Harvard Public Health NOW

Genes and Environment Initiative Launched at School

HSPH has funded three pilot projects as part of its flourishing Genes and Environment Initiative, designed to bring together several areas of traditional excellence at the School — environmental health research, population science, quantitative methods, and basic science — to contribute to understanding the combined effects of genetic and environmental factors on human health.

For several months, an interdepartmental steering committee led by Deans Barry Bloom and James Ware has worked to define the Initiative's scope. The Initiative consists of four "pillars" — quantitative genomics, environmental genetic epidemiology, mechanisms of environmental damage, and exposure biology.

HSPH teams submitted proposals in February, and selected projects were sent for external review. All School primary faculty were eligible to be co-PIs. Efforts could include collaborators from the HSPH research community — faculty, research scientists, and postdoctoral fellows.

For more information about the Genes and Environment Initiative, contact Alix Smullin at asmullin@hsph.harvard.edu.

Arsenic in the Endoplasmic Reticulum

Team: Quan Lu of Department of Environmental Health; Gökhan Hotamisligil of Department of Genetics and Complex Diseases; David Christiani of Departments of Environmental Health and Epidemiology; and Xihong Lin of Department of Biostatistics

While arsenic is a naturally occurring element, its ingestion by humans can be deadly. Epidemiological studies have observed that drinking arsenic-contaminated water is associated with the development of pre-cancerous skin lesions, vascular diseases, neurological problems, skin cancer, bladder cancer, lung cancers, and diabetes mellitus. And some people around the world get their drinking water from supplies contaminated by arsenic. Much of the well water in Bangladesh, for example, is thought to be contaminated with the toxin.

Despite knowing the potential outcomes of exposure to arsenic, scientists do not understand well what happens in the body that makes people so ill.

In this effort, entitled "Gene-Environment Interactions in the Mechanisms of Arsenic Toxicity: A Multidisciplinary Approach," the research team will examine the biological results of arsenic exposure within cells, map the mechanisms determining the cellular responses, and then try to deduce how that exposure may lead to diseases such as diabetes and cancer.

Several years ago, Hotamisligil postulated that diabetes may begin when a system of membranes and tubules in cells called the endoplasmic reticulum (ER) becomes deeply stressed. The ER is the site where the body manufactures proteins and complex lipids.

Studies in cells and in mice have indicated that ER stress may lead to the activation of genes and proteins involved in inflammation and metabolic control.

The team assembled through the Genes and Environment Initiative proposes that arsenic, like obesity, may stress the ER so much that molecular pathways implicated in diabetes will trigger.

The project will involve bench science under way in Hotamisligil's lab and epidemiological work from an established study in Bangladesh conducted by Christiani.

Say the researchers, "We believe that our multidisciplinary approach will allow us to uncover genes and pathways that are involved in arsenic toxicity and facilitate the establishment of a comprehensive map, which will be integrated into genetic and genomic studies of populations with arsenic exposure."

Mercury, Selenium, and Genes

Team: Dariush Mozaffarian of Department of Epidemiology; David Christiani of Departments of Environmental Health and Epidemiology; Gökhan Hotamisligil of Department of Genetics and Complex Diseases; David Hunter of Departments of Epidemiology and Nutrition; Xihong Lin of Department of Biostatistics; and Eric Rimm of Departments of Nutrition and Epidemiology

The wisdom of eating fish has become a subject for debate. Mercury in some fish species has led to worries about possible mercury toxicity. At the same time, selenium found in some seafood may protect against both cardiovascular disease and against the toxic effects of mercury. As a result, these two dietary factors may have mutually important and potentially opposing roles in human health, say the team now working on "Dietary Biomarkers, Genetic Variation, and Novel Markers of Metabolic and Cardiovascular Risk."

The team plans to use genomewide array scans to examine how genes play a role in people's individual responses to mercury and selenium consumption. Once gene candidates are identified, the researchers hope to use fine mapping to zero in on areas of greatest interest.

The researchers also hope to use a similar approach to investigate how genetic variation affects the individual response to chronic zinc, chromium, and scandium exposure.

The project will use data and resources from the Nurses' Health Study and Health Professionals Follow-Up Study. Dietary information will be taken from questionnaires completed by participants. Levels of mercury and selenium will be measured from toenails clippings. Genetic information will be derived from cells taken from blood and cheek swabs.

Say the researchers: "This study will be the first to investigate the impact of genome-wide variation on mercury and selenium levels, as well as consider potential metabolic pathways of effect. Use of genome-wide association studies allows comprehensive evaluation of how common genomic variation affects these important biomarkers. Given the biologic relevance of mercury and selenium for human health and prior candidate gene studies demonstrating heritability, we anticipate discovery of major novel genetic regions that will greatly advance our understanding of the intersection between genes, dietary habits, and metabolism."

Mining Mitochondria for Chronic Disease Risk

Team: Eric Rimm of Departments of Nutrition and Epidemiology; David Cox of Department of Epidemiology; Ken Mukamal of Beth Israel Deaconess Medical Center; Joel Schwartz of Department of Environmental Health; and Xihong Lin of Department of Biostatistics

Mitochondria are important organelles that sit outside of a cell's nucleus in its cytoplasm. They are the major source of energy for cells, but their DNA has only one copy inherited from the mother. The DNA is substantially smaller and less complex than DNA that resides within a cell's nucleus. Mitochondria are highly metabolically active and are a source of so-called "reactive oxygen species" - damaging molecules that are a byproduct of the mitochondria's energy production. Scientists are interested in learning more about naturally occurring variation in mitochondrial DNA that may modify these important metabolic processes.

In this project, co-PIs Rimm and Cox will lead a team that will examine mitochondrial DNA for variants associated with risk of chronic illnesses, such as colon cancer, heart attacks, breast cancer, and decline in lung function. They also will look for how those risks may be modified by environmental factors such as alcohol, dietary antioxidants, and air pollution that promote reactive oxygen species.

For example, the research team is examining the relationship between alcohol consumption, mitochondrial DNA, and breast cancer risk. Preliminary work using the Nurses' Health Study has already suggested that an increase in risk of breast cancer associated with alcohol consumption is limited to women carrying a gene variant allele in their mitochondrial genomes. 

In total, the "Mitochondrial Haplogroups, Oxidative Stress, Inflammation, and Chronic Disease Risk" project will combine new genotyped samples from more than 6,000 individuals with resources already collected in the Nurses' Health Study, Health Professionals Follow-up Study, and Normative Aging Study. If results prove promising, said Rimm, the team will reach out to additional HSPH and HMS faculty to help unravel mechanisms underlying the associations.

"The Genes and Environment Initiative is a great move by the School to help foster relationships among researchers who otherwise may find it difficult to receive governmental funding because they do not have an established collaboration," said Rimm. "I am often aware of research conducted in other departments, but I do not always have the opportunity to reach out to those scientists to form what should be very fruitful relationships, particularly in a setting as complex as genes and the environment."

— Image of DNA helix from iStockphoto.com/David Marchal. Image of arsenic from iStockphoto.com/Daniel Tero. Image of ocean from iStockphoto.com/Tammy Peluso. Image of mitochondria from Sandia National Laboratories.