Our lab studies common forms of cardiovascular and metabolic disorders, using population-based approaches in both animal models and humans. We are particularly interested in complex interactions, such as gene-by-gene, gene-by-environment, and gene-by-sex interactions, that are difficult to investigate directly in humans. To dissect such interactions, we analyze common disease using a systems biology perspective, integrating clinical trait phenotypes with genetic, epigenetic, transcriptomic and other high-throughput data.
For example, we recently investigated responses to a high fat, high sucrose diet across a panel of 100 different strains of inbred mice. The strains exhibited striking differences in the development of obesity and diabetes, enabling us to map and characterize genes mediating the response. Among the important contributing factors to the response was the composition of the gut microbiota, and we were able to identify and validate certain bacterial taxa as being involved. We also observed dramatic differences in responses between the sexes, particularly for diabetes-related traits, and are currently trying to tie these to molecular signatures differing between males and females.
We have used similar approaches to examine cardiovascular phenotypes such as atherosclerosis and heart failure. In some cases, this has led to the identification of novel regulatory pathways that we are studying using experimental techniques such as CRISPR-Cas9 engineering of mouse models. For example, one important question that we have tried to address is why macrophages proliferate in atherosclerotic lesions. This has led us to focus on the transcription factor ZHX2 and on the growth factor macrophage colony stimulating factor as key regulators.
While much of our work is carried out in mouse models, we appreciate the importance of extending any conclusions to humans. For this, we have established close correlations with investigators such as Markku Laakso at the University of Eastern Finland and Stan Hazen at the Cleveland Clinic who have assembled well characterized human populations studied for cardio-metabolic traits.
Some recent publications that are representative of our approaches are the following:
- Bennett BJ, Farber CR, Orozco L, Kang HM, Ghazalpour A, Siemers N, Neubauer M, Neuhaus I, Yordanova R, Guan B, Truong A, Yang W, He A, Kayne P, Gargalovic P, Kirchgessner T, Pan C, Castellani L, Kostem E, Furlotte N, Drake TA, Eskin E, Lusis AJ. (2010) A high resolution association mapping panel for the dissection of complex traits in mice. Genome Res. 20:281-290. PMCID:PMC2813484
- Romanoski CE, Lee S, Kim MJ, Ingram-Drake L, Plaisier CL, Yordanova R, Tilford C, Guan B, He A, Gargalovic PS, Kirchgessner TG, Berliner JA, Lusis AJ. (2010) Systems genetics analysis of gene-by-environment interactions in human cells. Am J Hum Genet. 86:399-410. PMCID:PMC2833388
- Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 472:57-63. PMCID:PMC3086762
- Farber CR, Bennett BJ, Orozco L, Zou W, Lira A, Kostem E, Kang HM, Furlotte N, Berberyan A, Ghazalpour A, Suwanwela J, Drake TA, Eskin E, Wang QT, Teitelbaum SL, Lusis AJ. (2011) Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis. PLoS Genet. 7:e1002038. PMCID:PMC3072371
- Ghazalpour A, Bennett B, Petyuk VA, Orozco L, Hagopian R, Mungrue IN, Farber CR, Sinsheimer J, Kang HM, Furlotte N, Park CC, Wen PZ, Brewer H, Weitz K, Camp DG 2nd, Pan C, Yordanova R, Neuhaus I, Tilford C, Siemers N, Gargalovic P, Eskin E, Kirchgessner T, Smith DJ, Smith RD, Lusis AJ. (2011) Comparative analysis of proteome and transcriptome variation in mouse. PLoS Genet. 7:e1001393. PMCID:PMC3111477
- Orozco LD, Bennett BJ, Farber CR, Ghazalpour A, Pan A, Che N, Wen P, Qi, HX, Mutukulu A, Siemers N, Neuhaus I, Yordanova R, Gargalovic P, Pellegrini M, Kirchgessner T, Lusis AJ. (2012) Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell 151:658-70. PMCID:PMC3513387
- Bennett BJ, Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen S, Lusis AJ. (2013) Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17:49-60. PMCID:PMC3771112
- Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, Pan C, Civelek M, Rau CD, Bennett BJ, Mehrabian M, Ursell LK, He A, Castellani LW, Zinker B, Kirby M, Drake TA, Drevon CA, Knight R, Gargalovic P, Kirchgessner T, Eskin E, Lusis AJ. (2013) Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice. Cell Metab. 17:141-52. PMCID:PMC3545283
- Civelek, M., Lusis, A.J. (2014) Systems genetics approaches to understand complex traits. Nat. Rev. Genet. 15:34-48. PMCID:PMC3934510
- Ghazalpour A., Bennett BJ, Shih DM, Che N, Orozco LD, Pan C, Hagopian R, He A, Kayne P, Yang, W-p, Kirchgessner T.G, Lusis AJ. (2014) Genetic regulation of mouse liver metabolite levels. Mol Syst Biol. 10:730. PMCID:PMC4188043
- Parks BW, Sallam T, Mehrabian M, Psychogios N, Hui ST, Norheim F, Castellani LW, Rau CD, Pan C, Phun J, Zhou Z, Yang WP, Neuhaus I, Gargalovic PS, Kirchgessner TG, Graham M, Lee R, Tontonoz P, Gerszten RE, Hevener AL, Lusis AJ. (2015) Genetic architecture of insulin resistance in the mouse. Cell Metab 21:334-46. PMCID:PMC4349439
- Zhou X, Crow AL, Hartiala J, Spindler TJ, Ghazalpour A, Barsky LW, Bennett BB, Parks BW, Eskin E, Jain R, Epstein JA, Lusis AJ, Adams GB, Allayee H. (2015) The genetic landscape of hematopoietic stem cell frequency in mice. Stem Cell Reports 5:125-38. PMCID:PMC4618249
- Hui ST, Parks BW, Org E, Norheim F, Che N, Pan C, Castellani LW, Charugundla S, Dirks DL, Psychogios N, Neuhaus I, Gerszten RE, Kirchgessner T, Gargalovic PS, Lusis AJ. (2015) The genetic architecture of NAFLD among inbred strains of mice. Elife. 4:e05607. PMCID:PMC4493743
- Org E, Parks BW, Joo JW, Emert B, Schwartzman W, Kang EY, Mehrabian M, Pan C, Knight R, Gunsalus R, Drake TA, Eskin E, Lusis AJ. (2015) Genetic and environmental control of host-gut microbiota interactions. Genome Res. 25:1558-69. PMCID:PMC4579341
- Brænne I, Civelek M, Vilne B, Di Narzo A, Johnson AD, Zhao Y, Reiz B, Codoni V, Webb TR, Foroughi Asl H, Hamby SE, Zeng L, Trégouët DA, Hao K, Topol EJ, Schadt EE, Yang X, Samani NJ, Björkegren JL, Erdmann J, Schunkert H, Lusis AJ. (2015) Prediction of causal candidate genes in coronary artery disease loci. Arterioscler Thromb Vasc Biol. 35:2207-17. PMCID:PMC4583353
- Bennett BJ, Davis RC, Civelek M, Orozco L, Wu J, Qi H, Pan C, Packard RR, Eskin E, Yan M, Kirchgessner T, Wang Z, Li X, Gregory JC, Hazen SL, Gargalovic PS, Lusis AJ. (2015) Genetic architecture of atherosclerosis in mice: A systems genetics analysis of common inbred strains. PLoS Genet. 11:e1005711. Erratum in: PLoS Genet. 2016 Mar;12:e1005913. PMCID:PMC4687930
- Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WH, DiDonato JA, Brown JM, Lusis AJ, Hazen SL. (2016) Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165:111-24. PMCID:PMC4862743
- Wang JJ, Rau C, Avetisyan R, Ren S, Romay MC, Stolin G, Gong KW, Wang Y, Lusis AJ. (2016) Genetic dissection of cardiac remodeling in an isoproterenol-induced heart failure mouse model. PLoS Genet. 12:e1006038. PMCID:PMC4934852
- Rau CD, Romay MC, Tuteryan M, Wang JJ, Santolini M, Ren S, Karma A, Weiss JN, Wang Y, Lusis AJ. (2016) Systems genetics approach identifies gene pathways and Adamts2 as drivers of isoproterenol-induced cardiac hypertrophy and cardiomyopathy in mice. Cell Syst. [Epub ahead of print] PMCID: