PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center

Background&aims Single nucleotide polymorphisms (SNPs) including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is practical in clinical routine. Therefore, we aimed at investigating the usefulness of genotyping for four important SNPs in clinical routine in the assessment of the severity of CLD.

Methods Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score.

Results Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 66 %), and ACLD was present in 217 (28 %) patients. The PNPLA3-G-allele remained independently associated with higher LSM (adjusted-B: 2.508 [95 %CI: 0.887-4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95 %CI: 1.097-2.226], P = 0.013). SERPINA1-Z-allele was also independently associated with LSM (adjusted-B: 4.558 [95 %CI: 1.182-7.934], P = 0.008). Neither did TM6SF2 increase LSM (P = 0.208) or the risk of ACLD (P = 0.503), nor was HSD17B13 risk allele expression associated with LSM (P = 0.067) or with higher odds of ACLD (P = 0.462).

Combining all risk alleles into a polygenic score was significantly associated with LSM (adjusted-B: 0.948 [95 %CI: 0.153-1.743], P = 0.020).

Conclusion We provide data on the usefulness of genotyping for important risk alleles in a cohort of CLD patients with Caucasian background in clinical routine. PNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic. Although SERPINA1 might add additional information on further risk of developing (severe) liver disease, PNPLA3 was identified to be of central importance and its use may be justified in the clinical routine.

Publication History

Article published online:
01 September 2021