Study could identify how environmental factors such as smoking influence common diseases.

The time is right for an ambitious trial that could provide long-sought-after information on how environmental factors influence many common diseases, according to one of the visionaries of the Human Genome Project.

Francis Collins, Director of the US National Institute for Genomic Research, has outlined proposals for a US-wide study that would follow 200,000 people for two or more years to uncover how genes and the environment interact to contribute to the 40 most common diseases, such as how food intake influences in obesity and diabetes (Nature 429, 475–477 (2004)).

There are similar, but smaller, studies being conceived or carried out in other countries. However, Collins says that the US should seriously consider undertaking its own study, because other minority groups, such as African-Americans, Latinos and Native Americans, are likely to have different environmental risk factors.

A prospective cohort study that collects data on groups of subjects over time on this scale has several logistical hurdles, such as requiring large sample sizes, detailed characterization at the beginning of the study and prolonged follow-up for disease occurrence. But the payback is that this will provide additional information to the case-control approach used, for example, in standard randomized clinical trials, says Collins.

If what you want is an accurate estimate of the quantitative risk that's contributed by a particular genetic variant or a particular environmental exposure, the prospective study design will give you that. Francis Collins

“If what you want is an accurate estimate of the quantitative risk that's contributed by a particular genetic variant or a particular environmental exposure, the prospective study design will give you that,” he says. “The case-control approach tends in general to overemphasize the more severe end of the spectrum of the disease.”

Although many researchers are excited by Collins's proposals, they fear that any efforts to get this study off the ground could be restricted by current logistical limitations.

“I'm personally in favour of not getting started on it yet,” says Christopher Carlson, an epidemiologist at the University of Washington. “Right now, we're almost ready to do the genotypes; in a few years, we'll be ready to do some of the phenotypes; but the clinical stuff, I just don't see that being cheap enough yet.”

Carlson says that many environmental influences are difficult, if not impossible, to measure. Added to that, the more elaborate the phenotyping, the more expensive the study. Carlson estimates that finely phenotyping several hundred thousand individuals will boost the cost of the study into the billion dollar mark.

Similarly daunting, says William Evans, Scientific Director of St. Jude Children's Research Hospital, Memphis, Tennessee, will be the construction of a highly sophisticated data-management system to assemble and analyse the data. “Such a system has remained out of reach to date,” says Evans, “even when [the] scope of interest is much more narrow than the 100,000-patient prospective cohort study.”

But even if the study proves scientifically and technically feasible, informed consent, recruitment, public support and the cost pose significant challenges to getting the project off the ground. “The most important thing to do will be to convince a number of communities that this is the right thing to do, especially given the price tag,” says Aravinda Chakravarti, Director of the Institute of Genetic Medicine at Johns Hopkins University. “But the prospect is important and exciting enough to warrant such an effort,” he says.

At the moment, Collins stresses that all of those issues are in flux. “I would hope that by the end of the year, that they would coalesce into something that could be put in front of an interested audience — the government, leading scientists, and the public — and then [we'd] let them decide whether they think it makes sense or not.”