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Genes and ankylosing spondylitis: what makes some people more susceptible
than others?
All humans alive in the world today originally came from a small ancestral group
living somewhere in Africa around 200,000 years ago. The various ethnic groups
living outside Africa today almost certainly originated from a small migrant population
that left Africa around 80,000 years ago. Some of them reached Australia about
60,000 years ago via a coastal route that took them along the south coast of modern
day Iran, India, South East Asia and then “island hopping” through Indonesia to the
north of Australia. Curiously it wasn’t until rather later (perhaps 35,000 years ago)
that modern man reached Western Europe because, until then, the route from Africa
through the Middle East was impenetrable desert.
Studying the genes of different ethnic populations shows that modern humans are all
distantly related despite the fact that there are superficial racial differences. None the
less there are some interesting genetic differences between these groups that have
affected their susceptibility to various diseases. For example, the population that
established itself in Australia lacked the HLA-B27 gene while those in the circumpolar
regions of the Arctic had a rather high prevalence of B27. One of the consequences
is that ankylosing spondylitis is unknown in Australian aborigines but has a high
prevalence in the Inuit and certain American Indian groups, such as the Haida people
of British Columbia.
The association between B27 and AS has been known for nearly 40 years but
recently it has become obvious that many other genes are also involved in
determining an individual’s susceptibility to the condition. The past two decades have
seen extraordinary advances in the science of genetics that are likely to have a major
impact on our understanding and treatment of many common diseases in the not too
distant future.
The genetic code that determines much of our individual identity as humans is
contained in 22 pairs of chromosomes plus the sex chromosomes (the unpaired X
and Y chromosomes) in most cells of the body. These chromosomes are composed
of a protein scaffold combined with DNA, the extraordinary extended molecule that
contains the genetic code. Each human cell contains about 6 feet of DNA when
unravelled and it has been estimated that if all the DNA from a single human were
laid end to end it would stretch round the moon and back 25 times! DNA is comprised
of 4 basic building blocks (known as nucleotides) that function as the individual
“letters” of the genetic code. The code is read in combinations of 3 such letters
(known as codons) which then act as the blueprint for the manufacture of proteins
from their own building blocks (amino acids). And it is these proteins that not only
make up the structural framework of the body (e.g. bones, muscles, skin) but are also
responsible for most of the actions that make our bodies work (digesting food,
creating energy, getting rid of waste products etc.). We now know that there are
about 25,000 genes, rather fewer than used to be thought, and that these are
responsible for many human traits, including susceptibility to many diseases.
It therefore seems timely to recap some of the background to the genetic studies that
have flooded the medical and scientific press in recent years and show how they
relate to ankylosing spondylitis. Many readers of this newsletter are only too aware
that ankylosing spondylitis is at least in part a genetic disorder that can run in
families. However, it is quite distinct from the “classic” genetic diseases, which are
caused by mutations in single genes, in that an obvious recurring pattern of
inheritance cannot be clearly defined in AS. In contrast, classic single gene diseases
follow well defined inheritance patterns from one generation to another, typically
known as dominant or recessive inheritance.
Achondroplasia is a relatively common form of genetic dwarfism affecting 1 in 25,000
people that exhibits dominant inheritance. This means that parents with the condition
have a 50% chance of passing the condition on to their child each time they
conceive. It is caused by a very specific change (mutation) in a single gene (FGFR3)
on chromosome 4 that controls bone growth. As described above, all cells in the
body (with the exception of sperm and female eggs) have paired chromosomes.
Thus, there are two copies of each gene (including FGFR3) as well. It only takes one
overactive version of the FGFR3 gene to cause achondroplasia. During the process
of creating either an egg or sperm cell the number of chromosomes is reduced to
one. Each time an individual with achondroplasia produces one of these germ cells
there is an equal chance that it will contain the normal or the abnormal version of the
FGFR3 gene. When the egg and sperm fuse together the normal paired number of
chromosomes will be reconstituted (half from the mother and half from the father).
Whether the child gets achondroplasia depends entirely on whether it has inherited
the affected parent’s mutant FGFR3 gene; overall the risk will be 50% for each child.
In contrast, recessive inheritance requires the inheritance of an abnormal version of
the gene from both parents with the result that the offspring has two mutant versions.
For example, many enzyme disorders (e.g. lactase deficiency – the inability to digest
milk sugars properly that affects many people throughout the world) are recessive. In
this case it is quite easy to explain the difference; only complete loss of the lactose
enzyme will result in the inability to break down lactose whereas a 50% reduction is
perfectly adequate to do the job. In a recessive disease both parents will have 50%
activity of the gene but this is adequate for its purposes and therefore neither parent
is affected. Only 1 in 4 of their children will by chance have 2 mutant versions of the
gene and be affected although 2 in 4 will be unaffected “carriers” of the mutant gene.
What we can see from the above is that ankylosing spondylitis is quite different.
Although there is an increased risk of AS in the children of those that are affected it is
nowhere near 1 in 2 or 1 in 4 (the levels for dominant or recessive disease). In fact, it
is approximately 1 in 14 because susceptibility to AS does not follow simple patterns
of inheritance. The main reason for this is because susceptibility is contributed by
many different genes and it is only if the individual has inherited a sufficient number
of these that they will be affected. HLA-B27 seems to be almost (but not completely)
essential but requires the presence of at least some others. It is in the area of
identifying these other genes that the past 5 years has been so very productive.
Furthermore, these discoveries have also helped to explain why people with AS are
also more likely than the general population to have conditions like psoriasis or
inflammatory bowel disease which perhaps affect up to 15% of individuals with AS
between them.
In the early “noughties” my colleagues Matthew Brown, John Reveille and I
established the international genetics of AS (IGAS) consortium to study the genetics
of AS, subsequently followed by the Triple A (Australo-Anglo-American) Spondylitis
consortium (TASC). Building on the hugely successful innovations in molecular
genetic techniques that were being developed at that time in places like the Sanger
Centre in Cambridge and the Wellcome Trust Centre for Human Genetics in Oxford,
our aim was to study the differences in genetic makeup between individuals with AS
and the healthy general population. The technical details are beyond the scope of
this article but can be summarised very simply. Small differences in the coding
sequences of all genes are apparent throughout the general population (Darwin’s
“natural variation”). Our strategy was to measure this natural variation in large
populations with AS and to see if particular variants of particular genes were overrepresented in people with AS compared to the general population. However, to be
confident of our results this needed to be done on a massive scale, using samples
from literally thousands of individuals. Fortunately, we have found extraordinarily
willing allies in the members of NASS who have already contributed nearly 3,000
DNA samples, either from saliva or blood. (Massive vote of thanks to you all! We
couldn’t have done this without you but we still need more samples). We have now
completed the first 2 large-scale experiments of this sort and are halfway through the
third, which will test 600,000 genetic variants in about 5,000 individuals with AS.
The first two experiments have shown that, in addition to B27, two genes called
ERAP1 and IL23R are clearly involved in AS. ERAP1 is potentially involved in
inflammation and immunity in a number of different ways. Perhaps most intriguingly,
it may work in tandem with B27 to switch on the immune system in response to
particular foreign (or self) proteins. It is also possible that it has a role in influencing
the effects of tumour necrosis factor (TNF) through its receptor, although this has still
to be proved. My group in Oxford working with the Structural Genomics Consortium
is currently involved in trying to obtain the structure of the ERAP1 protein and
investigating its functions. NASS has very generously supported the work of David
Harvey, a DPhil student, to facilitate this work.
IL23R is a gene that encodes a molecular switch involved in the healthy maintenance
of a type of immune cell known as a Th17 lymphocyte. These are involved in
inflammatory responses, particularly in mucosal surfaces, like the skin and gut. It is
therefore tantalising that IL23R is also associated with inflammatory bowel disease
and psoriasis both of which are commoner in those with AS than the general
population. Th17 cells produce an inflammatory cytokine known as IL17. Currently
trials are in progress with an anti-IL17 monoclonal antibody, an agent that may block
some of the effects of these Th17 cells. The results are not yet known but eagerly
awaited.
From these experiments it is already clear that identifying genes involved in
susceptibility to AS can lead to potential new forms of treatment. We are on the
threshold of identifying many other genes that are involved in AS and at least some
of these will undoubtedly offer the prospect of exploring new forms of treatment, cure
or even prevention of the condition.
Further reading:
Genome-wide association study of ankylosing spondylitis identifies non MHC
susceptibility loci. TASC consortium Nature Genetics 2010; 42:123-7
Investigating the genetic association between ERAP1 and ankylosing spondylitis
Harvey et al Human Molecular Genetics2009; 18: 4204-12
Association between the interleukin 23 receptor and AS …… Karaderi et al
Rheumatology 2009; 48: 386-9
By Paul Wordsworth, Professor of Rheumatology, University of Oxford Institute of
Musculoskeletal Sciences