Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys

Abstract

Objective: To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys.

Study design: There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits.

Results: The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7^-07). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9^-07). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage.

Conclusions: In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies.

Keywords: Hispanic; fatty liver; fibrosis; genome wide; pediatrics.

Figure 1

Manhattan plots for NAS (A) and fibrosis (B). X-axis is chromosome number and y-axis is −log₁₀(P value) for the variant association differing from the expected frequency. Each point represents a single SNP.

Figure 2

(A) Regional plot for NAS. The −log₁₀(P value) from association analysis is shown for all SNPs in the region around the top SNP rs11166927 for NAS. X-axis shows position of the SNPs along chromosome 8; y-axis in the left gives −log₁₀(P value). P values were obtained by association analysis when including age and BMI Z-score as covariates and assuming an additive genetic model. Y-axis on the right shows recombination rate (cM/Mb). The r² shows measure of the linkage disequilibrium between this SNP and target SNP. The genes TRAPPC9 and KCNK9 are located in the region as indicated at the bottom of the figure. (B) Regional plot for fibrosis. The −log₁₀(P value) from association analysis is show for all SNPs in the region around the top SNP rs6128907 for fibrosis. X-axis shows position of the SNPs along chromosome 20; y-axis in the left gives −log₁₀(P value). P values were obtained by association analysis when including age and BMI Z-score as covariates and assuming an additive genetic model. Y-axis on the right shows recombination rate (cM/Mb). The r² shows measure of the linkage disequilibrium between this SNP and target SNP. The genes located in the region of ACTR5 are as indicated at the bottom of the figure.