Independent replication of an association of CNVR7113.6 with Crohn's disease in Caucasians.

BACKGROUND: A recent genome-wide association study (GWAS) of copy number variants (CNVs) in Crohn's disease (CD) confirmed association of three CNVs. The GWAS also provided evidence that a fourth CNV, CNVR7113.6, on chromosome 17 may alter susceptibility to CD (P = 0.0018). The aim of our study was to confirm the CNVR7113.6 association by genotyping two independent inflammatory bowel disease (IBD) cohorts and by conducting a subsequent meta-analysis. METHODS: In all, 1369 New Zealand Caucasians (489 CD patients, 463 ulcerative colitis [UC] patients, and 417 controls) and 2737 Spanish Caucasians (711 CD patients, 549 UC patients, and 1477 controls) were genotyped for a single nucleotide polymorphism (SNP), rs413778, in high linkage disequilibrium (r(2) = >0.99) with CNVR7113.6. Chi-square analysis was conducted to test for association of rs413778 with overall CD, UC, IBD, and with disease phenotype. New Zealand and Spanish genotypes were then combined with imputed rs413778 genotypes from the Wellcome Trust Case Control Consortium (WTCCC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) CD datasets to conduct a meta-analysis. RESULTS: The minor allele of rs413778 conferred protection against CD in the Spanish cohort (CD: P = 0.004, odds ratio [OR] = 0.82, 95% confidence interval [CI]: 0.71-0.94). A similar, albeit nonsignificant protective effect was observed in New Zealand CD patients (P = 0.098, OR = 0.83, 95% CI: 0.66-1.04). No association with UC or disease phenotypes was detected in either cohort. Meta-analysis found significant cumulative evidence for a protective effect of rs413778 in Caucasian CD (P = 1.19E-05, OR = 0.86, 95% CI: 0.80-0.92). CONCLUSIONS: This study provides the first independent replication of the association of CNVR7113.6 with CD.

Analysis of the influence of two CD24 genetic variants in Crohn's disease and ulcerative colitis.

The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646), were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. The "del" allele of the dinucleotide deletion was associated with an increased risk of CD (odds ratio = 1.61, 95% confidence interval = 1.17-2.21, p(FDR) = 6.4E-03) but not with UC. Moreover, this allele was significant associated with the age of CD diagnosis between 17 and 40 years, the ileocolonic location, and the inflammatory behavior of CD. We observed no significant differences between the allelic or genotypic frequencies of the A57V polymorphism in our studied IBD cohort. Our results suggest that the rs3838646 CD24 polymorphism is part of the genetic background of CD.

Déficit de vitamina D y densidad mineral ósea en la enfermedad de Crohn / Vitamin D deficiency and bone mineral density in Crohn's disease

Fundamento y objetivo: El déficit de 25-hidroxi-vitamina D (25OHD3) se ha propuesto como uno de los factores implicados en el desarrollo de la osteoporosis en la enfermedad de Crohn (EC). El objetivo de este estudio transversal es la determinación de la prevalencia del déficit de 25OHD3 y su posible relación con una densidad mineral ósea (DMO) baja en la EC. Pacientes y método: Se incluyeron 64 enfermos de Crohn de la provincia de Granada, en los que se midieron valores de 25OHD3 y hormona paratiroidea, además de la DMO en el cuello de fémur (CF) y la columna lumbar (CL) mediante absorciometría dual por rayos X.Resultados: Casi un 60% de los pacientes presentaron niveles de 25OHD3 <20 ng/ml, mientras que casi sólo un 16% presentaban valores considerados óptimos (≥30ng/ml). Un 4,7% de los pacientes presentó un Z-score ≤ -2 en el CF y un 20,3% en la CL. Con respecto al T-score, el 4,7 y 46,9% de los pacientes presentaron criterios de osteoporosis y osteopenia en el CF, respectivamente, mientras que en la CL estos porcentajes fueron del 6,25 y 42,2%, respectivamente. Aunque los pacientes con hipovitaminosis D presentaron una menor DMO tanto en el CF como en la CL, esta diferencia no fue significativa. Conclusiones: La prevalencia de hipovitaminosis D en los pacientes con EC es elevada en nuestro medio. Existe una tendencia entre nuestros pacientes hacia una DMO baja, tanto en CF como en CL, si bien no se ha encontrado una relación estadísticamente significativa (AU)

Background and objectives: Inadequate serum levels of 25-hydroxyvitamin D (25OHD3) are deemed as a possible risk factor for osteoporosis in Crohn's disease (CD). Our aim is to determine the prevalence of inadequate serum levels of 25OHD3 and its possible relationship with low bone mineral disease (BMD) in CD. Patients and methods: Sixty-four patients from the province of Granada (Spain) were enrolled. Serum levels of 25OHD3 and intact parathyroid hormone were measured. BMD was assessed by dual-energy x-ray absorptiometry at lumbar spine (LS) and femoral neck (FN). Results: Almost 60% of patients showed inadequate serum levels of 25OHD3, whereas only about 16% showed levels considered as adequate (≥30ng/mL). Z-score at FN was ≤ -2 in 4.7% of patients and 20.3% at LS. Regarding T-score, 4.7 and 46.9% of patients met criteria for osteoporosis and osteopenia at FN, respectively, whereas 6.25 and 42.2% did it at LS, respectively. Patients with inadequate serum levels of 25OHD3 had non-significant lower BMD, both at the LS and the FN. Conclusions: Prevalence of inadequate serum levels of 25-(OH)D was high in our series. A no statistically-significant tendency towards low BMD in patients with inadequate serum levels of 25-(OH)D both at the FN and the LS was observed (AU)

Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis.

BACKGROUND: The PTPN22 gene is an important risk factor for human autoimmunity. The aim of this study was to evaluate for the first time the role of the R263Q PTPN22 polymorphism in ulcerative colitis (UC) and Crohn's disease (CD), and to reevaluate the association of the R620W PTPN22 polymorphism with both diseases. METHODS: A total of 1677 UC patients, 1903 CD patients, and 3111 healthy controls from an initial case-control set of Spanish Caucasian ancestry and two independent sample sets of European ancestry (Dutch and New Zealand) were included in the study. Genotyping was performed using TaqMan SNP assays for the R263Q (rs33996649) and R620W (rs2476601) PTPN22 polymorphisms. Meta-analysis was performed on 6977 CD patients, 5695 UC patients, and 9254 controls to test the overall effect of the minor allele of R620W and R263Q polymorphisms. RESULTS: The PTPN22 263Q loss-of-function variant showed initial evidence of association with UC in the Spanish cohort (P = 0.026, odds ratio [OR] = 0.61, 95% confidence interval [CI]: 0.39-0.95), which was confirmed in the meta-analysis (P = 0.013 pooled, OR = 0.69, 95% CI: 0.51-0.93). In contrast, the 263Q allele showed no association with CD (P = 0.22 pooled, OR = 1.16, 95% CI: 0.91-1.47). We found in the pooled analysis that the PTPN22 620W gain-of-function variant was associated with reduced risk of CD (P = 7.4E-06 pooled OR = 0.81, 95% CI: 0.75-0.89) but not of UC (P = 0.88 pooled, OR = 0.98, 95% CI: 0.85-1.15). CONCLUSIONS: Our data suggest that two autoimmunity-associated polymorphisms of the PTPN22 gene are differentially associated with CD and UC. The R263Q polymorphism only associated with UC, whereas the R620W was significantly associated with only CD.

CD40: novel association with Crohn's disease and replication in multiple sclerosis susceptibility.

BACKGROUND: A functional polymorphism located at -1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn's disease (CD) lesions. METHODOLOGY: Genotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. PRINCIPAL FINDINGS: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01-1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06-1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93-1.17)]. CONCLUSION: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.

STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: a replication study.

Recently, the signal transducer and activator of transcription 4 (STAT4) gene has been associated with multiple autoimmune diseases. Interestingly, a recent work showed that the T allele of the rs7574865 STAT4 SNP was associated with inflammatory bowel disease (IBD) in a Spanish population. The aim of the present study was to reevaluate the role of the STAT4 rs7574865 polymorphism on IBD. The present case-control study included 498 Crohn's disease (CD) patients, 402 ulcerative colitis (UC) patients, and 1296 healthy matched controls. Genotyping was performed using a PCR system with a pre-developed TaqMan allelic discrimination assay for the rs7574865 STAT4 SNP. Moreover, a meta-analysis was performed with the previous work in a Spanish population and the current study, including a final sample size of 1574 IBD patients (820 with CD and 754 with UC) and 2012 healthy controls. No evidence of association was found for the current case-control study (CD: p = 0.23, OR = 0.9, 95% CI = 0.75-1.1; UC: p = 0.17, OR = 1.14, 95% CI = 0.95-1.38). However, the meta-analysis showed that the STAT4 rs7574865 T allele was significantly associated with susceptibility to UC (p = 0.012 pooled; OR = 1.20, 95% CI = 1.04-1.39) but not CD (p = 0.71 pooled; OR = 0.93, 95% CI = 0.65-1.34). Our data suggest that the rs7574865 STAT4 SNP is a genetic susceptibility variant for UC but not CD in the Spanish population.