Wellcome Trust Centre for Human Genetics, Headington, Oxford OX3 7BN and
1 Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, UK
SIR The association between HLA-B27 (B27) and ankylosing spondylitis (AS) has been known for 25 yr. Familial aggregation in AS is well established, and first-degree relatives of AS patients have been shown to be at increased risk of developing the disease. The recurrence risk in siblings of AS patients is quite uncertain, previous studies have variously reported recurrence risks between 6.9 and 27% [1, 2]. Accurate knowledge of the sibling recurrence risk is important both to advise families of the likelihood of disease recurrence, and in genetic statistical analyses utilizing Risch's recurrence risk ratio [3]. This study was designed to determine the risk of developing AS in siblings and to determine the role of the major histocompatibility complex in familial recurrence of AS.
Sixty-seven probands with AS (defined according to the modified New York Criteria [4]) were ascertained from the National Ankylosing Spondylitis Society (NASS) database using the criteria age 35 yr (disease penetrance is nearly complete at this age [5]), living in Oxfordshire or Avon (close to our hospital), with two or more siblings. Ethical approval for the study was obtained from the Central Oxford Research Ethics Committee. All siblings (n = 180) were approached by mail to participate in the study, and 176 siblings agreed to participate. Symptoms of spondyloarthropathy were obtained from a semi-structured telephone interview from 169/176 of these siblings (96%). Those without symptoms were considered unaffected, and those with a history suggestive of inflammatory back pain were examined clinically and radiologically with X-rays of the lumbar spine and sacroiliac joints. Blood samples available from 123 of these siblings (73%) and all probands were typed for B27 by polymerase chain reaction/sequence-specific primers [6]. The B27 distribution of the remaining siblings for which DNA was not available was calculated from the known B27 frequency in the British Caucasian population (8.8%) [6], and the known results of any family members (probands and siblings).
Of the 67 probands (47 male, 20 female), 58 were B27 positive (87%), and overall 83/169 siblings were B27 positive (49%). Of these, 10 siblings had AS, giving an overall sibling recurrence risk (Ks) of 5.9%. Considering only B27-positive siblings, the estimated recurrence risk was 12%. No sibling of a B27-negative proband developed disease (n = 29 out of n = 9 probands), and no B27-negative sibling of B27-positive proband developed disease (n = 43 out of n = 58 siblings). This suggests that B27 is almost essential for the inheritance of the disease, although sporadic cases may occur in its absence. The recurrence risk in brothers of female probands was greater than in sisters of male probands, although this did not achieve statistical significance (10.6% vs 2.3%, P = 0.2), consistent with other studies [7]. Given the population risk of AS (K) of 0.1% [8] the excess sibling risk (s) was calculated (
s = Ks/K) at 58. This figure is highly dependent on the population risk figure used, and so may differ from other estimates. Braun et al. have recently reported a population prevalence as high as 0.86% in Berlin [9], although that study used magnetic resonance imaging screening and different diagnostic criteria to those employed here, and is therefore not directly comparable with this study. We have used the population prevalence results reported by van der Linden et al. [8], as we believe the sensitivity of their screening to have been most similar to our own, and the same diagnostic criteria were employed. The high recurrence risk ratio, combined with the low attributable risk to B27 (12%) in this study and others, suggests that there is a substantial non-B27 component to familial recurrence of AS.
Notes
Correspondence to: M. Brown, Spondylitis Research Group, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, UK.
References