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MS genes and GWAS.

Posted Oct 22 2008 6:18pm

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Today I want to once again cool the hype from the media. There recently was astudyin the New England Journal of Medicine as well as a candidate gene study in the journal Nature Genetics which identify new risk factors forMultiple Sclerosis.

First what we know
Candidate-gene studies have validated associations between multiple sclerosis and polymorphic variants within the major histocompatibility complex (MHC), but no other loci with a definitive association with the disease have been found.

30 years ago scientists found that immune system proteins calledHLAs (human leukocyte antigens) are partly responsible for the genetic factor. HLAs are like identity tags, all cells of the body carry them and the immune system "inspects" them so it knows not to attack them when it's seeking out foreign cells or pathogens to destroy. The gene that codes for them is called HLA-DRB1 and having this variant increases one's chance of getting MS by four times.

Second let's take a hard look at the data

From the NEJM Article

A number of allelic variants had a significant association with multiple sclerosis. Of these, two SNPs in intron 1 of the IL2RA gene encoding the alpha chain of the interleukin-2 receptor (also called CD25, located at chromosome 10p15) are notable: rs12722489 (P=2.96x10–8; odds ratio, 1.25; 95% confidence interval [CI], 1.16 to 1.36) and rs2104286 (P=2.16x10–7; odds ratio, 1.19; 95% CI, 1.11 to 1.26)

A nonsynonymous coding SNP (rs6897932) in exon 6 of IL7RA, a gene located on chromosome 5p13 that encodes a transmembrane domain of the IL7R chain of the interleukin-7 receptor (CD127), also showed highly significant evidence of association with multiple sclerosis (P=2.94x10–7; odds ratio, 1.18; 95% CI, 1.11 to 1.26)

The HLA-DR locus was unequivocally associated with multiple sclerosis (P=8.94x10–81; odds ratio, 1.99; 95% CI, 1.84 to 2.15)

Analysis of the 925 SNPs from the MHC region (positions between 29 and 34 Mb on chromosome 6) conditional on HLA-DRB1*1501 revealed a highly significant residual association signal peaking at rs9270986 (P=1.83x10–17; odds ratio, 5.80; 95% CI, 3.53 to 9.53), which lies close to DRB1. A portion of this residual signal is probably related to allelic heterogeneity at DRB1

The study in Nature found similar findings. Before I say shame on the media for hyping this association I would like to put these numbers called odds ratios into context.

An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. In this case the odds ratio of having MS would be more likely if you carried the studied polymorphisms mentioned above. But not by much!!!

Let me give you an example. In patients who carry a single change in one of their clotting factors, Factor V Leiden the relative risk of developing a blood clot is 7. Yet when combined with other rsik factors like smoking and obesity, only a whopping 10% ever develop blood clots!

Granted relative risk is slightly different than Odds Ratios. It does tend to measure on the more conservative side... since relative risk is a more intuitive measure of effectiveness, the distinction is important especially in cases of medium to high probabilities. If action A carries a risk of 99.9% and action B a risk of 99.0% then the relative risk is just over 1, while the odds associated with action A are almost 10 times higher than the odds with B.
In medical research, the
odds ratiois favored forcase-control studiesandretrospective studies. Relative risk is used inrandomized controlled trialsandcohort studies. For more explanationclick here

I hope you are still following me. What this means is that an Odds Ratio less than 2 is not impressive. In fact it gives misleading data.

The Sherpa Says: Even with the most tightly linked data discovered over 30 years ago, we still have no curative therapies for Multiple Sclerosis. What that means to me is that we have no clue as to the true molecular mechanisms of this heterogeneous disease. Stay away from the DTC tests that will likely spring up from these studies. Never take a test for risk without the Odds Ratio being at least 2. Now shame on you media, for just publishing press releases and not doing the due diligence regarding these findings!

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