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

Updated: Feb 02, 2021
  • Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

The etiology of AS is unknown, but a combination of genetic and environmental factors works in concert to produce clinical disease. [31]

Genetic predisposition

The strong association of AS with HLA-B27 is direct evidence of the importance of genetic predisposition (see Table 1 below). [20, 21, 22, 32, 33, 34, 35] 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. [36] People who are homozygous for HLA-B27 are at a greater risk for AS than those who are heterozygous. [37]

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. [38] An epistatic interaction between HLA-B60 and HLA-B27 increases the risk of developing AS. [39]

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. [40] 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 or probably associated

HLA-B27

HLA-B60

ERAP1 (ART1)

IL23R

IL-1 gene cluster

IL-1R2

STAT3

 

6p21.3

6p21.3

5q15

1p31.1

2q12.1

2q11-12

17q21

 

Antigen presentation

Antigen presentation

ER aminopeptidase 1

IL-23 receptor

Modulator of inflammation

Decoy receptor for IL-1

Signal transduction for IL-5, 6, 11

Probably associated

CYP 2D5

ANKH

TLR4

KIR (Killer Ig-like receptor)

MEFV

22q13.1

5p15

9q32

19q13.4

16p13.3

Metabolism about xenobiotics

Ectopic mineralization

Pattern recognition receptor forLPS

NK cell receptor

Pyrin, innate immunity

Not associated

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

Multiple

Multiple

 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. [41, 34, 35]

IL23R, which encodes the receptor for IL-23, is also associated with AS. [41, 42, 43, 44, 34, 35] 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. [45]

The interleukin (IL)-1 gene cluster is an important locus associated with susceptibility to AS. [46, 47] CYP 2D6 and ANKH genes are probably associated with AS. [33]


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