Porphyria-associated genetic variation in heme biosynthesis genes: clinical manifestations and associations with clonal hematopoiesis in the UK Biobank

Abstract Porphyria comprises a group of disorders of heme biosynthesis characterized by marked genetic and clinical heterogeneity, and genotype–phenotype correlations remain incompletely defined in large-scale cohorts. Using individual-level data from the UK Biobank, we identified 17 variants in key heme biosynthesis genes among 53 of the 57 clinically diagnosed porphyria patients with available exome sequencing data; 8 of these variants had not been previously reported in porphyria. We examined their associations with hematologic traits, liver-related parameters, and clinical diagnoses, revealing distinct genotype–phenotype patterns across loci. PPOX c.251T > G (p.Val84Gly) was associated with reduced hematologic indices and an increased prevalence of anemia, while UROD c.637-54G > C was associated with elevated alanine aminotransferase and nonspecific liver abnormalities. Notably, CPOX c.685 C > T (p.Leu229=) was associated with higher malignancy prevalence in the absence of significant hematologic abnormalities, a pattern also observed in clinically diagnosed porphyria patients. We further observed that overall clonal hematopoiesis of indeterminate potential (CHIP) prevalence was comparable between porphyria patients and the reference group, whereas the proportion of individuals with large CHIP clones (VAF ≥ 10%) was higher among those with porphyria. Although no significant interaction between CHIP and porphyria was identified, CHIP remained independently associated with higher malignancy prevalence, whereas the association for porphyria did not reach statistical significance. Collectively, these findings expand the spectrum of porphyria-associated variants, delineate heterogeneous clinical manifestations across genetic loci, and identify an association between porphyria, CHIP, and malignancy prevalence, while suggesting that CHIP clones may undergo preferential expansion in the context of porphyria.