2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
tein. Our finding indicate that ABCB4 mutations seem to predispose to
ICP phenotype in less than 20% of the affected women, irrespective
of serum γGT levels.
P09.061
Variation in the interleukin-1 receptor-associated kinase 3 gene
and susceptibility to sepsis induced-acute lung injury
C. Flores 1,2 , M. Pino-Yanes 1,2 , T. Paula 3 , L. Perez-Mendez 1,2 , E. Espinosa 4 , A.
Corrales 1,2 , R. Sanguesa 4 , M. Hernandez 5 , A. Muriel 6 , M. Muros 1,7 , J. Blanco 1,6 ,
J. Villar 1,8 ;
1 CIBER de Enfermedades Respiratorias, Spain, 2 Research Unit, Hospital
Universitario NS de Candelaria, Spain, 3 Department of Environmental Health,
Harvard School of Public Health, Boston, MA, United States, 4 Department of
Anesthesia, Hospital Universitario NS de Candelaria, Spain, 5 Department of
Genetics, Universidad de La Laguna, Spain, 6 Intensive Care Unit, Hospital
Universitario Rio Hortega, Spain, 7 Department of Clinical Biochemistry, Hospital
Universitario NS de Candelaria, Spain, 8 MODERN, Research Unit, Hospital
Universitario Dr. Negrin, Spain.
Sepsis is the most common cause of acute lung injury (ALI), organ
dysfunction and death in critically ill patients. The Toll/NF-κB signaling
pathway has a key role in the immune response to infections. Variants
in two genes encoding for interleukin-1 receptor-associated kinases
(IRAKs) modify the immune response to pathogens and associate with
increased risk for severe complications during sepsis. Based on gene
expression data, showing up-regulation of IRAK3 in both animal models
of sepsis and in septic patients, here we explored whether common
variants of this gene were associated with susceptibility and outcomes
in severe sepsis. We re-sequenced 23 kb non-repetitive regions of the
gene in 32 Spanish samples, and selected a set of 7 tagging SNPs
(tagSNPs) that efficiently captured common variation in the population.
To test the association, tagSNPs were genotyped in 214 severe
sepsis cases and 336 population-based controls using the MassArray®
iPLEX Gold (Sequenom Inc.). One tagSNP showed a significant
association with ALI (p=0.005), and remained significant after multiple
testing adjustments. Indirect testing of untyped alleles revealed two
correlated SNPs (r 2 =0.85) from the 5’ flanking region of the gene associated
with ALI (permuted p=0.02), that were validated by further
genotyping and direct testing (pA
(rs6766410, p.N163K) coding variant to be associated with female
IBS-D (P= 0.0019; OR = 4.98 CI = [1.75-14.16]), whereas no association
could be found in males. Calcium influx analyses of the 5-HT 3A/C
p.163N and 5-HT 3A/C p.163K receptors resembling the homozygous
genotypes revealed identical potencies of 5-HT and two 5-HT 3 antagonists.
However, 5-HT showed decreased efficacy at 5-HT 3A/C p.163N
(78.1 ± 5.9 %) compared with 5-HT 3A/C p.163K (100 %, P < 0.01, n = 14)
receptors and radioligand binding assays revealed a reduced B max for
the 5-HT 3A/C p.163N (86.2 ± 3.7 %) compared with the 5-HT 3A/C p.163K
receptor (100 %, P