response was studied. Patients & methods: Metabolic syndrome patients of either sex were prescribed rosuvastatin 10 mg for 24 weeks. Clinical, anthropometric and lipid measurements were done before and after treatment. Geno- typing was done by pyrosequencing. Results & conclusion: No associations of SCAP and SREBF-1a geno- types with baseline lipids but signifcant associations with lipid reductions were observed. Signifcant ef- fect of SCAP (GG; B = -8.16, p = 0.001); SREBF-1a (GG; B = -7.47, p = 0.001) and SREBF-1a (–delG; B = -7.42, p = 0.001) was observed on total cholesterol reduction. Additive trend was found between SCAP genotypes and lipid reductions. A total of 88% responders have SCAP ‘G’ allele (p = 0.001). Patients car- rying SCAP (GG) and SREBF-1a (GG and –delG) have 9.5-, 8.6- and 14.6-times more likelihood of being responders (p < 0.05). ‘G’ allele in SCAP and SREBF-1a is signifcant predictor of rosuvastatin response. Keywords: lipid • obesity • polymorphisms • population • statins Metabolic syndrome (MetS) is a constellation of metabolic irregularities encompassing dyslipidemia, hypertension, hyperglycemia, insulin resistance, chronic proinflammatory and prothrombotic hypercoagulable state. The athero- genic dyslipidemia associated with MetS predispose to diabetes and cardiovascular events [1–3]. Additionally, MetS itself is a risk factor for micro- and macrovascular complications of diabetes mellitus [4]. Statins are established as a first-line remedy for reduction of cholesterol [5,6]. By inhibiting HMG-CoA re- ductase, hepatic de novo cholesterol synthesis is decreased, triggering multistep sterol regulatory element-binding factors (SREBF)–SREBF cleavage-activating protein (SCAP) pathway, ultimately increasing the hepatic low density lipoprotein (LDL) receptor expression and reducing blood cholesterol. Several large studies have reported their favorable effects in reduction of atherosclerotic cardiovascular mortality and morbidity [7–12]. In addition, statins have ‘pleiotropic’ effects, independent of their hypolipidemic action, for example, decreasing oxidative stress, plaque stabilization and increased nitric oxide availability and modulation of inflammation [13–16]. These actions benefit in reduction of MetS-associated risks. Rosuvastatin has revealed its superiority over other statins [17–25]. It has additional inhibitory action on cholesteryl ester transfer protein and hepatic lipase activity, leading to an increased high density lipoprotein (HDL). Rosu- vastatin also has minimal interaction with metabolizing enzymes. Age, sex and diurnal variation also do not affect its plasma concentrations. Nonetheless, polymorphisms in ABCG2 gene have shown to affect rosuvastatin pharmacokinetics [26–28]. Pharmacogenomics (Epub ahead of print) ISSN 1462-2416 10.2217/pgs-2017-0181 C  2018 Future Medicine Ltd