Hobbs-Cohen Laboratory

The central focus of our research program is how dysregulation of lipid uptake and trafficking contributes to human diseases. We use human genetics to identify genes that contribute to lipid disorders, and metabolic and biochemical studies to define the underlying mechanisms.  Since the optimal strategy to identify functional sequence variations contributing to disease depends on the underlying genetic architecture of the trait, we have used three complementary approaches:

  • Resequencing extremes: To identify alleles of large phenotypic effect, we resequenced candidate genes in individuals with extreme phenotypes in the general population (1). This strategy has revealed that severe loss-of-function alleles are more common than previously recognized, and provided the first direct evidence that rare variants play an important role in complex traits in the general population (1,2). The power of the “resequencing extremes” strategy is best illustrated by identification of loss-of-function alleles in PCSK9, which reduced plasma low density lipoprotein-cholesterol (LDL-C) levels and protect against coronary heart disease (CHD) (2,3).
  • Resequencing populations: Our “resequencing extremes” strategy suggested that severe loss-of-function alleles may be sufficiently common to allow a reverse genetics approach to determine the roles of genes in human physiology. We hypothesized that the phenotypic consequences of sequence variations in genes can be defined by sequencing large cohorts of well-characterized individuals. This approach was used to determine the effects of loss-of-function mutations in angiopoeitin-like proteins (ANGPTL3-5) in humans (4,5).  We showed that mutations in all three proteins are associated with reductions in plasma triglyceride levels.
  • Genome-wide association studies (GWAS): To identify novel genes, we have performed unbiased large-scale association studies in a large population with uniform, comprehensive phenotyping, the Dallas Heart Study. This approach yielded the first genetic locus (9p21) that is directly associated with CHD independent of known risk factors (6), and the first gene associated with nonalcoholic fatty liver disease (7,8).
  • Whole genome sequencing: The development of massively parallel DNA sequencing allows accurate resequencing of the whole-genome (or exome) of selected individuals.  We are using this technology to identify disease-causing mutations in individuals with atypical disorders of lipid metabolism (9). 

Identification of these genes in human populations and families has provided us with molecular handles for mechanistic studies to define key pathways in lipid metabolism in humans (10).  A major focus of our ongoing research program is to elucidate the roles of PCSK9, PNPLA3, and the ANGPTL proteins in the trafficking and processing of lipids and lipoproteins and to identify new genes contributing to fatty liver disease. Most recently, we identified a new member of the ANGPTL family, ANGPTL8, that is required for the trafficking of triglycerides to tissues in response to food intake (11,12).

  1. Cohen J.C., Kiss R.S., Pertsemlidis A., Marcel Y.L., McPherson R., Hobbs H.H. (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305:869-872.
  2. Cohen J., Pertsemlidis A., Kotowski I.K., Graham R., Garcia C.K., Hobbs H.H. (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37:161-165.
  3. Cohen J.C., Boerwinkle E., Mosley T.H., Hobbs H.H. (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.  N. Engl. J. Med. 354: 1264-1272.
  4. Romeo S., Pennacchio L.A., Fu Y., Boerwinkle E., Tybjaerg-Hansen A., Hobbs H.H., Cohen J.C. (2007)  Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39:513-516.
  5. Romeo S., Yin W., Kozlitina J., Pennacchio L.A., Boerwinkle E., Hobbs H.H., Cohen J.C. (2009). Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119:70-79.  PMCID:  PMC2613476
  6. McPherson R., Pertsemlidis A., Kavaslar N., Stewart A., Roberts R., Cox D.R., Hinds D.A., Pennacchio L.A., Tybjaerg-Hansen A., Folsom A.R., Boerwinkle E., Hobbs H.H., Cohen J.C. (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488-1491. PMCID: PMC271874
  7. Romeo S., Kozlitina J., Xing C., Pertsemlidis A., Cox D., Pennacchio L.A., Boerwinkle E., Cohen J.C., Hobbs, H.H. (2008). Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.  Nat. Genet. 40: 1461-1465.  PMCID: PMC2597056
  8. Cohen J.C., Horton J.D., Hobbs H.H. (2011) Human fatty liver disease: old questions and new insights. Science 332:1519-1523. PMCID: PMC3229276
  9. Rios J., Stein E., Shendure J., Hobbs H. H., Cohen J.C. (2010) Identification by whole genome resequencing of gene defect responsible for severe hypercholesterolemia, Hum. Mol. Genet. 19:4313-4318. PMCID: PMC2957323
  10. Cohen J.C. and Hobbs H.H. (2013) Simple genetics for a complex disease. Science 340: 2013-2014.   PMCID: PMC Journal – In Process
  11. Quagliarini F., Wang Y., Kozlitina J., Grishin N.V., Hyde R., Boerwinkle E., Valenzuela, D.M., Murphy A.J., Cohen J.C., and Hobbs H.H. (2012) Atypical angiopoietin-like protein that regulates ANGPTL3. Proc. Natl. Acad. Sci. USA, 109:19751-19756.  PMCID: PMC3511699
  12. Wang Y., Quagliarini F., Gusarova V., Gromada J., Valenzuela D.M., Cohen J.C., Hobbs H.H. (2013) Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc. Natl. Acad. Sci. USA., in press  PMCID: PMC Journal – In Process