Novel genetic markers in the 5'-flanking region of ANKH are associated with ankylosing spondylitis.
OBJECTIVE
To use a candidate gene approach for the identification of genetic markers that are significantly linked to and associated with ankylosing spondylitis (AS).


METHODS
We searched for novel polymorphisms in the ANKH gene (human homolog of the murine progressive ankylosis gene) and genotyped 2 polymorphic sites, one in the 5'-noncoding region and the other in the promoter region of ANKH, using DNA from affected (n = 273) and unaffected (n = 112) individuals from 124 AS families. We used these ANKH and other nearby polymorphisms to perform linkage and family-based association analyses.


RESULTS
We identified 2 novel polymorphic sites: one in the 5'-noncoding region of ANKH involving 1-2 copies of an 8-bp repeat (denoted as ANKH-OR), and the other in the promoter region involving different copy numbers of a triplet repeat (denoted as ANKH-TR). ANKH-OR and ANKH-TR were in complete linkage disequilibrium. Five markers (D5S1953, ANKH-TR, ANKH-OR, D5S1954, and D5S1963) were used for both the linkage and association analyses. Multipoint linkage analysis of 124 AS families showed a modest level of significance (nonparametric linkage score 2.15; P = 0.015) at the ANKH region. The contribution of ANKH to AS susceptibility (lambda(s)) was 1.9. A family-based association study on the same AS families revealed that both ANKH-OR allele 1 and ANKH-TR allele 7 were significantly associated with disease, assuming an additive model (for ANKH-OR allele 1, P = 0.03; for ANKH-TR allele 7, P = 0.04).


CONCLUSIONS
Our results indicate that ANKH-OR and ANKH-TR are novel genetic markers that are significantly associated with AS.
Tsui
Florence W L
FW
Toronto Western Research Institute and University of Toronto, Toronto, Ontario, Canada. ftsui@uhnres.utoronto.ca
Tsui
Hing Wo
HW
Cheng
Emily Y
EY
Stone
Millicent
M
Payne
Ursula
U
Reveille
John D
JD
Shulman
Marc J
MJ
Paterson
Andrew D
AD
Inman
Robert D
RD
D024506:5' Flanking Region / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009679:Nuclear Family; D028061:Phosphate Transport Proteins; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000378:metabolism
C498770:ANKH protein, human; D017931:DNA Primers; D005819:Genetic Markers; D008565:Membrane Proteins; D028061:Phosphate Transport Proteins