GENETIC STUDY OF PHACTR1 AND FIBROMUSCULAR DYSPLASIA, META-ANALYSIS AND EFFECTS ON CLINICAL FEATURES OF PATIENTS

Abstract

Objective: We have recently established a complex genetic basis for fibromuscular dysplasia (FMD), a common cause of renovascular hypertension (HTN). Here we aimed to replicate the association between the PHACTR1 locus and FMD in a Polish case control study, and assess the effect of this genetic locus on clinical features of patients. Design and method: Patients are part of the ARCADIA-POL study (75% women, mean age =45 ± 11yrs) with confirmed FMD in at least one vascular bed. All patients underwent detailed clinical evaluation including: ABPM, biochemical evaluation, duplex Doppler and whole-body angio-CT. Controls were randomly ascertained from the WOBASZ study, a population-based Polish cohort. Genotyping for rs9349379 was by direct sequencing. We used logistic regression and global effect estimation using METAL, Mann-Whitney test for continuous traits and Fischer exact test for categories. Results: We analysed 151 FMD patients and 298 controls, all with European ancestry. We confirmed the association between rs9349379 and FMD in the ARCADIA-POL case control study and found 56% increased risk for FMD risk per A allele (OR = 1.56; 95%CI = 1.14–2.13; P = 5.5 × 10–3). We now globally update the estimated effect of this risk variant on FMD through meta-analysis of 1,283 FMD cases and 4,193 controls, (OR = 1.40; 95%CI = 1.27–1.55; P = 1.8 × 10–11). Among the 151 Polish patients, we found equal distribution of rs9349379 genotypes in both sexes (P = 0.64), current (P = 0.27) or ex-smokers (P = 0.42) and multifocal and unifocal FMD sub-phenotypes (P = 0.33). Patients with AG/AA genotypes tend to be less likely to present multivessel FMD (19%vs48% in GG patients, P = 0.04). No differences were found between mean age of FMD (P = 0.70) of HTN (0.77) diagnosis. However, patients with AG/AA genotypes tend to have an average of 4.4 years more delay between HTN and FMD diagnosis (P = 0.04). Conclusions: We provide confirmatory association between PHACTR1 locus with FMD in this first genetic study in a Polish population and an updated global effect through the largest existing genetic meta-analysis for this disease. Further confirmation is required for the association we observed among the risk allele carriers with less arterial beds affected and in longer delay of FMD diagnosis.