Plasminogen alleles influence susceptibility to invasive aspergillosis.
Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.
Zaas
Aimee K
AK
Duke University Medical Center, Durham, North Carolina, United States of America. aimee.zaas@duke.edu
Liao
Guochun
G
Chien
Jason W
JW
Weinberg
Clarice
C
Shore
David
D
Giles
Steven S
SS
Marr
Kieren A
KA
Usuka
Jonathan
J
Burch
Lauranell H
LH
Perera
Lalith
L
Perfect
John R
JR
Peltz
Gary
G
Schwartz
David A
DA
D000483:Alleles; D000818:Animals; D001228:Aspergillosis / Q000235:genetics* / Q000382:microbiology* / Q000401:mortality / Q000473:pathology; D001232:Aspergillus fumigatus / Q000276:immunology / Q000472:pathogenicity; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008172:Lung Diseases, Fungal / Q000235:genetics* / Q000276:immunology / Q000382:microbiology* / Q000401:mortality; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D010958:Plasminogen / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*
D010958:Plasminogen