Primary biliary cirrhosis (PBC) is considered a prototypic female predominant autoimmune disease. We have completed the largest case-controlled epidemiological study and have been on the edge in defining the basis of autoreactivity. However, our efforts suggest that the etiological enigma necessitates a genome-wide association. We have support for the genetic basis of susceptibility based on data in monozygotic twins and prevalence in first-degree relatives. Our goal is to define the genetic loci that predispose to PBC and we will use an exceptional cohort of Italian patients and matched controls. The number of multiplex families with PBC is limited and therefore we propose a genome association study in which 800 cases and 800 controls will be individually genotyped with 500K SNPs. We will perform association tests using the genome wide SNP data to analyze all common (>5%) haplotypes as well as individual SNPs. This strategy will provide power to detect susceptibility loci. The use of our Italian population will minimize genetic heterogeneity and every case of PBC will be verified using international criteria. In our analyses we will also define and utilize population genetic structure and substructure to minimize both type 1 and type 2 errors. In the second phase of the study we will seek to confirm candidate SNPs/regions using 300 independent simplex family sets. This aspect will provide confidence that associations are not due to hidden population stratification using transmission disequilibrium testing. We will utilize population genetic structure and substructure in this phase to potentially increase power by examining a subset of families that may have reduced genetic heterogeneity. Further, we will examine the suggested loci and regions using ~1,500 individual SNPs specifically selected to include all exonic, flanking 5' and 3', and splice sites in genes within the putative susceptiblity regions. Finally, additional studies are proposed to define and ultimately provide evidence for identication of specific disease associated SNP variants. We submit that the data obtained herein will be important not only for PBC, but also of critical value in other autoimmune diseases. Lay Summary: In this application we hope to determine the genetic basis that leads to a prototypic autoimmune disease, called primary biliary cirrhosis. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056839-07
Application #
7493050
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Karp, Robert W
Project Start
1999-12-01
Project End
2012-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
7
Fiscal Year
2008
Total Cost
$679,115
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Kar, S P; Seldin, M F; Chen, W et al. (2013) Pathway-based analysis of primary biliary cirrhosis genome-wide association studies. Genes Immun 14:179-86
Juran, Brian D; Hirschfield, Gideon M; Invernizzi, Pietro et al. (2012) Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet 21:5209-21
Invernizzi, P; Ransom, M; Raychaudhuri, S et al. (2012) Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis. Genes Immun 13:461-8
Kosoy, R; Ransom, M; Chen, H et al. (2011) Evidence for malaria selection of a CR1 haplotype in Sardinia. Genes Immun 12:582-8
Tanaka, A; Invernizzi, P; Ohira, H et al. (2011) Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort. Tissue Antigens 78:65-8
Invernizzi, Pietro (2011) Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving. Hepatology 54:714-23
Bernuzzi, Francesca; Fenoglio, Daniela; Battaglia, Florinda et al. (2010) Phenotypical and functional alterations of CD8 regulatory T cells in primary biliary cirrhosis. J Autoimmun 35:176-80
Liu, Xiangdong; Invernizzi, Pietro; Lu, Yue et al. (2010) Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 42:658-60
Invernizzi, Pietro; Selmi, Carlo; Poli, Francesca et al. (2008) Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology 48:1906-12
Invernizzi, Pietro; Gershwin, M Eric (2008) The genetic basis of primary biliary cirrhosis: premises, not promises. Gastroenterology 135:1044-7

Showing the most recent 10 out of 15 publications