Genetic Modifiers of Cardiac Remodeling Severity in IVS4+919G>A-Associated Fabry Cardiomyopathy

The GLA IVS4+919G>A founder variant causes a late-onset, cardiac-predominant form of Fabry disease, yet the severity of cardiac remodeling varies markedly among affected men. We studied 167 unrelated male carriers. Genome-wide association analyses included 81 men aged ≥50 years for left ventricular hypertrophy (LVH; left ventricular mass index [LVMI] ≥ 51 g/m2.7) and septal hypertrophy (interventricular septal thickness at end-diastole [IVSd] ≥ 1.2 cm), and 149 men with plasma globotriaosylsphingosine (lyso-Gb3) measurements. Genotyping was performed with the Axiom Genome-Wide TPM 2.0 Array. Mean LVMI increased from 34.6 ± 11.3 g/m2.7 at 20–39 years to 75.1 ± 34.0 g/m2.7 at ≥60 years, although substantial variability persisted within each age stratum. rs1435166 and rs2572260, located in the adjacent EGLN1/SPRTN region, showed identical associations with LVH (both p = 4.14 × 10−8) and concordant genotypes in all 81 participants (dosage r2 = 1.00; D′ = 1.00), indicating a single regional association signal. The association remained evident in exact testing, Firth logistic regression, and an age-adjusted continuous-LVMI analysis yielded concordant results. In the age-adjusted analysis, each rs1435166 T allele was associated with a 12.8 g/m2.7 lower LVMI. Two intergenic variants met the exploratory threshold for septal hypertrophy, whereas no variant reached genome-wide significance for lyso-Gb3. These findings support the hypothesis that inherited genetic background contributes to variation in cardiac remodeling severity among carriers of the same pathogenic GLA variant. Independent replication, regional fine-mapping, and functional validation are required.