ANKHvariants associated with ankylosing spondylitis: gender differences

Abstract

The ank (progressive ankylosis) mutant mouse, which has a nonsense mutation in exon 12 of the inorganic pyrophosphate regulator gene (ank), exhibits aberrant joint ankylosis similar to human ankylosing spondylitis (AS). We previously performed family-based association analyses of 124 Caucasian AS families and showed that novel genetic markers in the 5' flanking region of ANKH (the human homolog of the murine ank gene) are modestly associated with AS. The objective of the present study was to conduct a more extensive evaluation of ANKH variants that are significantly associated with AS and to determine whether the association is gender specific. We genotyped 201 multiplex AS families with nine ANKH intragenetic and two flanking microsatellite markers, and performed family-based association analyses. We showed that ANKH variants located in two different regions of the ANKH gene were associated with AS. Results of haplotype analyses indicated that, after Bonferroni correction, the haplotype combination of rs26307 [C] and rs27356 [C] is significantly associated with AS in men (recessive/dominant model; P = 0.004), and the haplotype combination of rs28006 [C] and rs25957 [C] is significantly associated with AS in women (recessive/dominant model; P = 0.004). A test of interaction identified rs26307 (i.e. the region that was associated in men with AS) as showing a difference in the strength of the association by gender. The region associated with AS in women only showed significance in the test of interaction among the subset of families with affected individuals of both genders. These findings support the concept that ANKH plays a role in genetic susceptibility to AS and reveals a gendergenotype specificity in this interaction.

The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis

“…Significantly, we further showed that there are sex differences in the ANKH variants associated with AS 64. Intriguingly, there is heterogeneity even in multiplex AS families.…”

Gender Differences in Axial Spondyloarthritis: Women Are Not So Lucky

“…One study identified a sex-specific gene expression profile, showing 291 genes uniquely expressed in female AS patients, 1522 genes expressed in males with AS, and 650 genes expressed in both male and female AS patients compared with healthy matched controls [ 34 •]. Another study revealed that different loci of the ANKH gene were associated with AS in male versus female patient [ 37 ]. The ANKH gene encodes a progressive ankylosing protein, which is involved in the structural damage in axSpA patients.…”

Sex and gender differences in axial spondyloarthritis: myths and truths

“…A study considering the ANKH gene, which encodes a protein that is involved in osteogenesis and plays a role in ankylosis in AS, showed that different loci of the ANKH gene were expressed in men and women with AS [ 22 ]. Furthermore, in multiplex AS families, a specific tissue-non-specific alkaline phosphatase (TNAP) haplotype, which interplays with the ANKH gene in ossification, was associated with AS in men but not in women [ 23 ].…”