Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

Abstract

Celiac disease (CD) is an inflammatory condition affecting small bowel and triggered by gluten (or related proteins) ingestion in genetic susceptible individuals. Polymorphisms in three genes, SERPINE2, PPP6C and PBX3, have recently been associated with CD in the Spanish population. However, this association could not be replicated in the UK population using imputed data. As this second study analyzed a different population, we aimed at reevaluating the role of those polymorphisms using an independent Spanish sample. We genotyped three single nucleotide polymorphisms: rs6747096 in SERPINE2, rs458046 in PPP6C and rs7040561 in PBX3, in 417 CD patients, 527 ethnically matched healthy controls and parents of 304 CD patients. A case-control study using the w 2 -test and a familial study using the transmission disequilibrium test were performed. No association was detected in those analyses. Therefore, our results seem to discard the role of the previously described polymorphisms in SERPINE2, PPP6C and PBX3 in CD susceptibility. IntroductionCeliac disease (CD) is a complex disease mediated by immune processes triggered after ingestion of gluten or related proteins in genetically susceptible individuals. 1 The genetic basis of this disease is being slowly unraveled by advances in experimental techniques. Combining two different gene-search approaches, Castellanos-Rubio et al. 2 reported new CD risk variants in the Spanish Basque population. They combined information provided by whole-genome expression profiling experiments and linkage studies (that is, functional and positional information) and found significant association with four single nucleotide polymorphisms (SNPs) located in the SERPINE2 (serine protease inhibitor, clade E, member 2), PPP6C (protein phosphatase 6, catalytic subunit) and PBX3 (pre-B-cell leukemia homeobox 3) genes.The SERPINE2 gene maps in the CD linkage region 2q33-q35 and PPP6C and PBX3 in 9q33-q34. SERPINE2 is involved in extracellular matrix production and it has been widely studied in relation to COPD (chronic obstructive pulmonary disease). 3 PPP6C encodes a protein phosphatase which seems to be involved in cell-cycle regulation. 4 Finally, PBX3 is a transcription factor implicated in basic developmental functions, including some related to immune cells. 5 The association between those genes and CD susceptibility described by Castellanos-Rubio et al. was questioned by Hunt et al., 6 who used data from a genome-wide association study performed in the British population to impute data corresponding to the previously associated SNPs. No replication was obtained and the authors suggested different possible explanations. Therefore, the debate is open because for every SNP the imputation is not 100% accurate, an issue recently discussed. 7 As an explanation of the observed discrepancies between the two studies could be owed to population or clinical heterogeneity, we aimed at evaluating the role of those SNPs in an independent Spanish sample of pediatric typical CD patients. Results and discuss...

La enfermedad celíaca: Marcadores genéticos

“…Un estudio posterior no fue capaz de replicar la asociación del gen SERPINE2 con la enfermedad, por lo que, a pesar de los múltiples intentos, el factor genético que confere el riesgo en la región CELIAC3 aun no ha sido identifcado. 19…”