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Background & Aims: Genetic variation is invoked as a strong component underlying primary biliary cirrhosis (PBC) and other autoimmune disorders. Data suggest that some of this genetic risk is shared, affecting function of the immune mechanisms controlling self-tolerance. Cytotoxic T-lymphocyte antigen 4 (CTLA4) encodes a coinhibitory immunoreceptor that is a key regulator of self-tolerance with established genetic associations to multiple autoimmune diseases but conflicting evidence of involvement with PBC. We aimed to perform a more comprehensive assessment of CTLA4 genetic variation in PBC using a haplotype-tagging based approach. Methods: Single nucleotide polymorphisms (SNPs) were genotyped in 402 PBC patients and 279 controls and evaluated for association with PBC and with antimitochondrial antibody (AMA) status and prior orthotopic liver transplantation (OLT) among the PBC patients, both individually and as inferred haplotypes, using logistic regression. Results: All SNPs were in Hardy-Weinberg equilibrium. We identified a novel and relatively strong association between PBC and rs231725, a SNP in the 3′ flanking region of CTLA4 located outside of the area previously investigated in PBC. This SNP tags a common CTLA4 haplotype that contains a number of functionally implicated autoimmune CTLA4 SNPs, which was also found to be associated with PBC and to a lesser extent AMA status and prior OLT. Conclusions: Our findings suggest that CTLA4 has an impact on the risk of PBC and possibly plays a role in influencing AMA development as well as progression to OLT among PBC patients. Replication in a suitable, independent PBC cohort is needed.

Background: Select perinatal and early life experiences—such as low birthweight, nasogastric tube placement, and maternal separation—have been linked to irritable bowel syndrome (IBS) or IBS-like symptoms in humans and animals. However, confirmatory data regarding these events are lacking. Specific Aims: To determine whether there are specific perinatal and early life experiences associated with adult IBS. Methods: Participants in a previously constructed family case-control study were mailed new questionnaires asking about early life events. Subjects contacted included 506 cases and 462 controls. Continuous variables were compared between IBS-affecteds and controls using the t-test; categorical variables were compared with the Pearson chi-square test. Results: 642 (66%) responded. Median age for cases and controls was 49 years (range: 18.0-70.0) and consisted of 82% females, 98% were Caucasian. The distribution of IBS subtypes among cases was: 23% IBS-D, 9% IBSC, 26% IBS-M, and 42% other. Cases had similar birth weights to controls; low birthweight (≤2500g) was not associated with IBS status. Cases and controls reported similar gestational age at birth (median 40.0 wks), were equally likely to have reported health problems at delivery (8%) and to have received breast milk during infancy and for a similar duration. However, cases were more likely to have experienced infant colic (22% v. 11%, p

The efficacy of D-xylose testing in clinical situations has been reviewed in the light of recent kinetic studies. The standard 25-g D-xylose test in adults, based on analysis of 5-h urine collection and a 1-h serum sample, discriminates between normal subjects and patients with proximal small intestinal malabsorption with greater than 95% specificity and sensitivity. The 1-h serum level measured after administering this dose is also useful in evaluating malabsorption in patients with intermediate degrees of renal insufficiency and in the elderly. The 1-h serum test after administration of 5 g of D-xylose should be used in pediatrics and is greater than 91% sensitive and close to 100% specific. The [14C]D-xylose breath test with 1 g of D-xylose has been useful in identifying malabsorption caused by bacterial overgrowth in the small intestine.