What is the role of genetics in the etiology of ankylosing spondylitis (AS)?

Updated: Jul 17, 2018
  • Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

The strong association of AS with HLA-B27 is direct evidence of the importance of genetic predisposition (see Table 1 below). [18, 19, 20, 28, 29, 30, 31] Of the various genotypic subtypes of HLA-B27, HLA-B*2705 has the strongest association with the spondyloarthropathies. HLA-B*2702, *2703, *2704, and *2707 are also associated with AS. [32] People who are homozygous for HLA-B27 are at a greater risk for AS than those who are heterozygous. [33]

AS is more common in persons with a family history of AS or another seronegative spondyloarthropathy. The concordance rate in identical twins is 60% or less. HLA-B27–restricted CD8+ (cytotoxic) T cells may play an important role in bacterial-related spondyloarthropathies such as reactive arthritis. [34] An epistatic interaction between HLA-B60 and HLA-B27 increases the risk of developing AS. [35]

Table 1. Association of Spondyloarthropathies With HLA-B27 (Open Table in a new window)

Population or Disease Entity

HLA-B27 –Positive

Healthy whites

8%

Healthy African Americans

4%

Ankylosing spondylitis (whites)

92%

Ankylosing spondylitis (African Americans)

50%

Reactive arthritis

60-80%

Psoriasis associated with spondylitis

60%

IBD associated with spondylitis

60%

Isolated acute anterior uveitis

50%

Undifferentiated spondyloarthropathy

20-25%

The shared amino acid sequence between the antigen-binding region of several HLA-B27 genotypic subtypes, especially HLA-B*2705, and nitrogenase from Klebsiella pneumoniae supports molecular mimicry as a possible mechanism for the induction of spondyloarthropathies in genetically susceptible hosts via an environmental stimulus, including bacteria in the GI tract. [36] The specifics of this relationship remain unclear.

Several other genes have been studied with respect to their potential involvement in the development of AS (see Table 2 below).

Table 2. Genetics of Ankylosing Spondylitis (Open Table in a new window)

Genes

Chromosome Location

Gene Product/Function

Definitely associated

HLA-B27

IL-1 gene cluster

CYP 2D6

ARTS1 (ERAP1)

IL23R

6p21.3

2q12.1

22q13.2

5q15

1p31.1

Antigen presentation

Modulator of inflammation

Metabolism of xenobiotics

ER aminopeptidase 1

IL-23 receptor

Possibly associated

ANKH

HLA-DRB1

5p15

6p21.3

Ectopic mineralization

Antigen presentation

Not associated

TGF-ß, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFßBIL1, PTPN22, etc

Multiple

Multiple

The interleukin (IL)-1 gene cluster is an important locus associated with susceptibility to AS. [37, 38] CYP 2D6 is weakly associated with AS. [29] ARTS1 is also associated with AS. This gene encodes the endoplasmic reticulum aminopeptidase, which cleaves cytokine receptors for IL-6, TNF-α, and IL-1 from the cell surface and is important in antigen presentation by class 1 major histocompatibility complex (MHC) molecules. [39, 30, 31]

IL23R, which encodes the receptor for IL-23, is also associated with AS. [39, 40, 41, 42, 30, 31] IL-23 promotes survival of TH17 CD4+ T cells. TH17 cells play an important role in inflammatory responses by producing various proinflammatory cytokines (eg, IL-17, IL-6, and TNF-α) and recruiting other inflammatory cells (eg, neutrophils) in inflammatory and infectious diseases. Thus, they may play an important role cells in the pathogenesis of AS and other spondyloarthropathies. [43]

Genes possibly associated with ankylosing spondylitis include ANKH and HLA-DRB1. [29]


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