Relationship Between PNPLA3 rs738409 Polymorphism and Decreased Kidney Function in Children With NAFLD

Abstract

Emerging evidence suggests that patatin‐like phospholipase domain–containing protein‐3 (PNPLA3) rs738409 genotype (the major genetic variant associated with susceptibility to nonalcoholic fatty liver disease [NAFLD]) is associated with decreased kidney function in adults. Currently, it is uncertain whether this association also occurs in children/adolescents and whether any association is independent of liver disease severity. We enrolled a sample of 142 Caucasian children and adolescents with biopsy‐proven NAFLD, presenting to the Liver Unit of the “Bambino Gesù” Children's Hospital. The glomerular filtration rate (e‐GFR) was estimated using the Bedside Schwartz equation, whereas 24‐hour proteinuria was measured using a radioimmunoassay method. Genotyping for the PNPLA3 rs738409 genotype was undertaken using the single‐nucleotide polymorphism genotyping allelic discrimination method. Overall, 45 children had G/G, 56 had G/C, and 41 had C/C PNPLA3 rs738409 genotype, respectively. Children with G/G genotype had significantly lower e‐GFR (107.5 ± 20 versus 112.8 ± 18 versus 125.3 ± 23 mL/min/1.73 m2, P = 0.002) and higher 24‐hour proteinuria (58.5 ± 21 versus 53.9 ± 22 versus 42.9 ± 20 mg/day, P = 0.012) compared with those with either G/C or C/C genotypes. After adjustment for age, sex, systolic blood pressure, measures of adiposity, homeostasis model assessment–estimated insulin resistance and biopsy‐confirmed nonalcoholic steatohepatitis and stage of liver fibrosis, the presence of rs738409 G/G genotype was independently associated with both lower e‐GFR (β coefficient: −23.6; 95% confidence interval [CI]: −36.3 to −10.8; P < 0.001) and higher 24‐hour proteinuria (β coefficient: 15.3; 95% CI: 1.12 to 30.5; P = 0.046). Conclusion: Regardless of established renal risk factors and the histological severity of NAFLD, the PNPLA3 G/G genotype was strongly associated with decreasing kidney function and increasing 24‐hour proteinuria in children/adolescents with histologically confirmed NAFLD.

Nonalcoholic fatty liver disease and eGFR levels could be linked by the PNPLA3 I148M polymorphism in children with obesity

“…Moreover, recently, Targher et al showed that—in children with histologically confirmed NAFLD—the patients homozygous for the PNPLA3 rare allele had lower eGFR and higher 24‐hour proteinuria compared with other genotypes …”

PNPLA3 gene and kidney disease

“…These findings were also replicated in some cohorts of children and adolescents [28,29], although not in all [30]. For instance, in a sample of nearly 140 overweight children with NAFLD on histology, Targher et al [28], reported that rs738409 G/G genotype was independently associated with both decreasing e-GFR and increasing 24 h urinary protein excretion. Another cross-sectional study involving 591 Caucasian children with obesity, it was documented that those with G/G genotype had significantly lower eGFR levels than those with G/C or C/C genotypes [29].…”

“…Increasing evidence now supports the existence of an association between PNPLA3 G/G genotype and decreasing eGFR values or higher prevalence of CKD across different patient population, even after controlling for many CKD risk factors and for the presence of NAFLD [24][25][26][27][28][29][30] (Table 1). For instance, in a cross-sectional study of 740 Japanese individuals (about 16% of whom had NAFLD on ultrasonography), Oniki et al [24], showed that patients with rs738409 G/G genotype had lower eGFR values than those with G/C or C/C genotypes, even after adjustment for multiple cardio-renal and metabolic risk factors.…”

“…Specifically, some variants related to NAFLD risk, including rs738409, show divergent effects between the traditional metabolic alterations and the development of diseases, especially for cardiovascular complications [6,42]. However, at present, accumulating observational data for rs738409 seems to indicate that this single nucleotide polymorphism might be associated to the presence of CKD [24][25][26][27][28][29][30].…”

“…In the last 5-10 years, several observational reports have documented that imaging-diagnosed NAFLD is independently associated with an increased risk of developing CKD in patients with and without T2DM [10][11][12][13][14][15][16][17][18][19][20][21][22][23]. In addition, accumulating evidence now suggests that the rs738409 G allele is associated with lower values of estimated glomerular filtration rate (eGFR) as well as with a higher risk of CKD in adults but also in adolescents and children, even after adjustment for the presence of NAFLD and multiple CKD risk factors [13,[24][25][26][27][28][29][30]. This association may explain, at least in part, the epidemiological association between liver and kidney disease [10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”