Use of PNPLA3, TM6SF2, and HSD17B13 for detection of fibrosis in MASLD in the general population

BACKGROUND: Genetic testing can be used to evaluate disease risk. We evaluated if the use of three Single Nucleotide Polymorphisms (SNPs), alone or combined into a genetic risk score (GRS), can aid identify significant fibrosis in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD).

METHODS: We assessed three known risk variants: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567. The study included 414 adult individuals invited from the Danish population, who were defined as at-risk of MASLD due to elevated ALT and body mass index (BMI) >25 kg/m2. Participants were assessed clinically and by the Fibrosis-4 (FIB-4) index and Fibroscan.

RESULTS: In total, 17 participants (4.1%) had alcohol-related liver disease, 79 (19.1%) had no evidence of liver disease, and four (1.0%) were diagnosed with other liver diseases, including malignant disease. The remaining 314 participants (75.8%) were diagnosed with MASLD. Of the 27 who underwent a liver biopsy for suspected fibrosis, 15 had significant fibrosis (≥F2) and 12 had no/mild fibrosis (F0/F1). The GRS was not associated with significant fibrosis (p=0.09) but PNPLA3 was with an odds ratio of 6.75 (95% CI 1.29 - 50.7; p=0.039) risk allele CG/GG versus CC. The diagnostic accuracy of PNPLA3 combined with an increased Fib-4 (>1.3) was excellent for detecting significant fibrosis with a sensitivity of 1.00 (95% CI 0.72-1.00), but the specificity was no better than for FIB-4 alone.

CONCLUSIONS: This study found no evidence to support the use of GRS for diagnosing significant fibrosis in MASLD. However, the combination of PNPLA3 and Fib-4 increased sensitivity considerably. In addition, ALT remains a useful tool for screening diagnosing other liver diseases than MASLD.