Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility
Daniel Kastner, Elaine Remmers and colleagues perform an association study of Behçet's disease based on dense genotyping of immune-related loci. They identify new association signals near genes involved in host response to microbial exposure and extend evidence for shared susceptibility loci wi...
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Veröffentlicht in: | Nature genetics 2017-03, Vol.49 (3), p.438-443 |
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Zusammenfassung: | Daniel Kastner, Elaine Remmers and colleagues perform an association study of Behçet's disease based on dense genotyping of immune-related loci. They identify new association signals near genes involved in host response to microbial exposure and extend evidence for shared susceptibility loci with Crohn's disease and leprosy.
We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for
HLA-B*51
. In the Turkish discovery set, we identified three new risk loci,
IL1A
–
IL1B
,
IRF8
, and
CEBPB
–
PTPN1
, with genome-wide significance (
P
< 5 × 10
−8
) by direct genotyping and
ADO
–
EGR2
by imputation. We replicated the
ADO
–
EGR2
,
IRF8
, and
CEBPB
–
PTPN1
loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated
ADO
–
EGR2
and
IRF8
, and meta-analysis additionally identified
RIPK2
and
LACC1
. The disease-associated allele of rs4402765, the lead marker at
IL1A
–
IL1B
, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific
FUT2
SNPs showed strong disease association (
P
= 5.89 × 10
−15
). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility. |
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ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/ng.3786 |