Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease

Salvatore Petta, Luca Valenti, Antonino Tuttolomondo, Paola Dongiovanni, Rosaria Maria Pipitone, Calogero Cammà, Daniela Cabibi, Vito Di Marco, Anna Ludovica Fracanzani, Sara Badiali, Valerio Nobili, Silvia Fargion, Stefania Grimaudo, Antonio Craxì

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Abstract

The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). Conclusion: The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885–1893).

Original languageEnglish
Pages (from-to)1885-1893
Number of pages9
JournalHepatology
Volume66
Issue number6
DOIs
Publication statusPublished - Dec 1 2017

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Interferons
Fibrosis
Liver
Innate Immunity
Odds Ratio
Genotype
Confidence Intervals
Gene Expression
Phospholipases
Linkage Disequilibrium
Chronic Hepatitis C
Gastroenterology
Liver Cirrhosis
Hepatitis
Histology
Alleles
Non-alcoholic Fatty Liver Disease
Infection
Genes
Proteins

ASJC Scopus subject areas

  • Hepatology

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Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. / Petta, Salvatore; Valenti, Luca; Tuttolomondo, Antonino; Dongiovanni, Paola; Pipitone, Rosaria Maria; Cammà, Calogero; Cabibi, Daniela; Di Marco, Vito; Fracanzani, Anna Ludovica; Badiali, Sara; Nobili, Valerio; Fargion, Silvia; Grimaudo, Stefania; Craxì, Antonio.

In: Hepatology, Vol. 66, No. 6, 01.12.2017, p. 1885-1893.

Research output: Contribution to journalArticle

Petta, Salvatore ; Valenti, Luca ; Tuttolomondo, Antonino ; Dongiovanni, Paola ; Pipitone, Rosaria Maria ; Cammà, Calogero ; Cabibi, Daniela ; Di Marco, Vito ; Fracanzani, Anna Ludovica ; Badiali, Sara ; Nobili, Valerio ; Fargion, Silvia ; Grimaudo, Stefania ; Craxì, Antonio. / Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. In: Hepatology. 2017 ; Vol. 66, No. 6. pp. 1885-1893.
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abstract = "The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95{\%} confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95{\%} confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). Conclusion: The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885–1893).",
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AU - Valenti, Luca

AU - Tuttolomondo, Antonino

AU - Dongiovanni, Paola

AU - Pipitone, Rosaria Maria

AU - Cammà, Calogero

AU - Cabibi, Daniela

AU - Di Marco, Vito

AU - Fracanzani, Anna Ludovica

AU - Badiali, Sara

AU - Nobili, Valerio

AU - Fargion, Silvia

AU - Grimaudo, Stefania

AU - Craxì, Antonio

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N2 - The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). Conclusion: The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885–1893).

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