Is the HNF4A gene variant paradoxically associated with better prognostic in CAD patients?

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Abstract Background The Hepatocyte nuclear factor 4 A (HNF4A) gene was considered to be associated with susceptibility to atherosclerosis and coronary artery disease (CAD). It encodes a protein HNF4α, a genetic transcription factor regulating the genetic expression of thousands of genes playing essential roles in glucose and lipid metabolism. Its abnormal expression is emerging as a critical factor in diabetes, dyslipidemia, and cancer. Loss of function of specific mutations could attenuate its role in CAD pathogenesis and the progression of atherosclerosis. Aim To investigate whether a genetic variant (HNF4α rs1884613 C>G) could be associated with a low genetic function and, paradoxically, a better prognostic in CAD patients. Methods A cohort of 1,718 patients with coronary angiography (>70% stenosis of at least one main coronary vessel) from the GENEMACOR Study was investigated. Thirty-three genetic variants were genotyped using TaqMan assay methodology and HNF4A rs1884613 C>G genotype models were individually studied regarding the occurrence of Major Adverse Cardiovascular Events (MACEs). We used bivariate analysis to evaluate genotypic and allelic differences. Multivariate Cox regression analysis estimated variables independently associated with MACE, and Kaplan-Meier estimate methodology assessed the survival. Results Of the 1,718 CAD patients with the CC wild type, 73.4% had MACE, compared with 66.5% without. CG had 25.2% compared with 30.5% without. Finally, in the GG genotype, only 1.4% had events compared with 3.0% without (p=0.004). Cox regression analysis showed that GG genotype (mutated) is significantly and independently associated with 56% of MACE protection with a hazard ratio (HR) of 0.436; p=0.014. Physical inactivity and type-2 Diabetes remained independently associated with MACE occurrence (Fig.1). Kaplan-Meier cumulative event analysis disclosed that the carriers of the GG genotype were significantly associated with a better event-free time, and CC discloses a worse event-free time (Breslow test, p=0.001) (Fig.2). Conclusions The rs1884613 genetic variant of HNF4A is associated with a better CAD prognosis. This variant could probably induce gene downregulation and HNF4A gene function loss. Modifying and modulating hepatic lipase and lipid metabolism positively affected atherosclerosis progression. Future bioactive modulators for HNF4A variants could raise the possibility that diseases involving diabetes, lipid disorders, and cancer might be amenable to pharmacologic intervention.