Several research groups have identified new genomic markers in
various cohorts that have an association--albeit small--with MI or
coronary artery disease (CAD). The work appears as five papers online
February 8, 2009 in Nature Genetics, and some of the discoveries are
somewhat surprising, say experts.

Dr Nilesh Samani (University of Leicester, UK), who was involved in
three of the papers, told heartwire: "The bottom line is that if we
take this new research [on top of existing work], we now have at
least 10 loci that clearly affect the risk of heart attacks and CAD.
This is from a position where, two years ago, we didn't really have
any loci we were completely comfortable with. And most of these are
[associated with genes] we wouldn't hitherto have suspected of being
involved, so this provides new evidence, new pathology, that may be
involved in causing heart disease."

Dr Eric Topol (Scripps Translational Research Institute, La Jolla,
CA), who was not involved in any of this new research, told
heartwire: "Using various cohorts, several new genomic markers have
been found without any particular theme on type of gene; the only
common thread is that the effect is small: 1.1 to 1.2 odds ratio."

Haplotype Association Study Among Papers Identifying New Loci for
MI/CAD

Samani was involved in the work by Dr David-Alexandre Tregouet
(University Pierre and Marie Curie, Paris, France) and his team, who
have discovered a new gene cluster--SLC22A3-LPAL2-LPA--as a strong
susceptibility locus for CAD [1]. The novelty of this paper, says
Samani, is that they used "a slightly different technique to look at
the data that come out of genomewide association studies [GWAS]."
Rather than looking at individual differences in DNA sequence--single
nucleotide polymorphisms (SNPs)--the researchers looked at groups of
SNPs that are inherited together, known as haplotypes.

"Tregouet has slowly walked across the chromosomes identifying these
haplotypes to see whether the signal was better when looking at the
haplotype rather than individual SNPs . . . and one region showed
very strong evidence, which was apparent in the individual SNP
analysis but wasn't strong enough to be definite. By analyzing it in
this way [by haplotype], we found evidence that this locus is
strongly associated with CAD. So the findings are twofold: first, we
identified a new locus; and second, it shows we can extract more
information out of GWAS by doing a slightly more sophisticated
analysis," Samani asserts.

We can extract more information out of GWAS by doing a slightly more
sophisticated analysis.

The second paper that Samani is involved in is by Dr Jeanette Erdmann
(University of Lubeck, Germany) and colleagues, who identify a new
susceptibility locus for CAD on chromosome 3q22.3 following a three-
stage analysis of genomewide data in 1222 German individuals with MI
and 1298 controls [2].

Samani explains: "When we did the original genomewide scans, we
really looked at the low-hanging fruit--the signals that were very
strong--but we knew that, because of the nature of these studies,
there was a strong possibility that among the signals that were of
moderate significance, there must be some that were definitely
genuine. In this new Erdmann paper, we saw some signals that appeared
to be stronger when we combined everything together and then took it
through to replication in these populations, and we confirmed that
this locus was true."

Largest GWAS for MI to Date; No Association of MI With CNVs

Samani is also involved in the international Myocardial Infarction
Genetics Consortium research, a GWAS testing SNPs and copy number
variants (CNVs) for association with early-onset MI in 2967 cases and
3075 controls and replicated in an independent sample of 19 492 [3].

Corresponding author on the paper, Dr Sekar Kathiresan (Massachusetts
General Hospital, Boston, MA), told heartwire: "Our study is the
largest GWAS for MI conducted to date [and] the first to
comprehensively test whether CNVs are associated with MI."

Kathiresan explained that CNVs are large chunks of DNA that are
either deleted or duplicated, and it has been hypothesized that they
might be responsible for some of the inherited component of common
diseases. They found no evidence in this new study, however, that any
CNVs were associated with MI.

They did find that SNPs at nine loci reached significance, three of
which were new: 21q22, 6p24, and 2q33. The remaining six had
previously been observed, including one at 9p21, which is recognized
to be the strongest genetic predictor of early MI discovered to date.

"These nine variants in aggregate identify 20% of the population at
2.25-fold increased risk for MI," says Kathiresan.

Surprising Link Between Eosinophil Count and MI; New Data in Asian
Subjects

Probably the most surprising of the new reports is from Dr David F
Gudbjartsson (deCODE Genetics, Reykjavik, Iceland) and colleagues,
who find a link between a high-eosinophil-count gene and MI [4]. They
looked for sequence variants affecting eosinophil counts in the blood
of 9392 Icelanders and, using the most significant SNPs identified,
they studied them further in 12 118 Europeans and 5212 East Asians.

A variety of the SNPs were associated with asthma and one--a
nonsynonymous SNP at 12q24--was significantly associated with MI in
six different populations (6650 cases and 40 621 controls).

Topol says the Icelandic paper is "curious," with "the surprise link
of a high-eosinophil-count gene and MI. This wasn't at all surprising
for atopic asthma, but we would not have expected it to be the case
for MI."

Finally, Japanese researchers extend on prior work they have
conducted. Dr Kouichi Ozaki (Center for Genomic Medicine, RIKEN,
Yokohama, Japan) and colleagues have previously reported an
association of variants in LGALS2, encoding galectin-2, with MI
susceptibility in a case-control association in a Japanese
population.

Now, they identify BRCA-1 associated protein (BRAP) as a galectin-2
binding protein and report an association of SNPs in BRAP with MI
risk in a large Japanese cohort (OR 1.48, 2475 cases and 2778
controls), with replication in additional Japanese and Taiwanese
cohorts [5].

Topol says, "This has been a very interesting series of findings from
the group of Ozaki and [Dr Toshihiro] Tanaka over several years."

In conclusion, Topol says that he now believes "there are several
pathways that set up a genomic susceptibility to MI. Some are
ancestry-specific (such as galectin2-BRAP) and some are unanticipated
(eg, eosinophilia). While we see the common phenotype of MI, [it
appears] there are many ways to get there at the molecular level."


Tregouet D-A, Konig IR, Erdmann J, et al. Genome-wide haplotype
association study identifies the SLC22A3-LPAL2-LPA gene cluster as a
risk locus for coronary artery disease. Nat Genet 2009; DOI:
10.1038/ng.314. Available at: http://www.nature.com/ng.
Erdmann J, Grosshennig A, Braund PS, et al. New susceptibility locus
for coronary artery disease on chromosome 3q22.3. Nat Genet 2009;
DOI: 10.1038/ng.307. Available at: http://www.nature.com/ng.
Myocardial Infarction Genetics Consortium. Genome-wide association of
early-onset myocardial infarction with single nucleotide
polymorphisms and copy number variants. Nat Genet 2009; DOI:
10.1038/ng.327. Available at: http://www.nature.com/ng.
Gudbjartsson DF, Bjornsdittir US, Halapi E, et al. Sequence variants
affecting eosinophil numbers associate with asthma and myocardial
infarction. Nat Genet 2009; DOI: 10.1038/ng.323. Available at:
http://www.nature.com/ng.
Ozaki K, Sato H, Inoue K, et al. SNPs in BRAP associated with risk of
myocardial infarction in Asian populations. Nat Genet 2009; DOI:
10.1038/ng.326. Available at: http://www.nature.com/ng.