A new study from the US has revealed how genes and environment interact synergistically to boost disease risk and why looking for gene variants may only partly explain how diseases arise.

You can read about the study, which was funded by the The National Heart, Lung and Blood Institute and the American Heart Association, and led by researchers at the University of California, Los Angeles (UCLA), in an article published online on 18 February in The American Journal of Human Genetics.

The authors wrote in their background information that while knowing more about interactions between genes and their environment would help us better understand many human diseases like heart disease, diabetes and cancer, it is not easy to study them on a molecular level.

Also, as principal investigator Jake Lusis, professor of medicine, human genetics and microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA, explained to the media, most research tends to focus on “unraveling the genetic component of disease risk while ignoring the effect of environmental stimuli.”

Using cells cultured from the lining of arteries that surgeons had trimmed from 96 donated hearts before transplanting them into recipients, and unlike previous studies that focused on only one gene, Lusis and colleagues analysed the activity of thousands of human genes (“transcript abundance traits”) at rest and under stress, paying particular attention to gene expression, the process by which the “code” of the DNA is converted into cellular protein.

To create conditions of environmental stress, they exposed the cells to fats that trigger inflammation (“proinflammatory oxidized phospholipids”) and cause atherosclerosis, the process that leads to hardening of the arteries.

First author Casey Romanoski, a UCLA graduate student in human genetics said they found the genes responded differently to stress depending on their genetic make-up, and:

“About 35 percent of the most affected genes were influenced by the interaction between their genetic variants and the fats.”

The authors wrote that the interactions were primarily a result of “distal and trans-acting loci” but they also found a striking example of local gene-environment interaction for a gene called FGD6.

They cross-checked some of their findings on the distal interactions with “siRNA knockdown experiments” a recognized way of confirming findings like these by using “small interfering RNA”, that interfere with the expression of specific genes.

The authors concluded that:

“Our findings add to the understanding of the overall architecture of complex human traits and are consistent with the possibility that GxE [gene and environment] interactions are responsible, in part, for the failure of association studies to more fully explain common disease variation.”

Romanoski said essentially this shows that:

“You can’t effectively study genes divorced from their environment.”

“The missing link lies in the intersection of genes with their environment,” she added.

Lusis agreed:

“Our findings demonstrate that these interactions are important in humans and should be considered in genetic research,” he said.

“Improving our understanding of the molecular architecture of disease may one day provide us with a new tool for how we address common disorders like cancer, diabetes and heart disease,” he added.

These findings suggest that genes and environment work together to boost disease risk synergistically: where their joint effect exceeds the sum of their independent contributions:

“Smoking and high cholesterol, for example, each increase a person’s risk for heart disease,” said Lusis.

“But when you add them together, the total risk exceeds its parts. Their interaction creates a dangerous synergy that causes damage beyond what the two can cause independently,” he added.

“Systems Genetics Analysis of Gene-by-Environment Interactions in Human Cells.”
Casey E. Romanoski, Sangderk Lee, Michelle J. Kim, Leslie Ingram-Drake, Christopher L. Plaisier, Roumyana Yordanova, Charles Tilford, Bo Guan, Aiqing He, Peter S. Gargalovic, Todd G. Kirchgessner, Judith A. Berliner, and Aldons J. Lusis.
The American Journal of Human Genetics, published online 18 February 2010.
DOI:10.1016/j.ajhg.2010.02.002

Source: European Society of Cardiology.

Written by: Catharine Paddock, PhD