THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

被引:26
|
作者
Tsai, Ellen A. [1 ,4 ]
Gilbert, Melissa A. [1 ]
Grochowski, Christopher M. [1 ]
Underkoffler, Lara A. [1 ]
Meng, He [7 ]
Zhang, Xiaojie [7 ]
Wang, Michael M. [7 ,8 ,10 ]
Shitaye, Hailu [9 ]
Hankenson, Kurt D. [5 ,11 ,12 ,13 ]
Piccoli, David [2 ]
Lin, Henry [2 ]
Kamath, Binita M. [14 ]
Devoto, Marcella [3 ,6 ,15 ]
Spinner, Nancy B. [1 ]
Loomes, Kathleen M. [2 ]
机构
[1] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Childrens Hosp Philadelphia, Div Pediat Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA
[3] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Div Genet, Philadelphia, PA 19104 USA
[4] Univ Penn, Perelman Sch Med, Genom & Computat Biol Grad Grp, Philadelphia, PA 19104 USA
[5] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA
[6] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA
[7] Univ Michigan, Dept Neurol, Ann Arbor, MI USA
[8] Univ Michigan, Dept Physiol, Ann Arbor, MI 48109 USA
[9] Univ Michigan, Med Scientist Training Program, Ann Arbor, MI 48109 USA
[10] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA
[11] Michigan State Univ, Dept Physiol, Dept Small Anim Clin Sci, Coll Nat Sci, E Lansing, MI 48824 USA
[12] Michigan State Univ, Dept Physiol, Dept Small Anim Clin Sci, Coll Osteopath Med, E Lansing, MI 48824 USA
[13] Michigan State Univ, Dept Physiol, Dept Small Anim Clin Sci, Coll Vet Med, E Lansing, MI 48824 USA
[14] Univ Toronto, Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada
[15] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy
来源
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY | 2016年 / 2卷 / 05期
基金
美国国家卫生研究院;
关键词
JAG1; NOTCH2; Gene Modifier; Cholestasis; Genome-Wide Association Study;
D O I
10.1016/j.jcmgh.2016.05.013
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder. METHODS: We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus. RESULTS: We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased micro-vessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1-NOTCH2 interactions. CONCLUSIONS: Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1-NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.
引用
收藏
页码:663 / +
页数:15
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