Good news for tanning salons - sunlight and health

New research lauding the benefits of sunlight, and not because of vitamin D, brings up a general question about reductive research.  The work was reported in Edinburgh at the International Investigative Dermatology 2013 meeting, and suggests that sunlight helps reduce blood pressure, which leads to lower risk of heart attack and stroke.

Researchers found that UV rays from the sun caused their study subjects to release a compound that has this positive effect on blood pressure.  That's nitric oxide, apparently, which is released into the circulation when sunlight touches the skin.  The researchers note that hypertension and cardiovascular disease rates rise in the winter, and propose it's because of reduced exposure to sunlight.

And, Medical News Today quotes the lead author:

Richard Weller, Senior Lecturer in Dermatology, and colleagues, say the effect is such that overall, sun exposure could improve health and even prolong life, because the benefits of reducing blood pressure, cutting heart attacks and strokes, far outweigh the risk of getting skin cancer.

It's of course notable that these results are being presented at a dermatology meeting, because dermatologists have been telling us for years to reduce our exposure to sunlight, a prime cause of skin cancer.

La promenade (1875) by Claude Monet

Whether these results are valid or not is not our interest here.  Indeed, hypertension is high among African Americans and Afro-Caribbeans, though the data are equivocal for Africa itself. 

But, ok, let's assume there's something to this.  Indeed, let's assume that even a tenth of what people say about vitamin D is true, and that exposure to sunlight is good for our health for multiple reasons.  And that wouldn't be surprising, given that we've lived most of our evolutionary history exposed to sunlight, and if it were as bad for us as dermatology says it is, we'd not have made it this far.

That aside, this brings up the question of competing effects.  Sun exposure is bad because it causes cancer.  No, it's good because we need the vitamin D, and now the nitric oxide.  Red wine in moderation is good for us because it lowers heart disease risk, but it's bad because it causes breast cancer.  Eating fish is good because of antioxidants, but bad because of mercury.  Brown rice is good because it's a source of fiber and vitamins, but bad because it's loaded with arsenic. 

The list could, and does, go on and on.  In large part it's a product of reductive science, looking at single factors and determining single outcomes, ignoring complexity and context.

And life is a balancing of costs and benefits -- exercise is good for us, but running wears out knees, and bicycling brings risk of accidents.  You might decide that the benefits outweigh the costs, but how informed is that decision, really?  How do you decide whether or not to lie in the sun?  You might not in fact be at risk of hypertension, so sun exposure isn't a great benefit to you in terms of lowering your risk of heart disease, and so the potential cost of skin cancer might be greater for you than the benefits.

But, how would you know?  These results are based on population data, measuring only a subset of factors that are actually involved in the complex interactions that result in hypertension or skin cancer or breast cancer or heart disease, and certainly not measuring your personal set of factors, exposures and risk.

In the end, we probably should make these lifestyle and dietary decisions based less on this week's data -- indeed, a lot of the relevant data we don't have and don't even know we should have -- but on how much we enjoy that glass of wine, or lying in the sun.

Are we closer to personalized genomic medicine yet?

A large study of 200,000 people with breast, ovarian or prostate cancer and controls was reported widely last week as one of the most comprehensive studies ever of these diseases.  The study was carried out by the  Collaborative Oncological Gene-environment Study, COGS, and the thirteen papers published in five different journals were collated by Nature and presented in an open access site, with commentary.

The aim of the study was to identify risk factors with which to stratify the population by risk status, and thus to be able to determine who to most intensively screen to prevent or detect cancers early. They identified 74 new genetic loci (chromosome regions, whether or not an actual causal site has been found, as usually it hasn't, to date) associated with risk; 49 with breast cancer, 8 for ovarian cancer and 29 for prostate cancer.  There's a lot of material, and we can't cover it all, but we'll give it a go.  Keep in mind that they aren't yet saying they've identified genes 'for' these cancers, but that their genomewide associate studies have located chromosomal regions that are statistically associated with disease, and the assumption is that they are involved in affecting the probability or risk of disease.  

Prostate
The genetic loci that increase risk of prostate cancer that have been reported to date have been common and 'low-penetrance' alleles, meaning that even if a man carries one or more of them his risk of getting prostate cancer is low.  The new study identifies 29 new loci associated with susceptibility to prostate cancer.  They are less common than the previously identified risk factors, presumably found by the COGS now because their study is larger than previous studies.

The consortium stratified their sample into aggressive and non-aggressive disease and found different though overlapping patterns of loci associated with each.  Of the new loci, 16 are associated with both forms of the disease.  The researchers say that each of the loci contains 'plausible' candidate genes.  That is, the causal genes in the chromosomal location the disease mapped to have not yet been identified.  It is a slight stretch to say 'plausible' rather than 'possible', but that temptation's not unusual, and identifying the true causal genes can be tricky (e.g., see our previous posts on mapping genes for traits, here and here.)  But ok.  The paper discusses these candidates, but the consortium can't (yet) confirm any of them.

More than 70 loci have now been reported for prostate cancer, which, according to the researchers, explains "~30% of the familial risk for this disease." That means that this is found in those who already have a family history of risk--that is, an enriched subsample most likely to be carrying genetic risk factors. This study reports that those at highest genetic risk of prostate cancer, the top 1% of the risk distribution in the population, are at 4.7-fold higher risk than average.  High risk was considered to be aggressive prostate cancer or prostate cancer in patients younger than 55.

Essentially this means that if we tote up your alleles in these 70 regions, and add up their separate independently estimated effects, the net risk is 4.7 times higher than that of a random person in the population.  These are subtle and often slippery issues when it comes to assessing how important the actual risk assessment is--even if the method of computing summed risk is appropriate.
 
Breast and ovarian
Twenty-seven loci associated with familial breast cancer risk have previously been identified, accounting for about 30% of familial risk.  This study reports 49 new susceptibility loci, and estimates that approximately 1000 genes will eventually be found to be associated with risk of breast cancer. 

With respect to genes already known to be major risk factors for disease, the study looked for additional genetic markers in women who carry BRCA1 or 2 mutations, which put them at higher risk of breast and ovarian cancers than the general population.  They replicated previous findings, and also identified new 'modifier genes' that increase risk of breast cancer in BRCA1 carriers, and 8 new genes that increase risk of ovarian cancer, bringing the total to 10 and 12 known genes associated with breast and ovarian cancer, respectively. They identified a new risk allele specific to BRCA2 carriers, as well.  They also found 21 genetic loci associated with risk in east Asian women. 

The consortium reports that these results will one day allow those BRCA1 and 2 carriers at highest and lowest risk of developing cancer to be identified.  Risk estimates for BRCA2 carriers now range from "21–47% risk of developing breast cancer by the age of 80 years for the 5% of the BRCA2 mutation carriers at lowest risk compared to 83–100% risk for the 5% at highest risk" (source).

It is a somewhat separate question what the same non-BRCA sites do, if anything, in those not carrying BRCA mutations.

Gene-environment interactions and breast cancer
The consortium made a stab at addressing the question of gene-environment interaction, acknowledging that risk alleles are rarely determinative (they do apparently believe they've found at least one set of genes that may increase risk to 100% for some breast cancer).  Even the risk associated with BRCA1 and 2, among the most clear cut genetic risk factors known, has been shown to vary considerably by year of birth, presumably because of the interaction between the gene and some environmental risk factor.

King et al., 2003; Science 302:643-646

The study looked at whether relative risk associated with other risk alleles was modified by 10 factors already thought to be associated with risk: age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, use of hormone replacement therapy after menopause, alcohol consumption, smoking, and exercise.

They replicated previously reported interactions between specific loci and parity and alcohol consumption, with risk increasing with lower parity and, they assume, a genetic variant of the LSP1 gene, and with a variant of CASP8 and alcohol consumption.

Import
A commentary in Nature Genetics discusses the public health implications of the work.  Remember that the aim of the study was to facilitate the identification, on an individual basis, of those at highest risk of breast, ovarian and prostate cancer, in order to prevent and detect disease.  But how to translate this to population public health measures is another question. 

But we've got a ways to go on this. Tests for prostate cancer are very unreliable, and there is no screen for ovarian cancer.  Whether a risk prediction is accurate may depend on whether the cancer is found because it is symptomatic or by extensive testing.  That's an issue since it's known that many or perhaps even most prostate cancers, and at least some breast cancers, regress on their own.

The chromosome regions now identified to increase risk of ovarian cancer are estimated to double the average population risk to just 3%.  The cost-effectiveness of mammography is still the subject of intense debate, and genetic susceptibility to cancer, even for those alleles known to be major risk factors, is never 100% and usually much lower. And testing carries its own risk, as does being told you're at higher risk--so such information had better be accurate if this is about public health!

Further, risk is always estimated from past environmental exposures, and future environments cannot be predicted.

Family history and the simulation of mendelism
We already know that family history is a good--generally, clearly one of the best predictors of these kinds of diseases.  So far, genetic risk studies haven't done much to improve on that; whether the current batch does isn't clear to us, at least not yet.

The other major risk factors are sex and age.  Generally these are far more powerful than individual gene identification, but of course the reason would be at least in part because family history reflects the presence of those genetic variants.  We also know that sampling and studying families with multiple cases enriches for whatever factors, genetic or environmental or even tendency to have testing done by high-grade clinics, in those family members.  This can make the presence of the disease seem Mendelian, as if due to a single or very few genes.  Such 'simulation of Mendelism' can raise the apparent risk of an identified gene shared by the affected family members to values far above those the same would have in the population at large.

This kind of bias is but one of several that make actual risk estimation very difficult, and GWAS type case-control studies are known theoretically and empirically to generate inflated estimates of effects.

So there is a lot that must follow these studies if they are to be judged to satisfy the media noise that they have generated.

GM: truth or consequences?

Whenever science tries something new, and especially perhaps if it is tried by a big business, you can count on a reaction.  But when is it just reactionary?

We are skeptical and critical of many things in science, including crass or misleading commercialism, hyperbole, or waste of research resources in genomics.  But we try to keep it to the science and to be fair and balanced (not in the Fox 'News' sense!).

GM crops have created much contentious controversy.  Many have condemned the capitalist exploitation that is involved in many instances, or the push towards transgenic monocropping.  Sometimes this has been sociopolitical protest.  It's a mix of back-to-the-land nostalgia, belief in mixed, small-farm agriculture, and feeling for the exploited farmers around the world--and allegations against GM crops.  And anger at agri-business for making farmers buy new seed each year.

The scientific (non-political) complaints have been, essentially, that:  (1) the crops spread genomic uniformity in a world where evolutionary variation is required, so that pests can eventually overcome the anti-pest modifications in some GM crops; (2) the transgenes may spread to wild strains, making future diversity unavailable even if needed; (3) the transgenic crops may devastate needed insect pollinators, pest-eaters, and so on; and (4) the crops may contain items harmful to their consumers (us, or our livestock).

GM manufacturers may be greedy and crass, and worthy of scorn and deserving of regulation, but they certainly do at least test their modified crops. They aren't pulling their claim that the transgenic protein changes aren't harmful to people or cattle out of thin air.  Years of use have not revealed many, if any, serious problems of this sort.

So when a story is circulated like this one, that animals fed on GM produce lose fertility and have stunted growth, how should we react? 

Yet another study has concluded that feeding animals GMOs results in higher rates of infant mortality and causes fertility problems. Russian biologist Alexey V. Surov and other researchers fed Campbell hamsters (which have fast reproduction rates) Monsanto GM soy for two years. It should be noted that hamsters do not evolutionarily eat soy—just as cows fed Monsanto corn are actually ruminants and would not naturally eat corn.

Many animals on the GM diet even displayed rare, strange pathologies like hair growing in recessed pouches inside their mouths. “Some of these pouches contained single hairs,” said Surov in Doklady Biological Sciences, “others, thick bundles of colorless or pigmented hairs reaching as high as the chewing surface of the teeth. Sometimes, the tooth row was surrounded with a regular brush of hair bundles on both sides.  The hairs grew vertically and had sharp ends, often covered with lumps of mucous.” Surov and other authors concluded that because rates of hairy mouths occurred more frequently in third-generation GM-fed animals, the condition may have resulted of the GM feed. Surov says contaminants and herbicide residue (like Roundup) could be to blame as well.

We need to be as suspicious of underlying motives of authors of such reports, just as we are of positive claims by promoters of GM crops.  If this report truly indicts GM soy, how could such a result not have been noticed before?

First, was this study well-conducted?  Did they feed control animals non-GM soy (hard to find, granted) so they could eliminate the possibility that any experimental effect was due to the transgene rather than simply a diet of soy?  And, what about the possibility that it is contaminants and herbicide residue that could be to blame?   In either case, indicting the GM diet is premature.  And note, we aren't defending GM foods here, just good science!  Using bad science even for a good cause isn't much help to that cause.

And, second, to show harm, drug companies or regulators often hugely overload test animals with exposure to the test agent.  This could be the case here, too.  If so, one could defend the GM crops by saying that many things in massive doses cause harm, but are harmless and routine in daily life.  In that sense, this story is an exaggeration that misrepresents risk--even if there are no problems with the study.

Another point of view would be that most things in evolution are gradual, small, and slow, but accumulate over time.  It is obvious from the accumulating data about GM crops that they don't have dramatic effect or they'd' not ever be marketed, even by agribusiness.  The thing to fear and object to, if there is anything like that, would be small risks to individuals, even if substantial to large populations.

We avoid unnecessary X-rays because though the risk is small, on a population basis they may in fact cause many cases of disease.  Likewise here, if GM crops do have some risk, it is almost necessarily going to be small.  Again, if it were very large, nobody would ever market the crops.

If this is the case here--and we can't judge just from this story--then it's an instance of the politics of population risk vs corporate gain, or gain in efficiency, pest-control, or whatever.  The political issues need to be re-framed.

Much of life consists of small risks.  How we deal with them scientifically or politically, is not easy to decide.