Keratin variants predispose to acute liver failure and adverse outcome

Race and ethnic associations

Pavel Strnad, Qin Zhou, Shinichiro Hanada, Laura C. Lazzeroni, Bi Hui Zhong, Phillip So, Timothy J. Davern, William M. Lee, M. Bishr Omary

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background & Aims: Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans. Methods: We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects). Results: Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008). Conclusions: KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

Original languageEnglish (US)
JournalGastroenterology
Volume139
Issue number3
DOIs
StatePublished - 2010

Fingerprint

Acute Liver Failure
Keratins
African Americans
Exons
Keratin-8
Keratin-18
K-18 conjugate
Liver
Wounds and Injuries
Acetaminophen
Introns
Genes
Liver Diseases
Fibrosis
Animal Models
Transplantation
Amino Acids
Control Groups

Keywords

  • Acetaminophen Toxicity
  • Acute Hepatitis
  • Intermediate Filaments
  • Keratin Mutations
  • Keratins 8 and 18

ASJC Scopus subject areas

  • Gastroenterology
  • Medicine(all)

Cite this

Strnad, P., Zhou, Q., Hanada, S., Lazzeroni, L. C., Zhong, B. H., So, P., ... Omary, M. B. (2010). Keratin variants predispose to acute liver failure and adverse outcome: Race and ethnic associations. Gastroenterology, 139(3). https://doi.org/10.1053/j.gastro.2010.06.007

Keratin variants predispose to acute liver failure and adverse outcome : Race and ethnic associations. / Strnad, Pavel; Zhou, Qin; Hanada, Shinichiro; Lazzeroni, Laura C.; Zhong, Bi Hui; So, Phillip; Davern, Timothy J.; Lee, William M.; Omary, M. Bishr.

In: Gastroenterology, Vol. 139, No. 3, 2010.

Research output: Contribution to journalArticle

Strnad, P, Zhou, Q, Hanada, S, Lazzeroni, LC, Zhong, BH, So, P, Davern, TJ, Lee, WM & Omary, MB 2010, 'Keratin variants predispose to acute liver failure and adverse outcome: Race and ethnic associations', Gastroenterology, vol. 139, no. 3. https://doi.org/10.1053/j.gastro.2010.06.007
Strnad, Pavel ; Zhou, Qin ; Hanada, Shinichiro ; Lazzeroni, Laura C. ; Zhong, Bi Hui ; So, Phillip ; Davern, Timothy J. ; Lee, William M. ; Omary, M. Bishr. / Keratin variants predispose to acute liver failure and adverse outcome : Race and ethnic associations. In: Gastroenterology. 2010 ; Vol. 139, No. 3.
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abstract = "Background & Aims: Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans. Methods: We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49{\%} acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects). Results: Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1{\%}) versus controls (3.7{\%}) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23{\%} combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8{\%} vs 0.6{\%}, respectively; P = .008). Conclusions: KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.",
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T2 - Race and ethnic associations

AU - Strnad, Pavel

AU - Zhou, Qin

AU - Hanada, Shinichiro

AU - Lazzeroni, Laura C.

AU - Zhong, Bi Hui

AU - So, Phillip

AU - Davern, Timothy J.

AU - Lee, William M.

AU - Omary, M. Bishr

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N2 - Background & Aims: Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans. Methods: We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects). Results: Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008). Conclusions: KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

AB - Background & Aims: Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans. Methods: We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects). Results: Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008). Conclusions: KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

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