Impact of sex on inheritance of ankylosing spondylitis: a cohort study

doi:10.1016/S0140-6736(99)03219-5

The Lancet

Volume 354, Issue 9191, 13 November 1999, Pages 1687-1690

https://doi.org/10.1016/S0140-6736(99)03219-5 Get rights and content

Summary

Background

Ankylosing spondylitis is a genetically determined and commonly familial disorder. Men and women differ in their susceptibility to ankylosing spondylitis, with about 2·5 men affected for every woman with the disease. We investigated the influence of the sex of the index case on disease penetrance within families.

Methods

The ages at which 50% and 75% of patients were diagnosed with ankylosing spondylitis were ascertained from a database of 4400 cases. Index patients with children or siblings who were old enough to have obtained a diagnosis (50% and 75% rates) were assessed for prevalence of disease among relatives. Confirmation of diagnosis for affected relatives was sought for all offspring and a random 25% selection of siblings.

Findings

Ankylosing spondylitis was more prevalent among children (odds ratio 1·9 [95% CI 1·2–3·0], p<0·005) and siblings (1·5 [1·2–1·9], p<0·0001) of female index cases than among those of male cases. Analyses restricted to index cases with a young age at onset (≤21 years) indicated that children of women had an even higher incidence of ankylosing spondylitis (7·2 [1·5–34], p=0·013) than did children of men at similar age at onset. 38% of children of female cases had disease compared with 8% of male cases. There was no difference in sex distribution among affected children or siblings of female patients with ankylosing spondylitis. By contrast, the sons and brothers of male patients had a higher prevalence of the disease (odds ratio 2·6 [1·4–5·2], p=0·003) than did daughters and sisters (1·7 [1·3–2·2], p<0·0001).

Interpretation

The influence of female sex is greater than that of male sex in determining increased susceptibility to ankylosing spondylitis in children. The striking maternal effect is greatest for women with young age at onset, which is not seen in men. The sex ratio of affected children depends on the sex of the affected parent.

Introduction

The genes of the HLA region control a variety of functions involved in immune responses and influence susceptibility to more than 40 diseases. Many HLA-associated diseases clearly involve heterogeneity in HLA components, as well as non-HLA genetic factors.¹ In the case of ankylosing spondylitis, susceptibility genes in the HLA region include B27, B60, and DR1. However, familial studies show that the HLA region explains only a third of the genetic influence on ankylosing spondylitis² and that other non- HLA genes are involved. Moreover, concomitant disorders associated with ankylosing spondylitis have been linked to different chromosomes, including chromosome 16, implicated in Crohn's disease,³ uveitis,⁴ and psoriasis.⁵

Disease expression differs in men and women, with about 2·5 men affected for every woman with the disease.⁶ Men develop more severe spinal disease.⁷ Women have more peripheral joint involvement.⁸ These differences may be due to genetic factors in the sex chromosomes,⁹ which would lead to a difference in the sex ratio of children and siblings who inherit the disease.

We investigated the influence of the sex of the index case of ankylosing spondylitis on disease inheritance among offspring and siblings, irrespective of HLA-B27 status.

Section snippets

Patients

We studied 4400 individuals with ankylosing spondylitis (3143 men, 1257 women), who were outpatients of the Royal National Hospital for Rheumatic Diseases (RNHRD) or members of the National Ankylosing Spondylitis Society (NASS) and had been recorded on our database. Patients referred to the RNHRD had their diagnosis confirmed according to the New York criteria.¹⁰ all NASS members who completed our questionnaire were asked to complete the form only if they had received a positive diagnosis of

Results

The frequency distribution of age of diagnosis showed a mean 10-year delay from onset of symptoms to diagnosis (figure 1). Men and women did not differ in mean age at onset (24·5 [SD 10·1] vs24·4 [10·5] years) or mean age at diagnosis (31·7 [11·5] vs33·2 [11·4] years). The sex ratio of sporadic (simplex family) cases (74%) was 2·8, whereas the male/female ratio of familial (first-degree relatives, multiplex family) cases (22%) was 1·7 (p<0·0001). Further relatives (ie, second and third degree;

Discussion

Our study may have been biased because patients who have a relative with ankylosing spondylitis are more likely to join a self-help group, resulting in a greater number of patients with a positive family history. However, this would apply irrespective of the sex of the relative and should not influence the comparison of ratios for each sex affected by ankylosing spondylitis. The proportion of affected relatives in this study (11%) is similar to that of other studies.11, 12, 13 A further issue

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Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors, and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole genome linkage studies were published in the 1990s, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease.
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Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole-genome linkage studies were published in the 1990's, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease.
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and relevance: Most of the currently available data on the descriptive epidemiology of axSpA come from the studies performed in patients with AS. The lack of specific ICD codes for axSpA and related disease subcategories and the misuse of the existing diagnostic labels are significant barriers to the correct analysis and interpretation of the data stored in electronic health databases. The differences between the characteristics of patients with nr-axSpA and AS suggest that different factors are involved in the initiation and progression of the disease. Prospective long-term cohort studies of well-defined patient populations are needed.
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The Lancet

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

References (17)

Ankylosing spondylitis.

Clin Rheum Dis

HLA disease associations: models for the study of complex human genetic disorders.

Clin Lab Sci

The HLA component of the genetic contribution to ankylosing spondylitis.

Br J Rheumatol

Confirmation of a susceptibly locus IBDI for Crohn's disease on chromosome 16.

Gasteroenterology

Considine E. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash and uveitis to chromosome 16.

Am J Hum Genet

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.

Hum Mol Genet

Patterns of radiological axial involvement in 470 ankylosing spondylitis (AS) patients.

Arthritis Rheum

Ankylosing spondylitis.

Cited by (75)

Family studies: A useful tool to better understand spondyloarthritis

Family studies: A useful tool to better understand spondyloarthritis

Epidemiology of Axial Spondyloarthritis

The role of HLA-B27 in the pathogenesis and diagnosis of axial spondyloarthritis: 50 years after discovery of the strong genetic association

Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis

Age and symptoms at onset of ankylosing spondylitis in Japanese patients

ArticlesImpact of sex on inheritance of ankylosing spondylitis: a cohort study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Clin Rheum Dis

HLA disease associations: models for the study of complex human genetic disorders.

Clin Lab Sci

The HLA component of the genetic contribution to ankylosing spondylitis.

Br J Rheumatol

Confirmation of a susceptibly locus IBDI for Crohn's disease on chromosome 16.

Gasteroenterology

Considine E. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash and uveitis to chromosome 16.

Am J Hum Genet

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.

Hum Mol Genet

Patterns of radiological axial involvement in 470 ankylosing spondylitis (AS) patients.

Arthritis Rheum

Ankylosing spondylitis.

Articles
Impact of sex on inheritance of ankylosing spondylitis: a cohort study