Novel genetic markers in the 5′‐flanking region of <i>ANKH</i> are associated with ankylosing spondylitis

Tsui, Florence W. L.; Tsui, Hing Wo; Cheng, Emily YiQin; Stone, Millicent; Payne, Ursula; Reveille, John D.; Shulman, Marc J.; Paterson, Andrew D.; Inman, Robert D.

doi:10.1002/art.10844

Cited by 61 publications

(49 citation statements)

References 27 publications

(39 reference statements)

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“…The best explanation for the discrepancies is that the contribution of each non-MHC gene to the overall susceptibility to AS is likely small ( s Ͻ 2.0), and the number of sibpairs examined by our group (n ϭ 244) and by Laval et al (n ϭ 255) (10) may not, when examined individually, provide adequate power to discern such "small effect" genes. Further evidence for this is provided by the identification of significant association of AS in our families with the ANKH gene encoded on chromosome 5p (21), despite the fact that this region was not identified by the ABI PRISM linkage map MD-10 marker panel used in this study. Alternatively, the marker density could be increased, using microsatellite markers spaced much more closely.…”

Section: Discussionmentioning

confidence: 79%

Genetic studies in familial ankylosing spondylitis susceptibility

Zhang¹,

Luo²,

Brückel³

et al. 2004

Arthritis & Rheumatism

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104

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Objective. To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially nonmajor histocompatibility complex (MHC) genes.Methods. The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the AlleleSharing Model (ASM) computer program.Results. Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA-DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P ‫؍‬ 6.8 ؋ 10 ؊20 for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58-174.71 cM) in multipoint analysis, with the smallest P value (4.2 ؋ 10 ؊3 ) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P ‫؍‬ 6.2 ؋ 10 ؊5 ). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P ‫؍‬ 0.014); this was confirmed by subsequent fine mapping studies.Conclusion. Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.Ankylosing spondylitis (AS) is a common chronic inflammatory disorder primarily affecting the spine, although the peripheral joints and the attachments of ligaments and tendons to joints (the entheses) are also frequently involved, as well as the eyes, and, less com-

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Section: Discussionmentioning

confidence: 79%

Genetic studies in familial ankylosing spondylitis susceptibility

Zhang¹,

Luo²,

Brückel³

et al. 2004

Arthritis & Rheumatism

Self Cite

104

View full text Add to dashboard Cite

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“…Since ANKH is a growth factor (17) and an androgenresponsive gene (18), it is possible that cytokines generated by inflammation dysregulate the expression of ANKH, resulting in neo-ossification. We previously tested whether ANKH is one of the susceptibility genes for AS (19), and we later showed that ANKH is linked to, and associated with, AS in 201 Caucasian multiplex families (20). However, another study concluded that ANKH did not significantly contribute to susceptibility or specific disease expression in AS patients from the UK (21).…”

Section: Conclusion Our Results Indicate That the Tnap Haplotype Rs3mentioning

confidence: 99%

Association of a TNAP haplotype with ankylosing spondylitis

Tsui¹,

Inman²,

Reveille³

et al. 2007

Arthritis & Rheumatism

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Objective. To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS).Methods. We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single-nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissuenonspecific alkaline phosphatase, and performed family-based association analyses.Results. In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/ rs1780329 (T) was significantly associated with AS (P ‫؍‬ 0.032 by additive model). Haplotype-Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P ‫؍‬ 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P ‫؍‬ 0.001 by additive model). The HBAT -p option (haplotype permutation test) was used to compute the "exact" P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2-sided P value for haplotype rs3767155[G]/rs3738099 [G]/rs1780329 [T] ‫؍‬ 0.00059, the smallest observed P value among all the individual haplotype scores ‫؍‬ 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families.Conclusion. Our results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.

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“…However, weakly positive findings have been reported by some authors, and the association may be strong in women 7,8 . Pimentel-Santos, et al showed that ANKH is not a major determinant of susceptibility to AS and ANKH polymorphism does not influence AS severity 1 .…”

Section: Ankh and Renal Stone Formation In Ankylosing Spondylitismentioning

confidence: 79%