Keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations.
OBJECTIVE
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.
Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany. pavel.strnad@uniklinikulm.de
Pavel
P
Strnad
Qin
Q
Zhou
Shinichiro
S
Hanada
Laura C
LC
Lazzeroni
Bi Hui
BH
Zhong
Phillip
P
So
Timothy J
TJ
Davern
William M
WM
Lee
M Bishr
MB
Omary
D000082:Acetaminophen / Q000009:adverse effects; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D001213:Asian / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000208:ethnology / Q000235:genetics* / Q000401:mortality; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D053538:Keratin-18 / Q000235:genetics*; D053533:Keratin-8 / Q000235:genetics*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000208:ethnology / Q000235:genetics* / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*; D055815:Young Adult
D018712:Analgesics, Non-Narcotic; C488421:KRT18 protein, human; C426203:KRT8 protein, human; D053538:Keratin-18; D053533:Keratin-8; D000082:Acetaminophen