S Laval

Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis

OBJECTIVES It has long been suspected that susceptibility to ankylosing spondylitis (AS) is influenced by genes lying distant to the major histocompatibility complex. This study compares genetic models of AS to assess the most likely mode of inheritance, using recurrence risk ratios in relatives of affected subjects. METHODS Recurrence risk ratios in different degrees of relatives were determined using published data from studies specifically designed to address the question. The methods of Risch were used to determine the expected recurrence risk ratios in different degrees of relatives, assuming equal first degree relative recurrence risk between models. Goodness of fit was determined by χ2 comparison of the expected number of affected subjects with the observed number, given equal numbers of each type of relative studied. RESULTS The recurrence risks in different degrees of relatives were: monozygotic (MZ) twins 63% (17/27), first degree relatives 8.2% (441/5390), second degree relatives 1.0% (8/834), and third degree relatives 0.7% (7/997). Parent-child recurrence risk (7.9%, 37/466) was not significantly different from the sibling recurrence risk (8.2%, 404/4924), excluding a significant dominance genetic component to susceptibility. Poor fitting models included single gene, genetic heterogeneity, additive, two locus multiplicative, and one locus and residual polygenes (χ2 >32 (two degrees of freedom), p<10−6for all models). The best fitting model studied was a five locus model with multiplicative interaction between loci (χ2=1.4 (two degrees of freedom), p=0.5). Oligogenic multiplicative models were the best fitting over a range of population prevalences and first degree recurrence risk rates. CONCLUSIONS This study suggests that of the genetic models tested, the most likely model operating in AS is an oligogenic model with predominantly multiplicative interaction between loci.

Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis.

The objective of this study was to investigate TNF promoter region polymorphisms for association with susceptibility to ankylosing spondylitis (AS). The TNF −238 and −308 polymorphisms were genotyped in 306 English AS cases and 204 ethnically matched healthy B27-positive controls, and 96 southern German AS cases, 58 B27-positive and 251 B27-negative ethnically matched controls. Additionally, the TNF −376 polymorphism was genotyped in the southern German cases and controls. In the southern German AS patients a significant reduction in TNF −308.2 alleles was seen, compared with B27 positive controls (odds ratio 0.4, P = 0.03, 95% confidence interval 0.2–0.9), but no difference in allele frequencies was observed at TNF −238. Significant association between AS and both TNF −238 and TNF −308 was excluded in the English cases. These results confirm previous observations in the southern German population of association between TNF promoter region polymorphisms and AS, but the lack of association in the English population suggests that these polymorphisms themselves are unlikely to be directly involved. More likely, a second, non-HLA-B, MHC locus is involved in susceptibility to AS in these two populations.

The X-chromosome and susceptibility to ankylosing spondylitis

OBJECTIVE Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (lambda(s) = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X-chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility. METHODS A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis. RESULTS No linkage of the X-chromosome with susceptibility to AS was found. Model-free multipoint linkage analysis strongly excluded any significant genetic contribution (lambda > or = 1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] <-2.0). Smaller genetic effects (lambda > or = 1.3) were also found to be unlikely (LOD <-1.0). CONCLUSION The sex bias in AS is not explained by X-chromosome-encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.