Tuesday, November 30, 2010

Is asthma 'catching'? Is everything? Who said we'd defeated infectious disease?

The incidence of childhood asthma skyrocketed through the 1980s and 1990s and no one knows why.  Environmental epidemiologists have attributed the cause to a wide variety of factors including breastfeeding, bottle feeding, absence of helminth infestation, dirt, excessive cleanliness, air quality (good or bad), presence of pets in the household in infancy, the absence of pets, the use of acetaminophen in infancy, and even Facebook -- note that many of these are directly contradictory.  A few studies early on found that kids who grow up on farms tend to be at lower risk of asthma, and this led to the "Hygiene Hypothesis" which posits essentially that an immune system without enough to do is an immune system that goes awry.

A trend in epidemiology in the last few decades, in direct response to the inability to definitively identify environmental causes of complex diseases such as asthma or heart disease or type 2 diabetes, has been to look inward instead, to look for genes 'for' these diseases.  This isn't surprising, given the promises made by the Human Genome Project, for example, that knowing the genome would allow us to explain the majority of disease.  And, in fairness, given the great successes of human genetics early on at finding single genes for rare largely pediatric diseases like cystic fibrosis or Tay Sachs, the idea that genes could explain other diseases (even most diseases) was highly appealing and seductive.

But this meant that diseases were geneticized that, in our opinion, should have been left to the environmental epidemiologists -- genes can't explain an epidemic that took off as fast as the asthma epidemic did because gene frequencies don't change nearly fast enough.  Even if you posit that those who are affected have a genetic susceptibility to whatever environmental factor is triggering the disease, still it's clear that something rapidly changed in the environment, and, for our money, research dollars should be going toward finding that rather than genes.  (Why epidemiology has such a hard time finding such factors is another story, but it's largely because the tools of the trade are best at finding risk factors with large effects, such as infectious agents.  Though, why that hasn't been true of asthma, which, given the nature of the spike in incidence, seems to have had a main effect cause, is perplexing.)

But, largely because of this failure, many genetic studies of asthma have been done in the last several decades, including large genomewide association studies (GWAS).  And, just as with other genetic studies of complex diseases, in what is a rather repetitive drumbeat for trait after trait, nothing major has been found to reliably explain this epidemic.  Sure, some genes have been reported, but they just don't explain enough to be the answer.  Now researchers still interested in the genetics of asthma are suggesting, as with other complex diseases, that there must be numerous interacting genes with small effect.  Which is much more likely than one or two causative genes, yes, but it doesn't answer the question of what caused the epidemic.

There have been many ideas about the environmental component, most of them having to do not with pathogens but with pollutants, a number of candidates being listed above.  But now Science reports in the 26 November issue that there may be a bacterial link with asthma.  Again, the 'more microbes is better' hypothesis:
As odd as this might sound, there's mounting evidence that bacteria matter. Babies born via cesarean section, who experience a more sterile entry into the world than those born vaginally, are more likely to get asthma. So are young children treated with many courses of antibiotics. Along with animal studies, these observations suggest that the balance of bacteria and other microbes help guide immune development—and that when the balance is disrupted, disease may follow.
But it's complex.
All of us play host to bacterial residents. But children who develop asthma, researchers are learning, are home to different bacteria—and sometimes a less diverse mix—than those who stay healthy. “It's really coming down to the bacterial community structure, who's there, and in what numbers, and where,” [University of Michigan immunologist] Huffnagle says. 
So far, the evidence linking asthma and bacteria are associations, not proof that an imbalance of bacteria causes the disease. The big question, says Martinez, is, “Do asthmatics have an immune system that makes them be colonized by different things? … Or is it because they were colonized by different things that caused them to have asthma?” 
Researchers are currently comparing the microbiome (the community of microbes that colonize an individual) of kids with asthma and kids without, kids on farms, and kids in cities, to try to answer this question.  This is another way to ask if it's genes or environment -- which came first, the microbes, or the host environment?  And, of course many kids born by C section don't get asthma, and many kids born vaginally do.  It's complex indeed.

Microbiome analysis has some merits, beyond being yet another genomic Golden Calf for research labs. But we can predict that it is yet again a hunt for needles in a needle-stack of complexity.  We're likely still to be left with the problem that as a complex phenotype, like all other complex phenotypes, asthma is hard to explain, and hard to define.  In fact, an editorial in The Lancet several years ago suggested that every case should be considered unique, causally, physiologically and in how it's treated.

It is interesting, however, that schools of public health  abandoned their infectious disease departments in the '70s, declaring effectively that we'd won that battle (cheered on,  naturally, by geneticists seeing themselves as the funding beneficiaries).  Now, not only are clearly infectious issues like HIV/AIDS, multiple antibiotic resistant TB, SARS, and various influenzas still plaguing us, along with resurgent malaria and other neglected tropical diseases.  But many GWAS 'hits' are landing in genes involved in the immune system.

Inflammatory bowel disease, Crohn's disease, macular degeneration, and even schizophrenia are in this category.  If these pan out (and the first ones seem clearly to have done so), it means that non-acute, sub-clinical infection of long duration may build into diseases that did not seem either contagious or infectious.  If that's so, and the message sinks in, then GWAS may have done a service.  And epidemiologists like the sometimes-fringy Paul Ewald who have been touting the role of infectious role in chronic disease will have been vindicated.

1 comment:

Anne Buchanan said...

Just a slight correction -- the title of this post is a little misleading. The idea isn't that asthma is caused by a bacterium in the way that, say, the flu is. Rather it's that there's something about the immune response to either a deficit of microbe exposure (is there really such a thing, though, outside of a literally sterile bubble?) or to a subset of microbes inhabiting someone presumably predisposed that leads to asthma, the hyper reactive inflammatory response in the lungs.

This isn't as surprising as, say, Ewald's idea that homosexuality is infectious, because asthma has long been known to involve an immune response, but it could at least lead the hunt away from genes 'for' the disorder and back in the direction of an environmental trigger as primary.