SECTION 9 ■ SPONDYLOARTHRITIS
116 Genetics of axial spondyloarthritis
■ MATTHEW A. BROWN ■ HUJI XU
■ Susceptibility to and severity of ankylosing spondylitis, the prototypic
axial spondyloarthritis, are highly heritable.
■ Although HLA-B27 is the main genetic variant associated with axial
spondyloarthritis, many other genes are involved in both HLA-B27+ and
HLA-B27−disease.
■ In particular, genes in the interleukin-23 response pathway and genes
encoding aminopeptidases involved in peptide processing before HLA
class I presentation are overrepresented among ankylosing spondylitis–
associated variants.
GENETIC EPIDEMIOLOGY OF
ANKYLOSING SPONDYLITIS
For more than 40 years, ankylosing spondylitis (AS) has been known to run
in families. Familiality occurs because of shared susceptibility factors among
family members, which may be environmental (random or common) or
genetic.
Twin studies confirm that susceptibility to AS is almost entirely geneti-
cally determined, with two studies now formally estimating heritability as
greater than 90%.1,2 Heritability of clinical manifestations of disease is also
significant, with age of symptom onset, disease activity measured by the
widely employed Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI) and Functional Index (BASFI) questionnaires, and radiographic
severity being 40%, 51%, 76%,3,4 and 62% heritable,5 respectively.
The association of HLA-B27 with AS is among the strongest genetic
associations in any common disease, and yet studies in families suggest that
less than 50% of the overall genetic risk is due to HLA-B27 and that it is
likely that several other genes are involved. First-degree relatives of AS
patients have a 5 to 16 times greater risk of developing AS than HLA-B27+
individuals in the general population, which implies the existence of factors
modifying the risk of AS apart from HLA-B27.6,7 The most likely models of
the disease suggest that genes modifying the effect of HLA-B27 determine
the risk of getting the disease in HLA-B27 carriers.8 It is likely that, in addi-
tion to HLA-B27, there are a small number of genes with moderate effect
and a large number of genes with small effect. Certainly, large multicase
families, which are typical in diseases with a monogenic cause, are extremely
rare in AS. The risks of developing AS in different degrees of relatives to a
proband with the condition are given in Table 116.1.
MAJOR HISTOCOMPATIBILITY COMPLEX GENES
The major histocompatibility complex (MHC) on chromosome arm 6p is
strongly linked and associated with AS.9-15 Although most of the genetic
association of this locus is driven by the association of AS with HLA-B27,
the association is clearly more complex than that.
HLA-B27 and B27 subtypes
HLA-B27 is more common in Northern Europeans and is rare in Africans
and Australian Aboriginals. The prevalence of AS generally follows the
frequency of HLA-B27 in that population. In most studies, 80% to 95% of
AS patients are HLA-B27+; thus in white Europeans the odds ratio for AS
in HLA-B27 carriers is more than 50.16-18 Homozygotic HLA-B27 carriers are
956
at an increased risk of AS compared with heterozygotes (odds ratio, 2.07;
P = .0025).18-21 Despite that, only a minority of HLA-B27 carriers develop
AS, and thus HLA-B27 has not been found useful in population screening.
However, in patients with inflammatory low back pain, HLA-B27 testing is
a useful component of the diagnostic workup (Fig. 116.1). This testing is
further facilitated by the discovery of single nucleotide polymorphisms
(SNPs) that accurately tag the HLA-B27 allele (rs116488202, sensitivity and
specificity for HLA-B27 of 98.5% to 100% in white Europeans and East
Asians), so that a cheap and robust SNP assay can be used rather than the
more expensive and complex HLA-B27 assays.
There is strong evidence in specific populations that different subtypes
of HLA-B27 have different strengths of association with AS. Over 90
HLA-B27 subtypes have now been reported (see the Anthony Nolan Trust
database at http://hla.alleles.org/class1.html), with a rapid increase in the
number of subtypes occurring over the past 5 years related to increased use
of DNA-based HLA typing. In most cases the subtypes involved have been
reported in only a few unaffected individuals, and therefore it is not possible
to say whether or not they are associated with AS. However, some subtypes
are sufficiently prevalent that the relative strengths of their association with
AS can be compared.
AS (not just undifferentiated spondyloarthritis) has been reported to
occur with the following subtypes of HLA-B27: *2702, *2703, *2704,
*2705, *2706, *2707, *2708, *2710, *2714, *2715, and *2719. Until
recently, no case of AS had been reported with B*2709, and this subtype is
protective for the disease, relative to B*2705.22 Six cases with spondyloar-
thritis have now been reported in B*2709 carriers, although only two of
these had classical axial AS, and in each case there were other potential
explanations for the development of AS.23,24 These cases confirm that B*2709
is not absolutely protective for AS, although it is underrepresented in cases
in Sardinia, due to its weaker association with disease than B*2705.
B*2706 similarly has been shown to be less strongly associated with AS
than B*2704 in Southeast Asia, although these studies are complicated by
ethnic differences in B*2704 and *2706 carriers, because B*2704 carriers
are more likely to be of Chinese descent, whereas B*2706 carriers are more
likely to be of Malay descent.24-27 There is increasing evidence that B*2704
is more strongly associated with AS than B*2705. A recent study in Taiwan-
ese of Han Chinese descent supported this conclusion and also reported
cases of AS in carriers of B*2706, confirming that the protective effect of
this B27 subtype is not absolute.28
Other major histocompatibility complex genes
The MHC, situated on chromosome arm 6 (6p21.3), extends over 3.6 mega-
bases and contains about 220 genes, many of which have immunoregulatory
functions. Although compelling evidence has been published suggesting
that the HLA-B allele HLA-B60 is associated with AS, this finding was not
supported by the large International Genetics of Ankylosing Spondylitis
Consortium study, perhaps because of difficulties imputing HLA alleles
using single SNPs rather than direct genotyping.18 This study did show that
HLA-A*0201 is significantly associated with AS, although with a much
smaller effect size than HLA-B27 (odds ratio of 1.21 in HLA-B27+ cases,
1.36 in HLA-B27− cases, compared with an odds ratio of 46 for HLA-B27
itself).
NON–MAJOR HISTOCOMPATIBILITY
COMPLEX GENES
Association with the MHC explains less than half of the familiality of AS.
Major advances have occurred in the last several years in identifying the