We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10−4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5×10−8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression.

Approximately 5-10% of cystic fibrosis (CF) patients develop multilobular cirrhosis during the first decade of life. Most CF patients later develop signs of portal hypertension with complications, mainly variceal bleeding. Liver failure usually occurs later, after the paediatric age. Annual screening for liver disease is recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt disease progression. Liver disease should be considered if at least two of the following variables are present: abnormal physical examination, persistently abnormal liver function tests and pathological ultrasonography. If there is diagnostic doubt, a liver biopsy is indicated. All CF patients with liver disease need annual follow-up to evaluate the development of cirrhosis, portal hypertension or liver failure. Management should focus on nutrition, prevention of bleeding and variceal decompression. Deterioration of pulmonary function is an important consideration for liver transplantation, particularly in children with hepatic dysfunction or advanced portal hypertension.

Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.

We identified 15 kindreds including 29 individuals affected with ARC syndrome. First, we excluded linkage to the candidate genes ATP8B1 and ABCB11 (ref. 10), which are implicated in other disorders that cause neonatal cholestasis with low gGT activity. We then carried out a genome-wide linkage scan using the Affymetrix 10K SNP chip [11][12][13][14] in seven affected individuals from six consanguineous kindreds with ARC. This scan identified eight regions of extended homozygosity shared by all affected individuals. We analyzed these regions further by typing microsatellite markers in 64 individuals from 14 consanguineous families ( Fig. 1 and Supplementary Fig.

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Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.