Genetics of Non-HLA Marker Genes in HLA-B27-positive and -negative Ankylosing Spondylitis Families

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Abstract
In families of HLA-B27+ ankylosing spondylitis (AS) patients, the occurrence of secondary cases of sacro-iliitis (SI) among B27+ first degree relatives is more than tenfold higher than expected from the population association of AS with HLA-B27. Secondary cases of SI also occur in relatives of HLA-B27- AS patients. We addressed the question whether other genetic factors than HLA-B27 played a role in the familial occurrence of AS and SI in B27+ and B27- AS cases. To this we tested 24 genetic marker systems including GM and PI in first degree relatives of AS patients: 118 first degree relatives with 16 secondary SI cases in families of 23 B27+ AS probands and 74 relatives with 6 secondary SI cases in families of 14 B27- AS probands. With a LIPED analysis we found no significant evidence for linkage for any of the markers tested, including HLA. In a co-segregation analysis we found a significant deviation from random segregation for HLA-B27 (p=0.0005) and for HLA haplotypes (p=0.052) to affected B27+ AS/SI siblings. No such deviation was found to B27- AS/SI cases. For GM and PI we found no significant co-segregation with AS/SI in B27+ and B27- families. In conclusion, apart from HLA-B27, we found no significant effect of any of the genetic marker systems tested in explaining the familial clustering of AS and SI among B27+ and B27- AS patients.