Abstract
BackgroundAnkylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis.MethodsWe used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient.ResultsWe identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort.ConclusionsTogether these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association.
Highlights
Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world
AS is the major subtype of spondyloarthritis, a spectrum of inter-related rheumatic diseases that includes reactive arthritis (ReA), psoriatic arthritis (PsA), juvenile spondyloarthritis (JSpA), enteropathic arthritis, and undifferentiated spondyloarthritis (USpA) [2, 3]
The AS9 ankylosing spondylitis pedigree Using the modified New York criteria for ankylosing spondylitis [19], a diagnosis of AS was made on three individuals (AS9_1, AS9_2, AS9_9) of a three-generation pedigree of the Han Chinese (Fig. 1, Fig. 2a and Additional file 1: Table S1)
Summary
Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. Ankylosing spondylitis (AS) is a severe, debilitating and incurable autoimmune disease affecting multi millions of people in the world [1]. The average AS prevalence varies among different populations, with 0.24% in Europe, 0.17% in Asia, 0.3% in North America, 0.1% in Latin America and 0.7% in Africa. Based on these ratios, it is estimated that the number of AS cases in Europe and Asia alone could reach 1.30–1.56 million and 4.63–4.98 million, respectively [1].
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