BALTIMORE, MD - A team of scientists at Johns Hopkins and elsewhere has discovered
that a single alteration in the genetic code of about a fourth of
African-Americans helps protect them from coronary artery disease,
the leading cause of death in Americans of all races.
Researchers found that a single DNA variation -- having at least one
so-called guanine nucleotide in a base pair instead of a combination
without any guanine -- on a gene already linked to higher risk of
coronary disease in other races is linked in blacks to decreased
risk. Specifically, the study showed that otherwise healthy
African-American men and women with the alternative genetic code had
a fivefold reduction in the likelihood that their arteries would
narrow or clog.
For African-Americans who inherited two copies of the guanine gene
variant, one from each parent, the risk reduction was even more
dramatic. They were 10 times less likely to have coronary heart
disease, which disproportionately afflicts a greater number of
African-Americans than whites or any other ethnic group. Nearly 17
million Americans have an arterial problem plaguing the heart,
causing a half-million deaths, annually.
"What we think we have here is the first confirmed hereditary link to
cardiovascular disease among African-Americans and it is a protective
one," says senior study investigator and health epidemiologist Diane
Becker, M.P.H., Sc.D. "This newly found link in African-Americans
was not only protective instead of harmful but was also found at a
precise location on gene CDKN2B, a gene close to the single base pair
modification tied to other increased risk of coronary artery disease
in other races."
Becker emphasizes that only an estimated quarter of blacks have the
protective CDKN2B code, and only 6 percent have two copies, so "while
a lot of African-Americans have this protective genetic modification,
most do not." Advance testing for the genetic marker, she says, could
ultimately in the future assist physicians in risk-stratifying those
without inherited protection so they could be monitored more closely
for early signs and symptoms of disease.
Becker, a professor at both the Johns Hopkins University School of
Medicine and the university's Bloomberg School of Public Health, and
a team that included researchers at Duke and Emory universities, also
say their results, based on blood analysis from 548 black men and
women in the Baltimore region and confirmed in several hundred more
in the Atlanta and Durham, N.C., regions, help explain why earlier
studies found potentially dangerous genetic connections to this type
of heart disease in Caucasians, Hispanics and Asians, but failed to
find a negative tie-in to the disease in blacks.
Earlier studies, says Becker, had involved genome-wide reviews in
multiracial populations and taken "a needle in the haystack approach"
to finding that one change in a string of some 58,000 base pairs, in
a chromosomal region known as 9p21. That region, which includes
CDKN2B, is associated with higher rates of coronary disease in non-blacks.
The team's latest analysis was successful, she believes, because it
had a large and sufficiently broadly based black volunteer
population. The study group comprised men and women between the ages
of 26 and 60. Investigators also focused on the 9p21 region and a
subsection of genetic material within called ANRIL that overlaps and
is closely held to CDKN2B, but away from the deleterious genetic
variant found earlier.
Johns Hopkins cardiologist Brian Kral, M.D., M.P.H., says the
abundance of activity in this particular region of the genome,
including CDK2NB and ANRIL, suggests that everyday replication of
this zone could play a more fundamental, underlying role in the
progression of coronary artery disease in all races.
Kral, an assistant professor at Johns Hopkins and its Heart and
Vascular Institute. was co-lead investigator of the latest study,
along with Johns Hopkins genetic epidemiologist Rasika Mathias, Sc.D.
The team next plans to further investigate the ANRIL subregion of
9p21 to see if any single genetic changes speed up or slow down
progression of coronary diseases.
Blood samples for the genetic analysis came from a larger study being
led by Becker of some 4,000 people from white and African-American
ethnic backgrounds. Called the Genetic Study of Atherosclerosis Risk
(GeneSTAR), under way at Johns Hopkins since 1983, it involves
participants who were all healthy upon enrollment, with no existing
symptoms of heart disease. All were monitored for at least five
years with periodic check-ups to see who developed heart disease and
who did not. Each had a sibling or a parent who had a history of
coronary artery disease or some other symptom of blocked arteries,
such as chest pain or shortness of breath. The latest study was
based on results collected through 2007, by which time 35 black study
participants had suffered some form of heart attack or needed an
angioplasty or X-ray scan of the heart's blood vessels to confirm or
rule out arterial blockages.
Study funding was provided by the National Heart, Lung and Blood
Institute (NHLBI), a member of the National Institutes of Health, and
the Johns Hopkins Clinical Research Center.
In addition to Becker, Kral and Mathias, other Hopkins researchers
involved in this report are Bhoom Suktitipar, M.D.; Ingo Ruczinski,
Ph.D.; Dhananjay "Jay" Vaidya, M.B.B.S., Ph.D.; Lisa Yanek, M.P.H.;
and Lewis Becker, M.D. Arshed Quyyumi, M.D.; Riyaz Patel, M.D.; A
Maziar Zafari, M.D., Ph.D.; and Viola Vaccarino, M.D., Ph.D., all at
Emory University in Atlanta, also contributed to the
research. Further study assistance and support was provided from
Elizabeth Hauser, Ph.D., and William Kraus, M.D., both at Duke
University Medical Center in Durham, N.C.