Lp(a) and aortic stenosis: How genomics points the way

The recent discovery of an association between an Lp(a) gene variant and aortic stenosis once again brings genomics into the limelight. How do we act on findings in genomics? What are the implications of this study?

Disclosure:

Dr Topol has no conflicts of interest relevant to this digital technology.

See also:

Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013; 368:503-512. Abstract.

Lp(a) gene variant associated with aortic stenosis

Transcript:

Dr Eric Topol: It's time for genomics again. I know this is not easy—it's not a subject that generates a lot of comments and interaction—but there was a very important finding in the February 7, 2013 New England Journal of Medicine about calcific aortic stenosis.

This is a genome scan paper looking at a million or so single nucleotide variants across the genome, not genome sequencing, and finding our friend Lp(a) as the minor allele in about 7% of people strongly associated with an odds ratio of 2.0, the same variants that are known to be associated with coronary artery disease with calcific aortic stenosis. 

In well over 6000 individuals, where they had computed tomography of calcium and then replicated across many different cohorts—and not just for calcium but for the need for aortic-valve replacement (for example, in the Swedish cohort and along with other cohorts)—there was unquestionable genomewide significance with multiple points of replication.

They also looked at mitroannular calcification. There was an interferon gene variant that was not consistently replicated, so we have to hold back on making that pronouncement.

But certainly for aortic stenosis, Lp(a) held up an odds ratio over 2, and even adjusted for Lp(a) levels, this Mendelian  randomization, basically the genomics play, clearly was influential with a 64% risk of aortic stenosis.

How do we translate these findings into useful actionable clinical information? We don't have a good way to lower Lp(a). And furthermore, we don't know if that's going to translate to preventing aortic stenosis. But we do know that these variants in Lp(a) that have a significant effect on a kringle (and this dysfunctional Lp(a) protein) clearly are incriminated, and we now have the substrate for testing lifelong therapy to suppress Lp(a) to see whether or not we can reduce the toll of aortic stenosis.

We need better agents and we need proof that this strategy would work. That is, by modulating this genetic-burden liability, can it change the natural history to aortic stenosis? Until now, we only knew genomics that were related to bicuspid aortic valve in the notch gene, but we didn't know about run-of-the-mill calcific aortic stenosis. This is a big finding, not yet actionable, but certainly worthy of treatments in the future, developed specifically for these individuals.

I think this is a very important common variant. As far as cardiovascular disease, atrial fibrillation, PITX2 and this one are the ones with the highest penetrance—odd ratios in the case of PITX2was 1.7, the odds ratio here of 2. That is very unusual for common genomic variants, which usually hover around 1.1, 1.2, but not at 2.0 (which is really striking!).

I hope you will cue into this and share your comments regarding Lp(a) showing up incriminated and explaining (at least in part) significant advanced age-related calcific aortic stenosis.

Thanks for your attention.

Your comments

	Lp(a) and aortic stenosis: How genomics points the way
	# 1 of 6	February 20, 2013 11:59 (EST)
	Larry Baruch	Effect of LDL lowering Could dramatically lowering LDL over a lifetime have an effect on the development of aortic stenosis in patients with this Lp(a) variant Author's disclosure (Feb 20, 2013) I have no relevant disclosures to make in connection with this topic.
	# 2 of 6	February 22, 2013 06:27 (EST)
	CJ McConnell	Only if the Lp(a) was < 30% 0f the LDL [LDL-P / Apo-B] This is why screeing Lp(a) is important,.. Author's disclosure (Feb 22, 2013) I have no relevant disclosures to make in connection with this topic.
	# 3 of 6	February 25, 2013 10:48 (EST)
	James J. King	DISEASE: Lp(a) and CAC-Coronary Artery Calcification 1. Genomic variation landscape of the human gut microbiome individual might have a unique metagenomic genotype, which may be exploitable for personalized diet. 2. As you wrote in “The Creative Destruction of Medicine”: The practical impact of variation is largely unexplored in the human microbiome. Therefore developed a framework for metagenomic variation analysis and applied it to fecal metagenomes and CAC. Author's disclosure (Feb 25, 2013) I have no relevant disclosures to make in connection with this topic.
	# 4 of 6	March 3, 2013 09:47 (EST)
	Carl Adler	is it that important? I routinely measure Lp(a) and if it is elevated then I treat it; some people will develop a problem and some won't; treatment is not expensive; we treat people with elevated other cardiac risk factors but some people with a high amount of risk factors still live to be very old without developing a problem; is really spending valuable money testing and measuring all this genomic variation that important clinically? Author's disclosure (Mar 3, 2013) I have no money but will gladly accept voluntary contributions.
	# 5 of 6	March 4, 2013 03:37 (EST)
	Robert Superko	Ethnic differences 1. Don't forget that rs10455872 (LPA intron 25)explains ~25% of Lp(a) variance so while there is a link, it is not 1 to 1. It is independent of rs3798220 (Aspirn response one). 2. There is also substantial ethnic variability with ~12% of caucasians having at least 1 risk allele, it is about 1-2% for Af Americans & Mexican americans (Li CircCardioGene 2011, Marcovina JLR 1996) 3. LPA intron 25 has a OR of 1.47/risk allele for CHD as seen in UCSF, Procardis, SHEEP/SCARF, ISIS, HPS etc. thus it is not just aortic calcification but general CHD that is important as well. Author's disclosure (Mar 4, 2013) Employed by Celera, a gene discovery company. Chief Medical Officer.
	# 6 of 6	May 21, 2013 11:56 (EDT)
	Steven Rourke	One post removed from this thread Please note that we removed a promotional post from this thread. While we aim to be as "hands off" as possible, please be sure to follow our forum guidelines as noted below. Author's disclosure (May 21, 2013) Editorial programming, theheart.org

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