Associations of PNPLA3 and TM6SF2 gene polymorphisms and systemic inflammation with MASLD severity in patients with heart failure

Abstract

Objective — to evaluate the influence of PNPLA3 (rs738409) and TM6SF2 (rs58542926) allelic variants and systemic inflammation on the severity of liver steatosis, fibrosis stage, metabolic profile, and myocardial functional parameters in patients with metabolic dysfunction‑associated steatotic liver disease (MASLD) and concomitant heart failure with preserved ejection fraction (HFpEF). Materials and methods. The study included 125 patients with MASLD and HFpEF. Genotyping for PNPLA3 (rs738409) and TM6SF2 (rs58542926) single nucleotide polymorphisms was performed using Real‑Time PCR. Controlled Attenuation Parameter (CAP) for hepatic steatosis and liver fibrosis stages (F0–F4) were evaluated using transient elastography. Laboratory evaluation included serum triglycerides, low‑density lipoprotein cholesterol, and HOMA‑IR index. C‑reactive protein and interleukin‑6 levels assessed systemic inflammatory status. Statistical analysis was performed using SPSS. Results. Carriers of the PNPLA3 (rs738409) G‑allele demonstrated significantly higher degrees of steatosis (S2 — S3) and progressive liver fibrosis (F2 — F3), which strongly correlated with marked insulin resistance (HOMA‑IR > 4.5, p<0.05). TM6SF2 (rs58542926) T‑allele carriers displayed maximal CAP values (S3). Notably, these patients presented a «metabolic paradox»: serum low‑density lipoprotein cholesterol and triglyceride levels were significantly lower compared to C‑allele carriers (p<0.05) due to impaired very‑low‑density lipoproteins/low‑density lipoprotein export from hepatocytes. The co‑occurrence of PNPLA3 G‑allele and TM6SF2 T‑allele was associated with peak hepatic lipid accumulation, advanced fibrotic transition (F3 — F4), and marked deterioration of left ventricular diastolic function. Conclusions. The PNPLA3 (G‑allele) and TM6SF2 (T‑allele) are independent genetic predictors of progressive liver fibrosis in MASLD. Normal or reduced levels of atherogenic lipids in TM6SF2 T‑allele carriers mask a high lipotoxic risk to the liver (a phenotype of «vascular protection at the cost of liver injury»). Systemic low‑grade inflammation triggered by steatohepatitis ultimately negates this peripheral vascular protection, exacerbating myocardial diastolic dysfunction in HFpEF patients.