Faculty

Jeremy Martinson, DPhil Assistant Professor, Department of Infectious Diseases and Microbiology and Human Genetics (Secondary Appointment) E-mail: jmartins@pitt.edu Phone: 412-624-5646 Fax: 412-383-8926 Address: 403 Parran Hall 130 DeSoto Street Pittsburgh, PA 15261

Education

BA; Oxford University; 1986
DPhil; Oxford University; 1991

Research Interests

Human genomic variation and resistance to infectious diseases; genetic variation in the innate immune response; genetic contributions to cardiovascular complications in HIV-positive individuals undergoing Highly Active Antiretroviral Therapy (HAART)

Research Summary

My research work has always combined molecular and population genetics in the study of genetic variation in human populations. This work examines the molecular processes that generate genetic variation, and also the consequences of such variation in humans. The main focus of my work at present is in the study of susceptibility and resistance to disease, both infectious and genetic, and shows how infectious diseases have long acted as a potent selective force in the shaping of the dynamic human genome. In addition to this, the data generated in my laboratory are also used to analyze the evolutionary and historical relationships between human populations, and the ways in which genetic variation is maintained and distributed throughout the genome. The recent completion of the Human Genome sequence, and the development of technologies for post-genomic study of gene interactions, have great promise for the analysis of infectious disease susceptibility in humans.

Current research projects in my laboratory include:

Susceptibility to HIV infection and AIDS. Many genes are now known to affect the extent to which a person develops AIDS following exposure to the HIV virus. The chemokine receptor gene CCR5 has a crucial role in conferring resistance to HIV infection by functioning as a secondary receptor for HIV-1 in macrophages and other CD4+ immune system cells. In particular, a 32-basepair deletion, denoted CCR5-Δ32, removes this secondary receptor and confers almost total resistance to HIV infection in homozygotes. Progression to AIDS in infected heterozygotes is delayed. Other mutations in CCR5 and the other members of its multigene family are known which either impair, or in some cases enhance, the ability of HIV to infect its target cells. I have previously published the first description of the global distribution of CCR5-Δ32, and am now using allelic variation at STR loci flanking the gene complex to estimate the age and population histories of the different known mutations.

Qualitative and Quantitative variation in the innate immune response. The CCR5 gene presents a fascinating evolutionary question, as it exhibits what appears to be contradictory behaviour. The gene itself is highly conserved between humans and other primates, and shows other evidence of strong natural selection acting to maintain the integrity of the CCR5 protein. However, the CCR5 gene is also polymorphic for a 'null' mutation that completely removes the protein in homozygotes. It may be that fluctuations in the amount of the gene are tolerated, but that variant forms are not. We have examined the extent of genetic variation in other genes involved in innate immununity, and have found a similar pattern where quantitative variation (i.e. polymorphisms affecting the amount of gene product) is common, but qualitative variation (i.e. polymorphisms that change the sequence of the product) is rare. We are currently conducting research in a larger set of innate response genes to verify these findings. If confirmed, this genetically-determined variation in the amount of innate immune and inflammatory molecules may explain inter-individual differences in both susceptibility to infectious diseases and in risk of inflammatory disorders.

Genetic factors affecting cardiovascular complications of HIV therapy. The introduction of Highly Active Antiretroviral Therapy (HAART) has transformed the lives of many HIV-positive individuals. For some individuals, however, HAART carries a risk of cardiovascular side-effects, although the etiology of this is unknown. It has been known for many years that HIV infection itself can contribute to cardiovascular disease risk in some patients, and we are investigating the extent to which host genetics, infection with HIV, and treatment with HAART interact to give rise to cardiovascular disease in patients enrolled in the Multicenter AIDS Cohort Study (MACS). We are currently investigating qualitative and quantitative variation in genes involved in lipid metabolism and transport as candidates to explain these side-effects

Recent Publications

• Shiels, M., S. Cole, S. Wegner, H. Armenian, J. Chmiel, A. Ganesan, V. C. Marconi, O. Martinez-Maza, J.J. Martinson, A. Weintrob, L.P. Jacobson and N.F. Crum-Cianflone. Effect of HAART on incident cancer and noncancer AIDS events among male HIV seroconverters. Journal of Acquired Immune Deficiency Syndromes, 48:485-490, 2008.
  
  
• Ouma, C., G. Davenport, G.A. Awandare, C. Keller, T. Were, M. Otieno, J. Vulule, J.J. Martinson, J.M. Ong'echa, R. E. Ferrell and D.J. Perkins. Polymorphic variability in the IL-1β promoter conditions susceptibility to severe malarial anemia and functional changes in IL-1β production. Journal of Infectious Diseases, 198:1219-1226, 2008.
  
  
• Lopez-Gatell, H., S.R. Cole, J.B. Margolick, M.D. Witt, J.J. Martinson, J. Phair, L.P. Jacobson. Effect of tuberculosis on the survival of HIV-infected men in a country with low tuberculosis incidence. AIDS, 22:1869-1873, 2008.
  
  
• Ouma, C., G.C. Davenport, T. Were, M.F. Otieno, J.M. Vulule, J.J. Martinson, J.M. Ong'echa, R.E. Ferrell and D.J. Perkins. Haplotypes of IL-10 promoter variants (-1082A/G, -819T/C and -592A/C) are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production. Human Genetics, 124:515-524, 2008.
  
  
• Luo, C., M. Bueno, J. Kant, J.J. Martinson and P. Randhawa. Genotyping schemes for Polyoma Virus BK, Using Gene-Specific Phylogenetic Trees and Single Nucleotide Polymorphism Analysis. Journal of Virology, 83:2285-2297, 2009.
  
  
• Horne, K.C., X. Li, L.P. Jacobson, F. Palella, B.D. Jamieson, J.B. Margolick, J.J. Martinson, V. Turkozu, K. Visvanathan and I.J. Woolley. Duffy Antigen polymorphisms do not alter progression of HIV in African Americans in the MACS cohort. Cell Host and Microbe, 5:415-417, 2009.
  
  
• Awandare, G.A., J.J. Martinson, T. Were, C. Ouma, G.C. Davenport, J.M. Ong'echa, W.K. Wang, L. Leng, R.E. Ferrell, R. Bucala, R. and D.J. Perkins. Macrophage Inhibitory Factor (MIF) promoter polymorphisms and susceptibility to Severe Malarial Anemia. Journal of Infectious Diseases, 200:629-637, 2009.
  
  
• Herbeck, J.T, G.S. Gottlieb, C.A. Winkler, G.W. Nelson, P. An, B. Maust, K.G. Wong, J.L. Troyer, J.J. Goedert, B.D. Kessing, R. Detels, S. Wolinsky, J.J. Martinson, L.P. Jacobson, J.B. Margolick, R.A. Kaslow, S.J. O'Brien and J.L. Mullins. Multi-Stage Genome-Wide Association Study Identifies an Locus at 1q41 Associated with Rate of HIV-1 Disease Progression to Clinical AIDS. Journal of Infectious Diseases, in press, 2009.
  
  
• Shiels, M.S., S.R. Cole, J. Chmiel, J. Margolick, J.J. Martinson, Z.-F. Zhang and L.P. Jacobson. A comparison of ad hoc methods to account for non-cancer AIDS among competing risks and death when estimating the effect of HAART on incident cancer AIDS among HIV-infected men. Journal of Clinical Epidemiology, in press, 2009.

Dr. Martinson's Lab