Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity.
Keratins (K) 8 and 18 variants predispose carriers to the development of end-stage liver disease and patients with chronic hepatitis C to disease progression. Hepatocytes express K8/K18, whereas biliary epithelia express K8/K18/K19. K8-null mice, which are predisposed to liver injury, spontaneously develop anti-mitochondrial antibodies (AMA) and have altered hepatocyte mitochondrial size and function. There is no known association of K19 with human disease and no known association of K8/K18/K19 with human autoimmune liver disease. We tested the hypothesis that K8/K18/K19 variants associate with primary biliary cirrhosis (PBC), an autoimmune cholestatic liver disease characterized by the presence of serum AMA. In doing so, we analyzed the entire exonic regions of K8/K18/K19 in 201 Italian patients and 200 control blood bank donors. Five disease-associated keratin heterozygous variants were identified in patients versus controls (K8 G62C/R341H/V380I, K18 R411H, and K19 G17S). Four variants were novel and included K19 G17S/V229M/N184N and K18 R411H. Overall, heterozygous disease-associated keratin variants were found in 17 of 201 (8.5%) PBC patients and 4 of 200 (2%) blood bank donors (P < 0.004, odds ratio = 4.53, 95% confidence interval = 1.5-13.7). Of the K19 variants, K19 G17S was found in three patients but not in controls and all K8 R341H (eight patients and three controls) associated with concurrent presence of the previously described intronic K8 IVS7+10delC deletion. Notably, keratin variants associated with disease severity (12.4% variants in Ludwig stage III/IV versus 4.2% in stages I/II; P < 0.04, odds ratio = 3.25, 95% confidence interval = 1.02-10.40), but not with the presence of AMA.


CONCLUSIONS
K8/K18/K19 variants are overrepresented in Italian PBC patients and associate with liver disease progression. Therefore, we hypothesize that K8/K18/K19 variants may serve as genetic modifiers in PBC.
Zhong
Bihui
B
Division of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Strnad
Pavel
P
Selmi
Carlo
C
Invernizzi
Pietro
P
Tao
Guo-Zhong
GZ
Caleffi
Angela
A
Chen
Minhu
M
Bianchi
Ilaria
I
Podda
Mauro
M
Pietrangelo
Antonello
A
Gershwin
M Eric
ME
Omary
M Bishr
MB
D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007583:Jejunum / Q000378:metabolism; D053538:Keratin-18 / Q000235:genetics* / Q000378:metabolism; D053539:Keratin-19 / Q000235:genetics* / Q000378:metabolism; D053533:Keratin-8 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged
D053538:Keratin-18; D053539:Keratin-19; D053533:Keratin-8