title: Association of a TNAP haplotype with ankylosing spondylitis.
abstract: 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.
authors.affiliation: Toronto Western Research Institute, Toronto, Ontario, Canada.
authors.forename: Hing Wo
authors.initials: HW
authors.lastname: Tsui
authors.forename: Robert D
authors.initials: RD
authors.lastname: Inman
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Florence W L
authors.initials: FW
authors.lastname: Tsui
mesh_terms: 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*
chemical_list: D002352:Carrier Proteins; D005819:Genetic Markers; C548267:ALPL protein, human; D000469:Alkaline Phosphatase