Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans.
Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.
Harrill
Alison H
AH
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Watkins
Paul B
PB
Su
Stephen
S
Ross
Pamela K
PK
Harbourt
David E
DE
Stylianou
Ioannis M
IM
Boorman
Gary A
GA
Russo
Mark W
MW
Sackler
Richard S
RS
Harris
Stephen C
SC
Smith
Philip C
PC
Tennant
Raymond
R
Bogue
Molly
M
Paigen
Kenneth
K
Harris
Christopher
C
Contractor
Tanupriya
T
Wiltshire
Timothy
T
Rusyn
Ivan
I
Threadgill
David W
DW
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000503:physiopathology*; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods; D013045:Species Specificity
C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D000082:Acetaminophen; D000410:Alanine Transaminase