Variants in ZNF365 isoform D are associated with Crohn's disease.
OBJECTIVE
Genome-wide association studies have identified multiple Crohn's disease (CD) susceptibility loci, including association with non-coding intergenic single-nucleotide polymorphisms (SNPs) at 10q21.


METHODS
To fine-map the 10q21 locus, the authors genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single-marker and conditional analyses using logistic regression.


RESULTS
Association with CD risk spanning 11 SNPs (p<0.001) was observed. The most significant association observed was at the non-synonymous SNP, rs7076156 (Ala62Thr), in ZNF365. The alanine allele was over-represented in CD (p=5.23×10⁻⁷; OR=1.39 (95% CI 1.22 to 1.58)); allele frequency of 76% in CD and 69.7% in controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified, and rs7076156 is located in an exon unique to ZNF365 isoform D. The authors demonstrated, using reverse transcription-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. Markedly reduced mean expression levels of ZNF365D were identified in Epstein-Barr virus-transformed lymphoblastoid cell lines from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD.


CONCLUSIONS
Collectively, these data support the hypothesis that the non-synonymous Ala62Thr SNP, rs7076156, underlies the association between 10q21 and CD risk and suggest that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. talin.haritunians@cshs.org
Talin
T
Haritunians
Michelle R
MR
Jones
Dermot P B
DP
McGovern
David Q
DQ
Shih
Robert J
RJ
Barrett
Carrie
C
Derkowski
Marla C
MC
Dubinsky
Debra
D
Dutridge
Phillip R
PR
Fleshner
Andrew
A
Ippoliti
Lily
L
King
Esther
E
Leshinsky-Silver
Arie
A
Levine
Gil Y
GY
Melmed
Emebet
E
Mengesha
Eric A
EA
Vasilauskas
Shabnam
S
Ziaee
Jerome I
JI
Rotter
Stephan R
SR
Targan
Kent D
KD
Taylor
D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001706:Biopsy; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D056914:Genomic Structural Variation; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D014157:Transcription Factors; C475725:ZNF365 protein, human; D012313:RNA
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