Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study

BACKGROUND: While there is extensive literature evaluating the impact of phytoestrogen consumption on breast cancer risk, its role on ovarian cancer has received little attention. METHODS: We conducted a population-based case-control study to evaluate phytoestrogen intake from foods and supplements and epithelial ovarian cancer risk. Cases were identified in six counties in New Jersey through the New Jersey State Cancer Registry. Controls were identified by random digit dialing, CMS (Centers for Medicare and Medicaid Service) lists, and area sampling. A total of 205 cases and 390 controls were included in analyses. Unconditional logistic regression analyses were conducted to examine associations with total phytoestrogens, as well as isoflavones (daidzein, genistein, formononetin, and glycitein), lignans (matairesinol, lariciresinol, pinoresinol, secoisolariciresinol), and coumestrol. RESULTS: No statistically significant associations were found with any of the phytoestrogens under evaluation. However, there was a suggestion of an inverse association with total phytoestrogen consumption (from foods and supplements), with an odds ratio (OR) of 0.62 (95% CI: 0.38-1.00; p for trend: 0.04) for the highest vs. lowest tertile of consumption, after adjusting for reproductive covariates, age, race, education, BMI, and total energy. Further adjustment for smoking and physical activity attenuated risk estimates (OR: 0.66; 95% CI: 0.41-1.08). There was little evidence of an inverse association for isoflavones, lignans, or coumestrol. CONCLUSIONS: This study provided some suggestion that phytoestrogen consumption may decrease ovarian cancer risk, although results did not reach statistical significance

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology characterised by inflammation and fibrosis of the biliary tree. The mean age at diagnosis is 40 years and men are affected twice as often as women. There is a reported annual incidence of PSC of 0.9–1.31/100,000 and point prevalence of 8.5–13.6/100,000. The onset of PSC is usually insidious and many patients are asymptomatic at diagnosis or have mild symptoms only such as fatigue, abdominal discomfort and pruritus In late stages, splenomegaly and jaundice may be a feature. In most, the disease progresses to cirrhosis and liver failure. Cholangiocarcinoma develops in 8–30% of patients. PSC is thought to be immune mediated and is often associated with inflammatory bowel disease, especially ulcerative colitis. The disease is diagnosed on typical cholangiographic and histological findings and after exclusion of secondary sclerosing cholangitis. Median survival has been estimated to be 12 years from diagnosis in symptomatic patients. Patients who are asymptomatic at diagnosis, the majority of whom will develop progressive disease, have a survival rate greater than 70% at 16 years after diagnosis. Liver transplantation remains the only effective therapeutic option for patients with end-stage liver disease from PSC, although high dose ursodeoxycholic acid may have a beneficial effect

Analysis of SNP-SNP interactions and bone quantitative ultrasound parameter in early adulthood

Background: Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease. Methods: The study population included 575 healthy subjects (mean age 20.41; SD 2.36). To assess bone mass QUS was performed to determine Broadband ultrasound attenuation (BUA, dB/MHz). A total of 32 SNPs mapping to loci that have been characterized as genetic markers for QUS and/or BMD parameters were selected as genetic markers in this study. The association of all possible SNP pairs with QUS was assessed by linear regression and a SNP-SNP interaction was defined as a significant departure from additive effects. Results: The pairwise SNP-SNP analysis showed multiple interactions. The interaction comprising SNPs rs9340799 and rs3736228 that map in the ESR1 and LRP5 genes respectively, revealed the lowest p value after adjusting for confounding factors (p-value = 0.001, β (95% CI) = 14.289 (5.548, 23.029). In addition, our model reported others such as TMEM135-WNT16 (p = 0.007, β(95%CI) = 9.101 (2.498, 15.704), ESR1-DKK1 (p = 0.012, β(95%CI) = 13.641 (2. 959, 24.322) or OPG-LRP5 (p = 0.012, β(95%CI) = 8.724 (1.936, 15.512). However, none of the detected interactions remain significant considering the Bonferroni significance threshold for multiple testing (p<0.0001). Conclusion: Our analysis of SNP-SNP interaction in candidate genes of QUS in Caucasian young adults reveal several interactions, especially between ESR1 and LRP5 genes, that did not reach statistical significance. Although our results do not support a relevant genetic contribution of SNP-SNP epistatic interactions to QUS in young adults, further studies in larger independent populations would be necessary to support these preliminary findings.This study was supported by a grant PI-0414-2014 from Consejería de Salud (Junta de Andalucía, Spain). Correa-Rodríguez M is a predoctoral fellow (FPU13/ 00143) from the Ministerio de Educación, Cultura y Deporte (Programa de Formación del Profesorado Universitario)

A Novel Approach for Mining Polymorphic Microsatellite Markers In Silico

An important emerging application of high-throughput 454 sequencing is the isolation of molecular markers such as microsatellites from genomic DNA. However, few studies have developed microsatellites from cDNA despite the added potential for targeting candidate genes. Moreover, to develop microsatellites usually requires the evaluation of numerous primer pairs for polymorphism in the focal species. This can be time-consuming and wasteful, particularly for taxa with low genetic diversity where the majority of primers often yield monomorphic polymerase chain reaction (PCR) products. Transcriptome assemblies provide a convenient solution, functional annotation of transcripts allowing markers to be targeted towards candidate genes, while high sequence coverage in principle permits the assessment of variability in silico. Consequently, we evaluated fifty primer pairs designed to amplify microsatellites, primarily residing within transcripts related to immunity and growth, identified from an Antarctic fur seal (Arctocephalus gazella) transcriptome assembly. In silico visualization was used to classify each microsatellite as being either polymorphic or monomorphic and to quantify the number of distinct length variants, each taken to represent a different allele. The majority of loci (n = 36, 76.0%) yielded interpretable PCR products, 23 of which were polymorphic in a sample of 24 fur seal individuals. Loci that appeared variable in silico were significantly more likely to yield polymorphic PCR products, even after controlling for microsatellite length measured in silico. We also found a significant positive relationship between inferred and observed allele number. This study not only demonstrates the feasibility of generating modest panels of microsatellites targeted towards specific classes of gene, but also suggests that in silico microsatellite variability may provide a useful proxy for PCR product polymorphism