Investigating genetic determinants of ankylosing spondylitis

Jaakkola, Elisa Johanna (2003). Investigating genetic determinants of ankylosing spondylitis. PhD thesis The Open University.



Ankylosing spondylitis (AS) is a common form of inflammatory arthritis, occurring in approximately 0.1% of the British and Finnish populations. The genetic contribution to the disease susceptibility accounts for >90% of the population variance, and the disease severity is also predominantly genetically determined. HLA-B27 has been strongly associated with the disease world-wide, but although it is almost essential for the inheritance of AS, the attributable risk of HLA-B27 has been estimated to be 16-50%, leaving a large component of the genetic variance to be discovered.

The influence of a positional and biological candidate gene, transforming growth factor β1 (TGFB1), was investigated in a Finnish and British population. A weak association between the rare TGFB1 1627 T allele and susceptibility to, and age of symptom onset of, AS was noted. However the lack of association of TGFB1 promoter polymorphisms, which are in LD with the TGFB1 1627 alleles, with AS in families with positive non-parametric linkage scores at the locus indicates that these polymorphisms do not explain the observed linkage of disease susceptibility to chromosome 19.

A novel high throughput HLA-DRB1 genotyping method based on multiplex primer extension reactions was developed. This method allows rapid and cost-effective screening of a large number of samples.

The effect of HLA genes and haplotypes in susceptibility to, and severity of, AS was investigated in the Finnish population. An overrepresentation of HLA-B27 homozygotes was noted in cases with AS compared with the expected number of HLAB27 homozygotes under Hardy-Weinberg equilibrium. Significant associations between both HLA-B27 and HLA-DRB1*08 and a younger age of symptom onset was noted suggesting that genes within the MHC are involved in determining the age of
symptom onset. A haplotype-based case-control study noted no association between HLA-DRB1-B27 haplotypes and AS susceptibility, but this study was underpowered.

The effect of CYP2D6*4 poor metaboliser allele was investigated in the Finnish AS families. No association was noted, but due to lack of power this study could not exclude a true positive association with the disease.

In summary, a novel HLA-DRB1 genotyping technique was developed to enable the assessment of the contribution of HLA-DRB1 genes in a large number of AS samples. HLA-B27 homozygosity was increased in cases with AS compared with the expected number of HLA-B27 homozygotes. HLA-B27 and HLA-DRB1*08 alleles were significantly associated with a younger age of symptom onset in AS. TGFB1 gene polymorphisms do not appear to have a major impact in AS.

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