Association of Genetic Variants in PNPLA3, MBOAT7, and MARC1 with Metabolic and Hematological Immune-Inflammation Indices in Adolescent Females with and Without MASLD: A Multilevel Risk-Allele Burden Analysis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized during adolescence and exhibits sex-specific characteristics. Its prevalence in late adolescent females is around 10% in the general population and exceeds 30% in obesity. Genetic variants in PNPLA3, MBOAT7, and MARC1 modulate hepatic fat accumulation and liver injury in adults, but evidence in adolescent females remains limited. This study examined MASLD-related variants (PNPLA3 rs738409, MBOAT7 rs641738, MARC1 rs2642438) in relation to metabolic and immune-inflammation indices in a late-adolescent female cohort. A cross-sectional analysis was performed in a prospectively assembled female cohort (n = 150; age 16–19 years). Ultrasound-defined MASLD prevalence was 16.7%. Although genotype-wise differences did not reach statistical significance, MASLD prevalence was directionally higher among PNPLA3 G- and MBOAT7 T-allele carriers, while a non-uniform, directionally favorable pattern was observed for the MARC1 A allele. Nominal, unadjusted differences were observed for low-density lipoprotein cholesterol (LDL-c) and systemic immune-inflammation index (SII) across MBOAT7 genotypes. Cumulative risk-allele burden analyses identified nominal trends for triglycerides (K-W p = 0.05; J-T p = 0.014) and triglyceride-glucose (TyG) index (K-W p = 0.034; J-T p = 0.008), which were not retained after adjustment for age and body mass index. Overall, these findings indicate modest, exploratory genotype-related patterns in metabolic and hematological immune-inflammation indices within a relatively healthy, late-adolescent female population. TyG and SII exhibited substantial inter-individual variability but did not demonstrate independent predictive value. Larger, longitudinal studies with advanced imaging are required to clarify the role of genetic variation and simple hematological metabolic-inflammation indices in early MASLD risk assessment in adolescent females.