Liam Brunham

LIAM R. BRUNHAM- PhD DEFENSE

“The Impact of Genetic Variation in ABCA1 on Cholesterol Metabolism, Atherosclerosis and Diabetes”

B.Sc., University of Manitoba, 2001
Tuesday, March 13, 2007, 9:00 am Room 200, Graduate Student Centre
Liam Brunham. PhD Defense program- pdf

SUPERVISORY COMMITTEE
Dr. Michael R. Hayden, Research Supervisor (Medical Genetics)
Dr. Jan M. Friedman (Medical Genetics)
Dr. Sylvie Langlois (Medical Genetics)
Dr. Cheryl L. Wellington (Pathology and Laboratory Medicine)

EXAMINING COMMITTEE

Chair: Dr. John McNeill (Pharmaceutical Sciences)
Supervisory Committee: Dr. Michael R. Hayden, Research Supervisor (Medical Genetics) Dr. Bruce Verchere (Pathology and Laboratory Medicine)
University Examiners: Dr. Robert McMaster (Medical Genetics), Dr. Brian Rodrigues (Pharmaceutical Sciences)
External Examiner: Dr. Gordon A. Francis, Department of Medicine and Biochemistry University of Alberta Edmonton, AB

Abstract:

The ATP-binding cassette transporter, sub-family A, member 1 (ABCA1) mediates the major pathway for cholesterol exit from non-hepatic cells and thereby controls the rate-limiting step in the biogenesis of high density lipoprotein (HDL) particles. In humans, ABCA1 deficiency results in Tangier disease, characterized by low levels of HDL cholesterol, cellular cholesterol accumulation and increased risk for atherosclerosis. More than 100 coding variants have been described in the ABCA1 gene. We attempted to understand how both naturally occurring and engineered mutations in ABCA1 impact its role in cholesterol transport in a variety of in vitro and in vivo systems. We attempted to correlate specific genetic variants in ABCA1 with phenotypes in patients carrying these variants, and used an evolutionary approach to predict which specific variants in ABCA1 would impact its function. We then turned to the study of tissue-specific genetic deletion of ABCA1 in mice to study its role in HDL biogenesis, atherosclerosis and glucose metabolism. We found that intestinal ABCA1 is an important site of HDL biogenesis and that activation of intestinal ABCA1 raises HDL levels in vivo. Hepatic ABCA1, which is a major site of HDL biogenesis, was shown to significantly contribute to susceptibility to atherosclerosis. Finally, we show that ABCA1 plays an unsuspected role in ß-cell function and insulin secretion. These studies have contributed to our understanding of the impact of genetic variation in ABCA1 on diverse biological and pathological processes, and have identified novel aspects of ABCA1 function in specific cell types.

SELECTED PUBLICATIONS

Brunham LR et al. The Role of ß-Cell ABCA1 in Insulin Secretion, Glucose Homeostasis and Response to Thiazolidinedione Treatment. Nat Med. 2007 (In Press)

Brunham LR et al. Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res. 2006 Sep 29;99(7):672-4.

Brunham LR, Singaraja RR, Hayden MR. Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. Annu Rev Nutr. 2006;26:105-29.

Brunham LR et al. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest. 2006 Apr;116(4):1052-62.

Brunham LR et al. Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene. PLoS Genet. 2005 Dec;1(6):e83.

Timmins JM, Lee JY, Boudyguina E, Kluckman KD, Brunham LR, Mulya A, Gebre AK, Coutinho JM, Colvin PL, Smith TL, Hayden MR, Maeda N, Parks JS. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J Clin Invest. 2005 May;115(5):1333-42.

Guan JZ, Tamasawa N, Brunham LR, Matsui J, Murakami H, Suda T, Ochiai S, Tsutsui M, Kudou K, Satoh K, Hayden MR. A case of Tangier disease with a novel mutation in the C-terminal region of ATP-binding cassette transporter A1. Am J Med Gen. 2004;130(4):398-401

Brunham LR*, Singaraja RR*, Visscher H, Kastelein JJ, Hayden MR. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32 *co-first authors

Wellington CL, Brunham LR, Zhou S, Singaraja RR, Visscher H, Gelfer A, Ross C, James E, Liu G, Huber MT, Yang YZ, Parks RJ, Groen A, Fruchart-Najib J, Hayden MR. Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1.

AWARDS

Pacific Blue Cross Medical Entrance Scholarship, 2001

CIHR MD/PhD studentship, 2002

BC Science Council GREAT award, 2002

Lowell Glasgow student research award, 2003

Michael Smith Foundation for Health Research Doctoral award, 2003

Canadian Society for Clinical Investigation Young Investigators Award, 2003

Gordon Research Conference on Lipoprotein Metabolism Outstanding Poster Award, 2004

ATVB Young Investigator Award, 2005

First Prize, Poster Competition, Gordon Conference on Atherosclerosis, 2005

Canadian Society for Clinical Investigation Young Investigators Award, 2005

SELECTED PRESENTATIONS

American Heart Association Scientific Sessions, Chicago, IL, November 14, 2007

American Heart Association Scientific Sessions, Dallas, TX, November 15, 2006

Western Region Islet Study Group, San Diego, CA, October 3-5, 2005

Canadian Society of Clinical Investigation Young Investigators Forum, Vancouver, BC, Sep 2005

Gordon Conference on Atherosclerosis, Maine, June 2005

American Heart Association Conference on Arteriosclerosis, Thrombosis and

Vascular Biology, Washington D.C., 2005

American Society of Human Genetics Annual Meeting, October 2004

Canadian Lipoprotein Conference, October 2004

Canadian Society of Clinical Investigation Young Investigators Forum, Ottawa ON, Sep 2004

Gordon Conference on Lipoprotein Metabolism, New Hampshire, June 2004

Canadian Lipoprotein Conference, Muskoka, ON October 2003

Canadian Society of Clinical Investigation Young Investigators Forum, Halifax NS, Sep 2003

Canadian Society of Clinical Investigation Young Investigators Forum, Ottawa ON, Sep 2002

Liam Brunham. PhD Defense program- pdf