Association of a TNAP haplotype with ankylosing spondylitis.
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 tissue-nonspecific 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.


CONCLUSIONS
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.
Tsui
Hing Wo
HW
Toronto Western Research Institute, Toronto, Ontario, Canada.
Inman
Robert D
RD
Reveille
John D
JD
Tsui
Florence W L
FW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009679:Nuclear Family; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D012737:Sex Factors; D013167:Spondylitis, Ankylosing / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*
D002352:Carrier Proteins; D005819:Genetic Markers; C548267:ALPL protein, human; D000469:Alkaline Phosphatase