Abstract: Background and aims: Elevated transaminase levels are frequently encountered. ACOX2 deficiency-associated hypertransaminasemia (ADAH) arises from an inherited disruption in bile acid synthesis, leading to recurrent hypertransaminasemia. The frequency of the ADAH-causing variant (rs150832314, c.673C>T) is globally low (0.014-0.089%), suggesting ADAH?s rarity, with only five affected families documented in Spain. Our aim is to ascertain the prevalence of recurrent or persistent hypertransaminasemia in the general population and scrutinize the variant?s frequency across diverse subpopulations. This exploration aims to distinguish whether ADAH qualifies as a rare disease or possibly goes undiagnosed. Method: To assess the prevalence of recurrent or persistent hypertransaminasemia (defined as more than two determinations with ALT, AST, or GGT values exceeding normal levels, spaced at least 3 months apart), we conducted a retrospective analysis of clinical records (2018-2022) within the Cantabria Cohort. This cohort recruited individuals aged 40-70 years (n = 24852) from the general population. Employing Taqman probes (Ref. C_169947759_10), we genotyped the ACOX2 gene in 97 subjects exhibiting recurrent hypertransaminasemia (DNA supplied by Valdecilla Biobank). Minor Allele Frequency (MAF) information for the c.673C>T variant, as identified in sequencing studies (TopMed, ExAC,1000Genomes, GO Exome Sequencing Project, Allele Frequency Aggregator, gnomAD, The PAGE Study, Medical Genome Project healthy controls from the Spanish population), was acquired from the dbSNP and Ensembl databases. Additionally, the MAF of the c.673C>T variant was scrutinized within the GCAT cohort, comprising individuals residing in Catalonia, with both genomic sequencing (n = 785) and genotyping data (n = 4988, TopMed panel). Results: Within the Cantabria Cohort, 13% of participants exhibited recurrent or persistent hypertransaminasemia. Databases indicates that the Spanish population report the highest MAF of the c.673C>T variant (0.70%), with subsequent frequencies observed in the Dominican, Cuban, Central American, and Mexican populations. In the GCAT cohort, sequencing studies revealed a MAF = 0.51%, slightly diminishing in genotyping and imputation analyses (MAF = 0.46%). Regarding the hypertransaminasemia population in Cantabria, three heterozygous carriers of the c.673C>T variant were identified, resulting in a MAF of 1.57%. Conclusion: According to allele frequency, an estimated prevalence of ADAH ranging from 21 to 49 cases per 10, 000 inhabitants in Spain in 2023 suggests that this condition may not be rare in our country. However, the actual prevalence is anticipated to be lower, considering the unknown penetrance and expressivity of this entity. A multicenter study is currently in progress to elucidate the precise prevalence and clinical spectrum of ADAH.

Autoría

Descargar referencia