|
 Soon
after a 30-year-old woman with primary pulmonary hypertension
(PPH) was referred to Jim
Loyd, MD, the first pieces of a
huge and complex puzzle began
falling into place. During the last
month of his residency at Vanderbilt
University School of Medicine
in 1980, as his pulmonary fellowship
was about to begin, Dr Loyd
began to see telltale evidence in
this patient’s medical history that flew in the face of
conventional wisdom at the time about the nature of
PPH. “Her family history revealed many mysterious
early deaths, including her mother, three maternal
aunts, and a cousin who had been a nurse at our
hospital.”
Because of pathologic interpretations, the prevailing
view was that PPH was many different diseases and
that trying to find a genetic link among families was
not feasible. In the era before prostacyclin therapy,
most investigators thought that a circulating vasoconstrictive
substance was responsible for PPH, or alternatively,
that microembolic pulmonary embolism was the
cause. Following the same patient who initially perked
his interest, Dr Loyd began a long thread of investigations
that eventually brought about a new basic understanding
of the cause of PPH. “That woman’s family
has now had 22 patients with PPH,” added Dr Loyd.
During the same month that this patient’s family history
became apparent, Dr Loyd was joined at Vanderbilt
by John Newman, MD, who was already primed to
address the problem after completing a pulmonary
fellowship at the University of Colorado.
“We began our studies by locating and contacting
the authors of prior reports on PPH families, and in our
first paper in 1984, we reported new information from
six of those families, including eight new cases; we
described inheritance patterns showing vertical transmission
that suggested an autosomal dominant pattern.” This
information pointed toward the implication of a single gene. At
the time, however, the actual identification
of the gene remained a fantasy, he said.
Building the Registry of Families with PPH
The pace of research quickened as Drs Loyd and Newman demonstrated
that multiple pathologic forms were present in PPH patients within
the same families, a finding that
validated the pleiotropic effects of the disease and thereby
justified grouping all of the PPH families together into
the same gene search. Slowly the network of families—and the
physicians who followed them—grew into a registry
compiled throughout the early and mid-1990s and a
turning point was reached when statisticians working with
Dr Loyd conducted power calculations that suggested a
genome-wide search might succeed. Vital to future
progress was an NIH grant and the organization of a
specimen bank collected for 15 years.
The work of Bill Nichols, PhD, was instrumental
because he conducted a genome-wide microsatellite
marker search and soon identified a large, 30-megabase
region near the end of the long arm of chromosome
2 that had a highly significant association with
the disease. The years following the linkage were very
exciting, as the team narrowed the linked region by
identifying recombinant individuals. Hope soared and
crashed as candidate genes at first looked promising
but then had to be abandoned. “Kirk Lane joined our
group and after reviewing all of the genes positioned in
the linked region, chose bone morphogenetic protein
receptor II (BMPR2) as a candidate gene because of
its membership in the TGFß superfamily.” From there
the first mutation was identified in a PPH family by
DNA fingerprinting and the first report appeared in
2000 describing BMPR2 mutations in seven of eight
PPH families. The database of families affected by
PPH has grown to 107, with a total of 283 patients.
Risk Stratification: One in Ten or One in a Million?
Although most of the families tested have mutations in
BMPR2, about a quarter have not shown evidence of such
mutation. Several features have emerged among the families:
the disease seems to begin at a younger age in subsequent
generations, it also skips generations and is much
more prevalent in women. “When we look at individuals
who have the BMPR2 mutation, only one in five actually
gets the disease, yet four in five people have the mutation
throughout their life span and never develop PPH. It is
very helpful when we know which mutation exists in a
family because family members at risk can request to be
tested. If the test is done and they do not have the mutation,
it changes their risk of PPH from one in ten to one
in a million,” said Dr Loyd.
One of the most intriguing questions that so far has
produced only speculative answers is why some
patients with the mutation develop the disease while
others do not. “We are beginning to look across all the
chromosomes using search strategies to identify
regions where there might be modifiers,” said Dr Loyd. Yet
so far, gender seems to be the only variable that is
known to modify clinical expression. In one family from
Tennessee, for example, with 22 PPH patients, 19 of them
are women. No one has been able to pinpoint why women
are at much greater risk than men, however.
When asked if a patient’s genetic or familial predisposition
could be related to the pathways widely recognized in
recent years as contributors to the pathophysiology of PPH,
Dr Loyd noted that this is one of the areas investigators are
exploring. As he described the potential for possibly associating
a genetic link with these pathways, he suggested
that the link may be “within a pathway that is not even
yet recognized, or in one that is known, but which is not
known to be related to pulmonary hypertension.” Such
a circumstance, however, is not new to Dr Loyd. This
quandary was similar in many respects to the position he
was in when he first began searching for the gene itself
25 years ago when so little was known about a familial
connection and a comparable mystery was waiting to be
solved. |
