The APOB R3500Q Mutation in Libya: Universal Heterozygosity and the Statin Masking Effect

الملخص

Familial defective apolipoprotein B-100 (FDB) is primarily driven by the APOB R3500Q (c.10580G>A) mutation. While extensively characterized in European cohorts, its prevalence and phenotypic expression in the Middle East and North Africa (MENA) region remain contested, and the diagnostic utility of standard lipid profiles in mutation carriers is increasingly compromised by aggressive lipid-lowering therapy. This study investigated the genetic prevalence, phenotypic expression, and cardiovascular implications of the APOB R3500Q mutation in a Libyan cohort. A retrospective case-control design with concurrent biomarker profiling was employed, comprising 59 participants (48 cases with severe coronary artery disease [CAD] and 11 healthy controls). Genotyping was performed using multiplex PCR and reverse-hybridization (CVD StripAssay®). Data were analyzed by multivariable logistic regression, Principal Component Analysis (PCA), and hierarchical clustering. All 59 participants (100%) carried the heterozygous (G/A) R3500Q genotype, a distribution that deviated significantly from Hardy-Weinberg equilibrium in the control group (χ²=11.0, df=1, P<0.001), suggesting a localized founder effect or a previously unmapped regional polymorphism. Cases unexpectedly showed lower LDL-C (P=0.034) and total cholesterol (P=0.044) than controls, a "pharmacological masking" effect attributable to high-intensity statin therapy in 87.5% of cases. The residual atherogenic risk was instead reflected in significant HDL-C depletion (P=0.047) and elevated TG/HDL ratios. Logistic regression identified age (OR=4.91, P=0.002) and hypertension (OR=3.75, P=0.008) as the principal independent predictors of CAD, consistent with a "triple hit" model in which genetic susceptibility requires cumulative temporal exposure and hemodynamic stress to precipitate clinical atherosclerosis. Cluster analysis further resolved this genetically uniform cohort into three distinct metabolic phenotypes. These findings indicate that the APOB R3500Q mutation is highly prevalent among Libyan patients but exhibits incomplete early-life penetrance, and that diagnostic and therapeutic strategies for FDB in heavily medicated populations should pivot from absolute LDL-C targets toward composite residual-risk markers such as HDL-C and the TG/HDL ratio. KEYWORDS: Apolipoprotein B; R3500Q mutation; familial defective apolipoprotein B-100; HDL-C depletion; cardiovascular disease; Libya