Liver disease is a cause of substantial morbidity and mortality in the U.S., and cholestasis (impairment of bile flow) is a common and devastating manifestation of liver disease. The experiments in this revised application are focused on increasing our understanding of the genetic etiology underlying development of cholestatic liver disease;such a goal is amongst those articulated in the """"""""Action Plan for Liver Disease Research,"""""""" a report prepared by the NIH in 2004. The genetic studies in this proposal include investigation of a rare, Mendelian disease, as well as a more common cholestatic disorder of presumed complex etiology.
In Specific Aim 1, the genetic lesion(s) responsible for lymphedema-cholestasis syndrome (LCS), located in the LCS1 candidate region on chromosome 15, will be determined. Results of this Aim will increase understanding of the etiology of cholestasis, and provide insight into the biological interplay between the liver and the lymphatic system.
In Specific Aims 2 -4, recent progress in understanding the genetic underpinnings of rare cholestatic disorders will be leveraged to increase our knowledge regarding a more common disorder intrahepatic cholestasis of pregnancy (ICP). ICP endangers babies, increasing the risk of premature delivery, fetal distress, and intrauterine death.
In Specific Aim 2, a study cohort of 400 women diagnosed with intrahepatic cholestasis of pregnancy (ICP), and matched controls, will be established;half of this cohort will be collected from the San Francisco Bay Area, and the other half, from Chile, where the disorder is particularly common.
In Specific Aim 3, genes previously implicated in the genetic etiology of primary cholestatic disorders will be sequenced in DNA from these patients and controls to identify rare genetic variants that likely increase susceptibility to ICP.
In Specific Aim 4, genotyping of single nucleotide polymorphisms (SNPs) in these genes will be performed in the Latina portion of the sample, with correction for admixture, to test the hypothesis of association between SNPs in these genes and susceptibility to ICP. The results of the studies in Specific Aims 2-4 will increase our understanding of the genetic etiology of this clinically important cause of perinatal mortality and morbidity. As a result of the program of research described in this proposal, our knowledge of the etiology of cholestasis will be significantly advanced.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
Program Officer
Karp, Robert W
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Bull, Laura N; Pawlikowska, Ludmila; Strautnieks, Sandra et al. (2018) Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. Hepatol Commun 2:515-528
Thompson, Richard J; Bull, Laura N (2015) Treating genetic disease: Expanding the options. Hepatology 62:349-51
Bull, Laura N; Hu, Donglei; Shah, Sohela et al. (2015) Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping. PLoS One 10:e0131211
Bull, Laura N; Vargas, Juan (2014) Serum bile acids in intrahepatic cholestasis of pregnancy: not just a diagnostic test. Hepatology 59:1220-2
Setchell, Kenneth D R; Heubi, James E; Shah, Sohela et al. (2013) Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology 144:945-955.e6; quiz e14-5
Shah, Sohela; Conlin, Laura K; Gomez, Luis et al. (2013) CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops. PLoS One 8:e75770
Rook, Michelle; Vargas, Juan; Caughey, Aaron et al. (2012) Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One 7:e28343
Bull, Laura N; Mahmoodi, Venus; Baker, Alastair J et al. (2006) VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. J Pediatr 148:269-71
Fruhwirth, Martin; Janecke, Andreas R; Muller, Thomas et al. (2003) Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome. J Pediatr 142:441-7
Bull, Laura N (2002) Hereditary forms of intrahepatic cholestasis. Curr Opin Genet Dev 12:336-42