Relative role of genetic and environmental factors in disease expression: sib pair analysis in ankylosing spondylitis

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Abstract
Forty-two sib pairs concordant for ankylosing spondylitis (mean disease duration 20.1 years) were assessed to define the relative role of genetic and environmental factors in determining age and calendar year of disease onset, systemic features, functional outcome and prognosis, and radiologic progression. Twenty-seven pairs were of the same sex (male/male n = 21, female/female n = 6). The correlation coefficient was not significant for age at onset (rs = 0.235), but was much higher for calendar year of onset (rs = 0.702, P < 0.01). These data were confirmed by two-way analysis of variance: between sibs, the F probability was 0.07 for age at onset (41 degrees of freedom, F ratio 1.6) and was < 0.001 for calendar year of onset (41 degrees of freedom, F ratio 5.45). Thus, it is suggested that environmental factors play the greater role in the timing of onset. Concordance for the presence or absence of uveitis was only 43%, again suggesting that genetic factors are less significant than the environment. Conversely, genetic factors are more important in influencing prognosis. A disability and pain index revealed that sibs had a closer score than expected by chance alone (P = 0.035); also, the correlation coefficient for blinded radiologic analysis (pelvic and lumbar views) was significant for pairs of sibs (rs = 0.859, P < 0.01), but was not significant for random pairs of subjects (rs = -0.144). In contrast, within–sib pair and random subject–pair analyses of hip radiographs revealed rs = -0.111 and -0.033, respectively, neither of which was significant. In summary, these results suggest that environmental factors are more important in determining date of onset, and therefore, coincidental age at onset, of ankylosing spondylitis. This in turn relates to the risk of hip involvement because younger age at onset is associated with greater risk of hip disease. Genetic factors have the greater influence on radiologic progression and disability. The phenotypic expression is a composite picture of both.