Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms

Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in nonalcoholic steatohepatitis (NASH). The goal of this study was to investigate the relationship between IL1B and IL6 gene polymorphisms and histologic features of NAFLD in the NASH CRN cohort. Methods 604 adult (≥18 yrs) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. Results The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. Conclusions These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1β and IL-6 suppression.

Whole‐Exome Sequencing Study of Extreme Phenotypes of NAFLD

“…In contrast, several variants enriched among high‐risk, low‐fibrotic NAFLD patients were observed in IL6‐related genes ( IL6 , IL32 , ORM1, and SLAMF7 ) in the NAFLD susceptibility investigation of protective versus population controls, suggesting a potential role for a pro‐inflammatory immune response. This finding is supported by recently published NASH Clinical Research Network data implicating pro‐inflammatory pathways, including common variants in IL1B and IL6 , with NAFLD fibrosis risk and ballooning . However, as protective individuals were obese with T2DM as part of the study design, the IL6‐related genes may also reflect T2DM risk.…”

“…Among progressors, two variants were enriched in IL1 signaling pathway genes (IRAK2 and VRK2), which could conceivably reflect disruption of this innate immune and tissue regeneration pathway in advanced fibrosis progression. (25) In contrast, several variants enriched among highrisk, low-fibrotic NAFLD patients were observed in IL6-related genes (IL6, IL32, ORM1, and SLAMF7) in the NAFLD susceptibility investigation of protective versus population controls, suggesting a potential role for a pro-inflammatory immune response. This finding is supported by recently published NASH Clinical Research Network data implicating pro-inflammatory pathways, including common variants in IL1B and IL6, with NAFLD fibrosis risk and ballooning.…”

“…Among the top associations in the NAFLD progressor versus protective comparison, several affected the immune genes, with distinct genes and biological processes observed for each phenotype. Among progressors, two variants were enriched in IL1 signaling pathway genes ( IRAK2 and VRK2 ), which could conceivably reflect disruption of this innate immune and tissue regeneration pathway in advanced fibrosis progression …”

“…This finding is supported by recently published NASH Clinical Research Network data implicating pro-inflammatory pathways, including common variants in IL1B and IL6, with NAFLD fibrosis risk and ballooning. (25) However, as protective individuals were obese with T2DM as part of the study design, the IL6related genes may also reflect T2DM risk.…”

Association between -174G>C polymorphism in the IL-6 promoter region and the risk of obesity

“…[ 26 ] A number of studies indicated that the IL-6–174G/C polymorphism was highly associated with obesity, fatty liver, insulin resistance, and the metabolic syndrome. [ 27 , 28 ] Meanwhile, many studies found that the IL-6–174G/C polymorphism was significantly associated with susceptibility to obesity. [ 13 , 20 ] However, some studies have reported no significant associations between adiposity and the IL-6–174G/C genotypes.…”