The University of Queensland Diamantina
Institute's researchers have played a leading role in a recent study into
osteoporosis, more than doubling the number of currently known genes in the
disease.
Osteoporosis
is a silent but frequent and devastating age-related disease: in Australia 25
per cent of women wtih hip fracture die
within 12 months, with an even higher mortality rate for men with hip fracture.
Women
older than 65 years are at greater risk for death after hip fracture than from breast cancer.
While
the consequences of osteoporosis are well established, the causes of the
disease remain elusive.
It has
been known for a long time that osteoporosis is strongly genetically
determined, but the responsible genes had remained largely unknown.
This
situation has changed dramatically, due to the recent discoveries of UQDI
researchers and their collaborators.
In
their study published in the leading genetic journal Nature Genetics,
variants in 56 regions of the genome have been discovered to influence the Bone
Mineral Density (BMD) of individuals.
Fourteen
of these variants were also found to increase the risk of fracture.
This
single study doubles the number of known genes for BMD, and is the first time
such large number of genetic variants have been found to be associated with
fracture risk.
Bone mineral density measured
by Dual Energy X-Ray absorptiometry (DXA)
is the most widely used measurement to diagnose osteoporosis and to assess the
risk of fracture.
In
general terms high BMD results in lower risk of fracture.
UQDI
researchers Associate Professor Emma Duncan and Professor Matt Brown played
leading roles in the international consortium of investigators from across
Europe, North America, East Asia and Australia, bringing together more than 50
independent studies.
Overall,
the study involved more than 80,000 individuals with DXA scans to assess BMD;
and more than 30,000 cases with fracture and 100,000 controls without fracture
were studied in what constitutes the largest genetic study in osteoporosis
performed to date.
“The
Australian Osteoporosis Genetics Consortium played a key role in this recent
paper,” Associate Professor Duncan said.
“Our
own study, involving bone researchers from Australia, New Zealand and the
United Kingdom, and supported by the National Health and Medical Research
Council of Australia, was particularly important because of our unique approach
of recruiting individuals with more extreme bone density.
"This
meant that although we contributed a modest number of individuals to this
current study, their impact was disproportionately powerful; and as a
consequence the Australian contribution was the most powerful individual
component of the entire project overall."
Further,
work by UQ's Dr Dana Willner during her time at UQDI was responsible for
identifying critical molecular pathways that are now candidates for therapeutic
applications.
Dr
Fernando Rivadeneira, who is an Assistant Professor at the Erasmus Medical
Centre in Rotterdam, Netherlands, and lead senior author of the study said:
“Such potential is highlighted by the identification (among others) of genes
encoding proteins that are currently subject to novel bone medications.
"Yet,
even more interesting is the identification of several factors that can constitute
targets for true bone-building drugs.”
This
research leads to greater understanding of the biology of skeletal health and
fracture susceptibility.
“In
addition to the known proteins and pathways we have identified we are also
confronted with completely new biology,” said Karol Estrada, scientific
researcher at Erasmus MC and first author of the publication.
“There
is, for example, very little known about the genomic region on chromosome 18
where we discovered the strongest genetic factor associated with fracture risk.
"Just
less than a month ago the factor underlying the genetic signal was recognised
as a gene, now known as FAM210A."
Dr
Douglas Kiel is Professor of Medicine at Harvard Medical School and the
Institute for Aging Research at Hebrew SeniorLife in Boston, MA in the USA and
senior author co-leading the study.
“We
also established that, as compared to women carrying the normal range of
genetic factors, women with an excess of BMD-decreasing genetic variants had up
to 56 per cent higher risk of having osteoporosis and 60 per cent increased
risk for all-types of fractures,”
he said.
“Even
more interesting is our discovery of groups of individuals with a smaller
number of variants which protected them against developing osteoporosis or
sustaining fractures."
André
Uitterlinden, Professor of Complex Genetics at Erasmus MC said the genome-wide
association approach would mean researchers could continue to identify hundreds
of common variants underlying the risk of osteoporosis and fracture.
“Nevertheless,
we will need new technologies and approaches to understand more,” he said.
Professor
Matthew Brown agrees.
“Researchers
at UQDI have been doing exactly this, by performing a whole-exome sequencing
project in 1000 individuals from our Australian Osteopororis Genetics
Consortium," he said.
"This
further study, also supported by the NHMRC, will help us to understand the
genetic underpinnings of this complex disease that is osteoporosis."
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