Single allele lowers heart risk

Selection of mutation may not have had anything to do with heart disease, however

Sep 8, 2004
Nick Atkinson(

Were it not for a single base pair insertion/deletion mutation in the MMP3 gene sequence, the incidence of heart disease among modern Europeans would be much higher, according to the authors of a study published this week in Current Biology. But others cast doubt on the suggestion that the gene necessarily played such an important role.

"Our analyses show how positive natural selection can shape variation in a human population, because we exclude other possibilities, said lead author Matt Rockman, of Duke University. "For a long time, it's been argued that genetic variation underlying disease is the result of deleterious mutations. That is, there's a 'good' version of the gene but occasionally a 'bad' mutation arises that leads to disease susceptibility."

"However, what we find in the case of MMP3, and what many researchers are finding in studies of other genes, is that the genetic variation underlying disease is often associated with new mutations that are favored by natural selection," Rockman told The Scientist. "Rather than increasing disease risk, therefore, such mutations actually confer some level of protection against it."

Rockman and his colleagues used a variety of approaches, including intra- and interspecific comparisons, to show that the 5T MMP3 allele–the products of which help to make arterial walls more elastic–is significantly more prevalent in European populations than might be expected by chance. Their results suggest that heart disease among modern Europeans is lower as a consequence, Rockman said.

"Middle aged European men would suffer approximately 43% more coronary heart disease events had this positive selection for the 5T allele not occurred," said Rockman, citing one of the analyses presented in the paper. "For example, this is equivalent to the reduction of 50,000 deaths per year in the United Kingdom alone," he said.

The allelic mutation first appeared somewhere around 24,000 years ago. However, Rockman was cautious about saying that its protective effects against heart disease were the reason for its rapid spread. "MMP3 is involved in dozens of completely distinct biological processes. For example, it plays a central role in the branching of ducts during mammary gland development." Other roles include a vital function in wound healing–no doubt a pressing issue for individuals of both sexes–in addition to the degradation of various harmful compounds.

"A story about heart disease in ice age Europe is appealing–the fat little Venus of Willendorf certainly suggests an atherogenic diet at that time–but ultimately heart disease is a bad candidate for a selective agent. This is because it doesn't usually happen until the affected individual has had time to reproduce." Rockman instead said that the beneficial effects of the MMP3 mutation in protecting against heart disease might be an evolutionary 'spandrel'–the term used by biologists to describe incidental effects of adaptations that are under selection for other reasons.

Bret Payseur, a population geneticist at Cornell University, agreed. "Speculating on the precise selective cause of the patterns of variation within the MMP3 gene is challenging," he said. But Payseur, who was not involved in the study, was enthusiastic about the approach used. "The clear demonstration of positive selection from comparisons within and between species, combined with knowledge of the effects of genetic polymorphism at this gene, makes this an important and exciting study," he said.

Professor Philip Poole-Wilson, at the National Heart and Lung Institute, London, was more skeptical of the findings, and warned that claims of such major genetic effects have, in the past, been overhyped. He also cites a study led by Salim Yusuf, published this week in The Lancet, which claims that the majority of heart attacks are caused by environmental rather than genetic factors.

"Although Rockman et al. use an impressive suite of methods, large-scale confirmation of their findings is still needed," he told The Scientist. "It's very difficult to see how, if a single gene could make such a difference, Yusef's study could have found non-genetic factors to be so important."