Genetic studies in familial ankylosing spondylitis susceptibility.
OBJECTIVE
To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non-major 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 Allele-Sharing 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 x 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 x 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 x 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.


CONCLUSIONS
Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.
Zhang
Ge
G
Center for Genome Information, University of Cincinnati, Cincinnati, Ohio 45267-0056, USA.
Luo
Jingchun
J
Bruckel
Jane
J
Weisman
Michael A
MA
Schumacher
H Ralph
HR
Khan
Muhammad A
MA
Inman
Robert D
RD
Mahowald
Maren
M
Maksymowych
Walter P
WP
Martin
Tammy M
TM
Yu
David T Y
DT
Stone
Millicent
M
Rosenbaum
James T
JT
Newman
Patricia
P
Lee
Juwon
J
McClain
Jo A
JA
West
O Clark
OC
Jin
Li
L
Reveille
John D
JD
D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002896:Chromosomes, Human, Pair 6; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008126:Lod Score; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D013167:Spondylitis, Ankylosing / Q000235:genetics*
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains