Nonalcoholic Fatty Liver Disease (NAFLD), But not Its Susceptibility Gene Variants, Influences the Decrease of Kidney Function in Overweight/Obese Children

Abstract

: Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of kidney disease in adults and children. However, it is uncertain whether this association is influenced by major NAFLD susceptibility genes. In a sample of 230 overweight/obese children, 105 with NAFLD (hepatic fat fraction ≥5% by magnetic resonance imaging) and 125 without NAFLD, rs738409 in PNPLA3, rs58542926 in TM6SF2, rs1260326 in GCKR, and rs641738 in MBOAT7 were genotyped. Abnormal kidney function was defined as estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m² and/or the presence of microalbuminuria (24 h urinary albumin excretion between 30 and 300 mg). In comparison with children without NAFLD, those with NAFLD showed increased prevalence of reduced eGFR (13.3% vs. 1.6%; p < 0.001) and microalbuminuria (8.6% vs. 3.4%, p = 0.025). TM6SF2, GCKR, and MBOAT7 risk alleles did not show any impact on kidney function, while the PNPLA3 G allele was associated with lower eGFR, but only in children with NAFLD (p = 0.003). After adjustment for confounders, NAFLD (OR, 4.7; 95% CI, 1.5-14.8; p_adj = 0.007), but not the PNPLA3 gene variant, emerged as the main independent predictor of renal dysfunction. Overall, our findings suggest that NAFLD remains the main determinant of decline in kidney function in overweight/obese children, while the PNPLA3 rs738409 prosteatogenic variant has a small impact, if any.

Keywords: NAFLD; PNPLA3 rs738409 gene polymorphism; children and adolescents; overweight/obesity; renal function.

Figure 1

eGFR levels according to PNPLA3, TM6SF2, GCKR, and MBOAT7 genotypes. eGFR is reported as mean ± SD, stratified by (A) PNPLA3 rs738409 C>G genotype, (B) TM6SF2 rs58542926 C>T genotype, (C) GCKR rs1260326 C>T genotype, and (D) MBOAT7 rs641738 C>T genotype. A dominant model of inheritance was assumed for the TM6SF2 rs58542926 polymorphism. * One-way ANOVA for comparisons between three groups; ^# Student’s t-test for comparisons between two groups.

Figure 2

Levels of albuminuria (mg/24 h) according to PNPLA3, TM6SF2, GCKR, and MBOAT7 genotypes. Urinary albumin is reported as median and interquartile ranges, stratified by (A) PNPLA3 rs738409 C>G genotype, (B) TM6SF2 rs58542926 C>T genotype, (C) GCKR rs1260326 C>T genotype, and (D) MBOAT7 rs641738 C>T genotype. A dominant model of inheritance was assumed for the TM6SF2 rs58542926 polymorphism. Kruskal–Wallis test for comparisons between three groups; ^# Mann–Whitney U test for comparisons between two groups.

Figure 3

Association between PNPLA3 genotypes and kidney function according to NAFLD status. (A) eGFR mean values and (B) urinary albumin median values, stratified by NAFLD status and PNPLA3 CC vs. CG + GG genotypes. A dominant model of inheritance was assumed for the PNPLA3 rs738409 polymorphism. NAFLD + and NAFLD - indicate children with and without NAFLD, respectively. (A) p for trend shows the linear association between eGFR mean values and PNPLA3 CC vs. CG + GG genotypes independently of NAFLD status; * p =0.003 for comparisons between PNPLA3 CC vs. CG + GG genotypes in NAFLD + children; * p_adj = 0.015 for comparisons between PNPLA3 CC vs. CG + GG genotypes in NAFLD + children adjusted for BMI-SD score and hepatic fat fraction (HFF%). (B) p for trend shows the linear association between urinary albumin median values and PNPLA3 CC vs. CG + GG genotypes independently of NAFLD status. Urinary albumin values have been log-transformed.