Combined functional and positional gene information for the identification of susceptibility variants in celiac disease.
OBJECTIVE
Celiac disease is a complex, immune-mediated disorder of the intestinal mucosa with a strong genetic component. HLA-DQ2 is the major determinant of risk, but other minor genes, still to be identified, also are involved.


METHODS
We designed a strategy that combines gene expression profiling of intestinal biopsy specimens, linkage region information, and different bioinformatics tools for the selection of potentially regulatory single-nucleotide polymorphisms (SNPs) involved in the disease. We selected 361 SNPs from 71 genes that fulfilled stringent functional (changes in expression level) and positional criteria (located in regions that have been linked to the disease, other than HLA). These polymorphisms were genotyped in 262 celiac patients and 214 controls.


RESULTS
We detected strong evidence of association with several SNPs (the most significant were rs6747096, P = 2.38 x 10(-5); rs7040561, P = 6.55 x 10(-5); and rs458046, P = 1.35 x 10(-4)) that pinpoint novel candidate determinants of predisposition to the disease in previously identified linkage regions (eg, SERPINE2 in 2q33, and PBX3 or PPP6C in 9q34).


CONCLUSIONS
Our study shows that the combination of function and position is a valid strategy for the genetic dissection of complex traits.
Castellanos-Rubio
Ainara
A
Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo-Bizkaia, Spain.
Martin-Pagola
Ainhoa
A
Santín
Izortze
I
Hualde
Idoia
I
Aransay
Ana María
AM
Castaño
Luis
L
Vitoria
Juan Carlos
JC
Bilbao
Jose Ramon
JR
D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016022:Case-Control Studies; D002446:Celiac Disease / Q000178:diet therapy / Q000235:genetics* / Q000276:immunology; D016000:Cluster Analysis; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000276:immunology; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology; D016017:Odds Ratio; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D058255:Protease Nexins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D058258:Serpin E2
D016564:Amyloid beta-Protein Precursor; D018398:Homeodomain Proteins; D058255:Protease Nexins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D058258:Serpin E2; C090466:proto-oncogene protein Pbx3; D005983:Glutens; D005903:Gliadin; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6