Thursday, December 24, 2009

Lp(a) Maybe there's something there that wasn't there before?

I unwrapped the NEJM this week and to my surprise it has a Lp(a) stuff in it. One of the things we do to prevent heart disease is take family histories. We also check cholesterol levels and include something called a Cardio-CRP. One thing we haven't been including is a Lp(a). Why? The only data I see that is good on this is on women.

We use validated risk tools like Reynolds and Framingham Risk. It was with great interest that I read about this recent "candidate gene" model of assessment for Lp(a) genetic link to levels and risk. Clarke et. al.

They also looked at the other GWAS linked regions and what they found was most surprising in my mind.

LPA, which encodes apolipoprotein(a), was the only true "candidate" gene on this custom array that was significantly associated with coronary disease.

Now why would the other regions not be as strongly linked? Or better yet, why was Lp(a) more likely to be linked and associated?

Well, LPA the gene produces a protein called Lp(a) which is hypothesized to carry oxidized proinflammatory phospholipids, thus promoting inflammation in coronary arteries in turn creating niduses for clot and heart attack.

What do the other regions do? Dunno. I think that is the teaching point here.

GWAS great for illuminating possible pathology, which then in turn must be dissected and validated.

Candidate screens are good for risk markers IFF there is some hint of WTF the proteins are doing for the disease.

This is why I am just flummoxed by the fact that people are still pushing tests which have little to no clinical use or even prognostic capabilities.

Listen, you want to discover yourself? Go get a cholesterol, Glycohemoglobin, and complete blood count. Check your blood pressure, check your BMI. If any of these are abnormal, go seek professional help.

But please, please, please don't use SNPs that have no science behind them as true science or clinical markers. research them, sure. But using them like MDVIP has........Risky guys.

Which reminds me. I am taking care of a patient who recently left MDVIP.......the patient had the Navigenics SNP scan done.........what do I find on family history?

The patient met Bethesda Criteria for HNPCC.........

Guess someone was too busy scanning Unproven SNPs.

That being said, this current study by Clarke suggests a few things

1. Two LPA SNPs explain approximately 36% of the overall variance in plasma Lp(a) lipoprotein levels. That could be like the CRP story. Yeah CRP levels but no association with risk. Big Whoop, but....

2. Both SNPs (one coding for the amino acid substitution I4399M and the other non coding) are associated with coronary disease. Ahem, like to see some replication here......But it could be true.

3. After adjustment for the plasma Lp(a) lipoprotein level, the association between LPA genotypes and coronary disease was abolished. Well.....that means to me, phenotypic testing with Lp(a) levels may be more useful than I had thought.....And definitely more useful than genotype testing.

The Sherpa Says: Hmmmm, maybe we will see much more of this trend. Non-genetic molecular testing being more valuable than genetic testing for risk prediction.....Wait a sec'

1 comment:

Keith Robison said...

Your timing was apropos considering that the apo(a( contains many Kringle repeats. I haven't followed this in nearly 2 decades; long ago there was an observed correlation between number of Kringle repeats (it is a site of intragenic copy number variation) and protein level