PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels

Abstract

Background & Aim: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys,but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of renal tubular injury (RTI) and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels. Methods: 217 patients with histologically-proven NAFLD, of which 75 had persistently nALT (below upper limit of normal for 3 months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction. Results: The nALT patient group had higher urinary neutrophil gelatinase-associated lipocalin levels (u-NGAL, a biomarker of RTI) (P <0.001), higher albuminuria (P =0.039) and greater prevalence of chronic kidney disease (CKD) (P =0.046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG 6 genotype was associated with higher u-NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration-based markers (β-coefficient: 22.29, 95% CI: 0.99-43.60, P =0.041). Conclusion: Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI.

PNPLA3 gene and kidney disease

“…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].…”

“…Additionally, in a recent cross-sectional study of nearly 100 Caucasian post-menopausal women with T2DM (approximately 44% of whom had NAFLD as detected by fatty liver index ≥ 60), Mantovani et al [26], showed that rs738409 G/G genotype was linked to lower eGFR CKD-EPI values and higher risk of prevalent CKD, even after adjustment for several cardio-metabolic risk factor and the presence of NAFLD. Recently, in a cross-sectional study of 227 Chinese adults with NAFLD on histology, Sun et al [27], reported that PNPLA3 GG genotype was associated with a higher risk of prevalent CKD, abnormal albuminuria or higher levels of urinary neutrophil gelatinase-associated lipocalin (a new marker of renal tubular injury), regardless of age, sex, hypertension, T2DM and severity of NAFLD.…”

“…Age, diabetes duration, hemoglobin A1c, insulin-resistance, systolic blood pressure, hypertension treatment, FLI Carriers of G/ G genotype had reduced eGFR levels and higher prevalence of CKD than to C/C or C/G genotypes Sun et al [27] Cross-sectional study: 227 Chinese patients with NAFLD biopsy G/G: n = 14 patients; G/C: n = 31 patients; C/C: n = 30 patients…”

“…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].…”