The splice variant rs72613567 (-/A) in HSD17B13 (17-beta-hydroxysteroid dehydrogenase 13) protects patients with NAFLD from severe histological outcomes, including fibrosis, ballooning and lobular inflammation

PIROLA CJ; FLICHMAN D; GARAYCOECHEA M; CASTANO GO; GAZZI C; SOOKOIAN S

San Francisco, CA

Congreso; 69th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2019; 2018

American Association for the Study of Liver Diseases

The rs72613567 (-/A) deletion/insertion(INS)-variant in HSD17B13 has been recently associatedwith serum levels of aminotransferases; the A-INS alleleconfers protection against chronic liver damage in European-Americans, in whom A-INS frequency is 24%. To what extentthese findings can be generalized to other populations isunknown. Methods: We explored the association betweenrs72613567 and the histological spectrum of NAFLD ina hospital-based case-control study (n=609 individuals,including 356 patients with biopsy-proven NAFLD).Genotyping was performed using a custom TaqMan assay,and confirmed by Sanger sequencing. Data imputation (57SNPs assessed, ~100 kb around HSD17B13 locus) from apopulation-based GWAS (Affymetrix Axiom Genome WideLAT1) (n=1038 individuals) was performed to assess thefrequency of rs72613567 in Latin American population.Results: Frequency of A-INS allele was 13% (populationbasedGWAS) and 16% (case-control study); distribution ofgenotypes was in Hardy-Weinberg?s equilibrium. In the casecontrolstudy, the rs72613567 was associated with reducedchances of having NAFLD (p=0.013, adjusted by HOMA-IRand PNPLA3-rs738409; odds ratio per A-allele (OR): 0.63,95% CI 0.43-0.90; additive model). The rs72613567 wassignificantly associated with the disease severity (p=0.014,adjusted by covariates). The presence of the A-INS allele wasassociated with a protective effect against severe histologicaloutcomes, including ballooning degeneration (p=0.022, OR:0.32 95%CI 0.32-0.91) and lobular inflammation (p=0.003,OR: 0.475 95% CI 0.290-0.778). Persons carrying the A-INSallele had lower chances to present fibrosis compared withhomozygous -A/-A (p=0.047, OR 0.627 95%CI 0.394-0.997),and had lower levels of serum ALT and AST. In addition,we found the variant associated with anthropometricalquantitative traits, including waist circumference (p=0.0032).Conclusion: Our study confirms that the presence ofrs72613567 A-INS, the functional consequence of which maybe a loss-of-function HSD17B13 protein, confers protectionagainst NAFLD-associated histological damage. Personscarrying the A-INS allele have 30%-lower odds of presentingliver fibrosis. The presence of the A-INS allele of rs72613567mitigates the progression of NAFLD in patients from SouthAmerica (SA); however, the frequency of the variant in SA ismuch lower than in Europeans. Variation across populationsmight explain differential prevalence/severity of the diseaseacross ethnic groups.