Thursday, June 24, 2010

So vitamins fail again, this time it’s folate and B12. Really?

Yet another clinical trial of folic acid and heart disease has been published – an extremely well designed trial where the results suggest true adherence to the vitamins vs. placebo regime. The conclusions are:
Taken together with the previous homocysteine-lowering trials, the results of SEARCH indicate that folic acid supplementation has no significant adverse effects on cancer or other major health outcomes, even if it also produces no beneficial effects on cardiovascular disease. In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.
JAMA: Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial, June 23/30, 2010, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group 303 (24): 2486 http://bit.ly/azza0X

First of all this is very good news regarding cancer especially as this would be considered a high risk group (where the majority were over 60 yrs old and therefore more likely to have precancerous lesions which excess folate could in theory accelerate the growth of see Ulrich, CEBP, 2008). This is important and the authors are right to highlight it – it is often used as a headline argument to oppose B vitamins but the details don’t support there being a real significant risk compared to the benefits, and this large study helps to confirm that.

Not so good news though for preventing heart disease, but what does it really tell us? They also mention osteoporosis, see below. This is a problem with trying to squeeze nutrition into a pharma type clinical research study. We are not dealing with a novel molecule with a precisely defined target but a common vitamin involved in complex biochemical pathways (inc. DNA synthesis and methylation) and it’s not surprising that perturbations to these pathways have multiple effects.

Homocysteine is a risk-marker for CVD, whether it is cause or effect is not established although there is reasonable evidence for it being involved (Wald et al, BMJ, 2002). It has been reported to have damaging effects on genome stability (Fenech, AJCN, 2010) and high levels have been linked to a host of diseases from osteoporosis to dementia (Selhub, 2006). The evidence strongly suggests that it is a good thing to keep it low. So why have all these trials shown more or less no effect of homocysteine on heart disease? Quite possibly because all of them are looking at secondary prevention, i.e. the study patients in all the trials are exactly that, patients, already ill with heart disease. Maybe it’s to late to start lowering homocysteine if the damage has been done – just like no-one really expects calcium and vitamin D to have much positive benefit in people who already suffer from osteoporosis (incidentally in the paper the authors say “Low folate status and increased homocysteine levels have been associated with osteoporosis and fracture risk but fracture incidence was similar in the 2 groups” – not at all surprising, osteoporosis prevention does not start at >60 yrs old).

Post infarct reduction of cholesterol levels have been shown to be effective in secondary prevention (indeed all patients in the SEARCH trial were on simvastatin) but the mechanisms are different. Cholesterol clogs a pipe whereas homocysteine, if it is indeed involved, is likely to do so via damaging blood vessel walls. So we can talk about plumbing. If a pipe becomes blocked following years of calcium deposits in a high calcium water area, once the blockage is treated, recurrence can be prevented by reducing the calcium content. If the pipe develops a leak due to years of erosion due to acidic water, even after repairing the leak the pipe walls will still be weak and neutralising the water is not going to make much difference, the damage is done.
The SEARCH study was well done and they make good points about cancer, but the final sentence was disappointing:
In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.
Drug treatments OK but talking about smoking and weight as of “proven benefit… for the prevention of cardiovascular disease” is misleading, it suggests that this study has something to say about primary prevention, which it certainly does not.

As discussed in the past
, clinical trials of nutrients for primary prevention are pretty much impossible, we have to rely on the best evidence we have to give nutrition advice – the evidence is strongly in favour of homocysteine lowering with levels of folic acid much lower than 2mg per day (RDA of 400µg is enough for most, those with polymorphism in MTHFR will need more, of course it goes without saying that there was not genetic component to this study…). SEARCH and all the other trials have often been misused in the folic acid/homocysteine debate, they have often been cited as proof that the homocysteine theory is wrong – but they do no such thing and it would help if the authors of these studies made it clear that all conclusions are relevant (and useful) only as far as secondary prevention is concerned.

Sunday, June 6, 2010

Not DTC and not even DTMD? – Genetichub announces itself

There is a new “old” kid on the block – announced last week at the Consumer Genetics Conference by Dr Stephen Murphy, aka @genesherpas, http://genetichub.com/

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This is just a short note about the site and service because it seems likely that it was finalised in a rush to get it ready for the CGC announcement. It’s too early to judge what it is and what it will become. Steve Murphy is of course very well known as an outspoken critic of most DTC genomics via his blog. I am wondering whether his now official status as a fully commercial genetics service provider, beyond his own medical practice, will affect the tone of his future posts. I doubt it…but it’s a fact that the situation is now different, the opposition is now the competition and a potential conflict of interest has to be acknowledged, at least. One thing is certain though – his blog history means that he has set himself very high standards regarding the delivery of genetic testing

So what is the Genetic Hub? At the moment the site has little content, most of it consisting of links to external sites or content:

  • What are Genes links to an embedded YouTube video of Francis Collins talking about…genes (DNA Day 2005)
  • Genetic Disorders links to University of Utah pages
  • Genetic Laws links to the excellent Genomics Law Report of Dan Vorhaus et. al
  • Genetics Blog looks to be the Sherpa blogs repackaged in GeneticHub clothes

As I said, it may have been a rush to get it ready in time. Anyhow, the hub of GeneticHub is of course business, selling products and services. The first (currently only, more coming soon for Coumadin and Tamoxifen) product is the CYP450 2C19 (PlavixTM) Gene Test together with a genetic physician consult. Clicking on the Buy Now link takes you to the pages of mymedlab.com who sell the test – the websites have similar designs but the relationship between mymedlab and genetichub is not clear. The test price includes 15 minutes with a “board-certified Genetic Physician across our secured platform”. Is that a phone call or a webchat? Expertise provided by “Dr. Steven Murphy and his Personalized Medicine Group”.

You can purchase the test straight away via the website so this IS actually a genetic test sold DTC. The difference between this and 23andme, decode, etc (but maybe not navigenics) is that 15 mins consult is included (and of course it is a declared clinical diagnostic test, not just for “educational use”). As I said, this is not a critical review, just an overview of a new provider of personal genetics services. There are a few questions and I am sure all will be cleared up by Dr Murphy in due course:

  1. 1. Does customer get the results before the consult?
  2. 2. If not can the customer get them before and choose to forgo the consult?
  3. 3. Is a medical prescription required (seems not, no mention on the site).
  4. 4. Can we see a sample results – what SNPs, what are the interpretations, etc? (I have no doubt that this service is high quality, but the next MD that comes along and sets up a company may be less knowledgeable – so transparency is, as always, a key requirement, for any provider).
  5. 5. Does insurance cover the costs?

Genetichub is actually entering into quite a competitive field. Pharmacogenetic testing has always been less controversial than the so-called predictive personal genetics and has been on offer, DTC and via MD, for several years. Among the the other offerings are

Genelex – they have a wide range of Pgx tests that are sold direct but only if customer has a medical prescription. I couldn’t find pricing, they say the test is billed direct to the insurer. They also give you 90 days access to their GeneMedRX “drug and gene interaction software so healthcare providers can see the effect of the genotype on all of your medications, herbals, and over-the counter medicines” Actually they will give a 30day free demo to anyone, even without any purchase. Does not appear to include a personal consult. Website provides a lot of information and a guide on how the results are interpreted.

DNAdirect test CYP2C19, plus many others. The CYP2C19 costs $199 with “toll free support” – not clear what this consists of as they also advertise Pre-test & Post-test Consultation for $250 per hour

The 23andme $429 health edition includes the CYP2C19 SNPs plus an interpretation of the results specifically for Plavix – recently announced partnership with Informed Medical Decisions provides genetic counselling consult for $99 or $375 for “Comprehensive Clinical Genetic Counseling” which they say will be reimbursed by insurance making the net cost just $35

Decodeme include the same SNPs but don’t seem to have a specific Plavix interpretation, they seem to have priced themselves out of the market at $2000 for the complete scan.

Pathway have a specific Plavix report in their $249 scan and access to Counselors but no indication of costs of this part of the service. (Still very unimpressed by the information available on their website).

Navigenics complete scan is $999, it specifically includes Plavix, among many other drugs and “Our counselors are available at any time to answer your questions, at no additional charge – even before you have signed up. You can call us any time at (866) 522-1585 to set up an appointment at your convenience.”

So with Genetichub and last weeks Existence Genetics it’s getting more and more crowded – bring on the NIH genetic testing registry please…(NIH is canvassing opinions, go here and give them yours, help them to get it right from the start).