A genetic basis of susceptibility to acute pyelonephritis.
BACKGROUND
For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.


RESULTS
We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.


CONCLUSIONS
The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring.
Lundstedt
Ann-Charlotte
AC
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
McCarthy
Shane
S
Gustafsson
Mattias C U
MC
Godaly
Gabriela
G
Jodal
Ulf
U
Karpman
Diana
D
Leijonhufvud
Irene
I
Lindén
Carin
C
Martinell
Jeanette
J
Ragnarsdottir
Bryndis
B
Samuelsson
Martin
M
Truedsson
Lennart
L
Andersson
Björn
B
Svanborg
Catharina
C
D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011704:Pyelonephritis / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics