Variants in ZNF365 isoform D are associated with Crohn's disease
Talin Haritunians1,
Michelle R Jones2,3,
Dermot P B McGovern1,3,4,
David Q Shih4,
Robert J Barrett4,
Carrie Derkowski4,
Marla C Dubinsky4,5,
Debra Dutridge1,
Phillip R Fleshner4,
Andrew Ippoliti4,
Lily King1,
Esther Leshinsky-Silver6,
Arie Levine7,
Gil Y Melmed4,
Emebet Mengesha1,
Eric A Vasilauskas4,
Shabnam Ziaee3,4,
Jerome I Rotter1,
Stephan R Targan4,
Kent D Taylor1
1Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
2Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
3Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
4Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
5Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
6Molecular Genetic Lab, Wolfson Medical Center, Holon, Israel
7Pediatric Gastroenterology Unit, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv, Israel
Correspondence to Dr Talin Haritunians, Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; talin.haritunians{at}cshs.org
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.
Design 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.
association study
http://dx.doi.org/10.1136/gut.2010.227256
Funding This study was supported in part by: NCRR grant M01-RR00425 to the Cedars-Sinai General Research Center Genotyping core; NIH/NIDDK grant P01-DK046763; the Southern California Diabetes Endocrinology Research Center grant, DK063491; Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds; the Feintech Family Chair in IBD (to SRT); the Abe and Claire Levine Chair in Pediatric IBD (to MD) and the Cedars-Sinai Board of Governors' Chair in Medical Genetics (to JIR); with additional funding through grants DK062413 (to DPBM), DK76984 (to MD) and DK084554 (to MD and DPBM).
Competing interests None.
Ethics approval This study was conducted with the approval of the Cedars-Sinai Medical Center IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
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