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Environmental Factors Can Override Genetic Ancestry for Gene Expression Linked to Disease

NEW YORK (GenomeWeb) – The environment where people live can have a greater effect on their transcriptomes than their genetic ancestry, and influences disease risk, according to a new study.

An Ontario Institute for Cancer Research-led team examined the impact of a range of environmental variables — air pollution levels, built environment features, and socioeconomic factors — on the blood transcriptomes and clinical endophenotypes of a cohort of about 1,000 French Canadians. Air pollution, they found, affects gene expression as well as cardio-metabolic and respiratory traits, even after controlling for the effects of genetic ancestry.

"Our findings demonstrate how the local environment directly affects disease risk phenotypes and that genetic variation … can modulate individual's response to environmental challenges," the authors wrote in their paper, which was published yesterday in Nature Communications.

OICR's Philip Awadalla and his colleagues drew on the CARTaGENE cohort, which includes more than 40,000 mostly French-Canadian individuals between 40 years and 70 years old. The 1,007 individuals in their new study live in three regions of Quebec: the large urban center of Montreal, the small urban center of Quebec City, and the less urbanized area of Saguenay-Lac-Saint-Jean. Genotyping of a portion of French-Canadian individuals using Illumina's Omni 2.5 assay showed that they form a genetic cluster that's distinct from other individuals of European descent. The researchers also noted regional genetic variation among the French-Canadian individuals that was in line with the settlement history of Quebec.

At the same time, they collected environmental data on a dozen measures in the regions where the participants lived. Those variables included sulfur dioxide and ozone levels, walkability scores, food availability, and population density, among others. These measures varied, as expected, with urbanization.

Finally, they measured gene expression in blood taken from participants from the full cohort after fasting by performing paired-end RNA sequencing on Illumina's HiSeq 2000 platform.

While Awadalla and his colleagues noted differences in gene expression among the various Quebecois populations by region, they also found that it varied with environmental exposures.

They compared differences in gene expression levels of people living in the three spots in Quebec, divvying them up by whether their genetic ancestry indicated they were local to the region or had moved there from another part of Quebec. Based on this, the researchers noted that the differences they observed in gene expression was more due to where the individuals lived than their genetic ancestry.

Then using a coinertia analysis, they searched for associations between 57 clinical endophenotypes — such as arterial stiffness, asthma, liver enzymes, and lung function —, environmental exposures, and the levels of differentially expressed genes and gene regulators.

They uncovered links between arterial stiffness, asthma, and other measures with annual ambient sulfur dioxide and ozone levels. In particular, they noted sulfur dioxide levels were strongly associated with unfavorable cardio-respiratory phenotypes and had the most reproducible association with gene expression differences.

The researchers dove deeper into the effects of sulfur dioxide by examining two-week exposure windows and correlating that with gene expression changes within subsequently collected blood samples from the Montreal-dwelling participants.

The expression of 170 genes varied between people with high or low exposure to sulfur dioxide, including genes involved in oxygen transportation and leukocyte migration during chronic inflammation. A sensitivity analysis indicated that this variation in gene expression is mostly due to ambient air pollution, rather than due to genetic ancestry, disease, or socio-economic factors. They further found that this link replicated not only within Montreal, but also within Quebec.

Four clinical traits — forced expiratory volume, lung disease, liver enzymes, and arterial stiffness — were also associated with these 170 differentially expressed genes, each of which have previously been found to be influenced by air pollution in other studies. Chronic diseases like asthma and cardiovascular disease develop from these endophenotypes and also have been associated with air pollution.

Awadalla and his colleagues also uncovered four expression quantitative trait loci that interact with air pollution levels. One of these eGenes, atad2, interacts with both nitrogen dioxide and sulfur dioxide levels, and it and another eGene, smarca2, encode ATPases with epigenetic roles. Atad2 has also been linked to a number of human diseases and is a marker of poor prognosis in a number of cancers, the researchers added.

"Our findings illustrate that the impact of the geographic region of residence on the blood transcriptome overrides that of ancestry," the researchers wrote.