Article

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
Nature Genetics (Impact Factor: 29.65). 03/2011; 43(4):329-32. DOI: 10.1038/ng.789
Source: PubMed

ABSTRACT In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10⁻⁸) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

0 Bookmarks
 · 
161 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A human betaretrovirus resembling mouse mammary tumor virus has been characterized in patients with primary biliary cirrhosis. The agent triggers a disease-specific phenotype in vitro with aberrant cell-surface expression of mitochondrial antigens. The presentation of a usually sequestered self-protein is thought to lead to the loss of tolerance and the production of anti-mitochondrial antibodies associated with the disease. Similar observations have been made in mouse models, where mouse mammary tumor virus infection has been linked with the development of cholangitis and production of anti-mitochondrial antibodies. The use of combination antiretroviral therapy has been shown to impact on histological and biochemical disease in mouse models of autoimmune biliary disease and in clinical trials of patients with primary biliary cirrhosis. However, the HIV protease inhibitors are not well tolerated in patients with primary biliary cirrhosis, and more efficacious regimens will be required to clearly link reduction of viral load with improvement of cholangitis.
    Current Infectious Disease Reports 02/2015; 17(2):460. DOI:10.1007/s11908-014-0460-7
  • [Show abstract] [Hide abstract]
    ABSTRACT: Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes. Method: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented. Results: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10(-7), OR = 1.70, 95%CI = 1.38 - 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10(-8), OR = 0.65(0.57 - 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10(-9), OR = 1.73 95%CI = (1.44 - 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10(-5), OR = 1.39, 95%CI = (1.19 - 1.61)], previously demonstrated in metabolic disease and diabetes in adults. Conclusion: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications.
    Frontiers in Genetics 11/2014; 5:401. DOI:10.3389/fgene.2014.00401

Full-text (2 Sources)

Download
73 Downloads
Available from
May 17, 2014