Nature and nurture

Exploring the complex relationship of genes, environment and complex diseases

By Jill Pease
Dr. Jinying Zhao

Dr. Jinying Zhao

With the decoding of the human genome in 2003 and subsequent identification of hundreds of genes linked to major diseases, many believed new treatments and cures wouldn’t be far behind.

But scientists have since learned that genetic mutations alone may only explain a small proportion of disease variability for a majority of complex disorders. That discovery was disappointing, says Jinying Zhao, M.D., Ph.D., a professor in the department of epidemiology in the College of Public Health and Health Professions and the College of Medicine who was hired as part of UF’s preeminence initiative, and it prompted her and fellow researchers to begin searching for other answers.

“As an investigator you think ‘Well, what else?’” said Zhao, who joined UF in August from Tulane University. “We started thinking about the environment and how it could integrate into the genome to change disease risk.”

Nature and nurture meet

The field of epigenetics, which explores the interplay of genes and environment and how they contribute to disease, may offer some explanations for individual’s disease risk, Zhao said. External factors, such as nutrition, physical activity, stress, smoking or exposure to toxic agents, don’t change a person’s DNA sequence, but they can alter how genes are expressed, and thereby influence disease risk.

“Epigenetics is fascinating because it can explain a lot of phenomena that genetic sequence alone cannot explain,” Zhao said. “I think epigenetics is the perfect mechanism that can link the environment, your genome and your disease risk.”

One well-known example comes from the Dutch Hunger Winter, a World War II-era famine that forced Dutch residents to subsist on 30 percent of their normal calorie intake. Scientists have tracked the health of these families, including people who were in their mothers’ wombs during the famine. As adults, these individuals have had a higher risk of diabetes, obesity, cardiovascular disease and other health problems, which researchers have linked to epigenetic changes in insulin-like growth factor II, a key factor in human growth and development. Surprisingly, there is evidence that these gene expression changes have been passed down to another generation: the grandchildren of women who lived during the Dutch Hunger Winter.

Another method for examining epigenetic influences, and one of the most effective, is the comparison of identical twins, Zhao says. Because identical twins share the same DNA sequence, disease differences between twin pairs are likely explained by environmental factors. Zhao is currently conducting a study of identical twins pairs where one twin has major depression and the other does not, collecting and analyzing the twins’ genetic and lifestyle data. She has completed similar studies in identical twins looking at epigenetic risk factors for obesity and diabetes and has identified specific profiles of DNA methylation — biochemical processes that silence or activate genes — associated with both conditions. Different methylation levels caused by different environmental exposures may lead to a gene being switched on in one twin and switched off in the other.

Calculating biological age

A person’s chronological age can provide some information about disease risk, but a truer measure may come from examining biological age, or the age of a person’s cells. Telomeres, which appear as caps at the end of DNA strands, act as a kind of protective coating for our chromosomes. Longer telomeres provide better protection while shorter telomeres can lead to damage in DNA strands and loss of cell function. Telomeres will shorten with age, but other external factors, such as smoking, stress, obesity and poor diet, can also cause shortening.

Zhao has a number of ongoing and completed telomere studies, including several conducted as part of the Strong Heart Study, a long-term study of cardiovascular disease risk factors among Native Americans. Supported by the National Heart, Lung, and Blood Institute, it is the largest epidemiological study of cardiovascular health of Native Americans.

Through collaboration with Elizabeth Blackburn, Ph.D., a professor at the University of California San Francisco and a Nobel Laureate for her pioneering research in telomeres, Zhao has examined telomere length and disease risk in thousands of Strong Heart Study participants. The researchers have demonstrated that shorter telomeres are associated with higher risk of diabetes, obesity and narrowing of carotid arteries. But there is also good news, Zhao says.

“We have found that people who are more physically active have longer telomere length,” she said, adding that physical activity could possibly counteract telomere shortening and help to reduce disease risk.

Making sense of all the data

At UF Zhao is building a new division of genetic epidemiology in the department of epidemiology.

“Genetic epidemiology’s first goal is to identify which genes or genetic pathways are associated with or underlie human disease,” Zhao said. “The second goal is related to precision medicine: customizing a specific treatment, intervention or prevention, based on a patient’s genetic background or personal profile.”

Genetic epidemiology is a relatively new discipline, but it is rapidly expanding alongside the explosion of genetic data, increase in computing capabilities and development of new statistical methods.

“While many universities have a course in genetic epidemiology, few programs have a full division with several faculty who are all focused on the same issue,” said Linda B. Cottler, Ph.D., M.P.H., chair of the UF department of epidemiology and PHHP’s associate dean for research and planning. “Many are looking for faculty and leaders in this area. We are fortunate that Dr. Zhao has joined the department. It is important for UF to be at the cutting edge of research on genetics and individual and population risk factors for major chronic diseases that people are concerned about, such as hypertension, diabetes, depression and Alzheimer’s disease.”

Zhao said one of genetic epidemiology’s challenges is working with the massive amounts of biological data produced by studies in the “omics,” such as genomics, epigenomics, metabolomics or proteomics.

“New statistical methodology is always a bottleneck because the new molecular technology, such as next generation DNA sequencing, is very fast and generates a lot of data,” Zhao said. “As scientists, we struggle with determining how to extract the most useful information from these high-dimensional data.”

Zhao was drawn to UF for its excellent resources and collaborative environment. She is exploring partnerships with members of UF’s Informatics Institute, Genetics Institute, Diabetes Institute, Clinical and Translational Science Institute and pharmacogenomics experts in the College of Pharmacy.

“There are so many faculty members doing excellent work here who could help me open up new pathways in my research,” Zhao said. “I’m looking forward to expanding and developing new research in the next few years.”

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