Abstract
THE SIGNIFICANT ASSOCIATION BETWEEN PNPLA3 G ALLELE AND ADVANCED FIBROSIS IN CHILDREN WITH NAFLD IS FURTHER INFLUENCED BY BMI AND type2 DIABETES
Background:
PNPLA3 rs738409 polymorphism, obesity, and type 2 diabetes mellitus (T2DM) are strongly associated with non-alcoholic fatty liver disease (NAFLD) and its severity in children. Whether PNPLA3 rs738409-related predisposition to NAFLD severity is influenced by obesity and T2DM in children with NAFLD is not known. Therefore, we examined the relationship between PNPLA3 rs738409, body mass index (BMI), T2DM, and the risk of advanced fibrosis in children with biopsy-proven NAFLD.
Methods:
1,047 children between 2 and 18 years of age with biopsy-proven NAFLD enrolled into Non-Alcoholic Steatohepatitis Research Network prospective studies were analyzed. The primary study outcome was biopsy-confirmed advanced fibrosis (fibrosis stage ≥3, ). T2DM was defined as self-reported, or HbA1c levels ≥6.5%, or fasting plasma glucose of ≥ 126 mg/dl, or current use of glucose-lowering medications. Logistic regression models were used to examine associations of rs738409 (additive model of inheritance; CC, CG, or GG), T2DM, and BMI with advanced fibrosis, while controlling for race/ethnicity, sex, and hypertension. Multiplicative interaction terms between rs738409, T2DM, BMI, and age were included in all models.
Results:
The cohort consisted of 724 Hispanics (69%) and 261 non-Hispanic Whites (25%).The PNPLA3 rs738409 variant was present at a frequency of 0.76. Among all children, rs738409 genotypes were distributed as follows: CC (n = 149, 14.3%), CG (n = 363, 34.6%), and GG (n = 535, 51.1%). The prevalence of advanced fibrosis was 13%. Out of 140 children with advanced fibrosis, 130 (93%) carried at least one PNPLA3 G allele (CG; 44/130 (33.8%) or GG; 86/130 (66.2%)). The PNPLA3 G allele was independently associated with a high risk of advanced fibrosis (OR: 1.55, 95% CI: 1.16-2.09). Compared with individuals with PNPLA3 CC genotype, , the risk of advanced fibrosis increased by 2.1-fold (95% CI: 1.0-4.3) for children with CG genotype and 2.8-fold (95% CI: 1.4-5.8) for children with GG genotype.
BMI was independently associated with advanced fibrosis, with stronger effects seen in children with PNPLA3 CG (OR: 1.03, 95% CI: 1.004-1.05) and GG (OR: 1.04, 95% CI: 1.014-1.06), compared with CC (OR: 0.99, 95% CI: 0.95-1.03) genotypes (Figure 1A), p for interaction <0.01. T2DM was positively associated with the risk of advanced fibrosis, with stronger effects among children with CG (OR: 3.6, 95% CI: 1.0-16.6) and GG (OR: 6.2, 95% CI: 1.4-28.0) compared with CC (OR: 2.9, 95% CI: 0.5-15.8) genotypes (Figure 1B), p for an interaction <0.01.
Conclusion:
PNPLA3 G-allele, higher BMI and T2 DM are significantly associated with advanced fibrosis in children with NAFLD, The adverse relationship between PNPLA3 G allele and advanced fibrosis is significantly worsened by higher BMI and type2 diabetes. This indicates aggressive attention to BMI and T2DM is particularly important in children with NAFLD carrying PNPLA3 G-allele.