Genetic studies in familial ankylosing spondylitis susceptibility

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Arthritis Rheum. 2004 Jul;50(7):2246-54.

Genetic studies in familial ankylosing spondylitis susceptibility.

Zhang G, Luo J, Bruckel J, Weisman MA, Schumacher HR, Khan MA, Inman RD,

Mahowald M, Maksymowych WP, TM, Yu DT, Stone M, Rosenbaum JT,

Newman P, Lee J, McClain JA, West OC, Jin L, Reveille JD.

Center for Genome Information, University of Cincinnati, Cincinnati,

Ohio 45267-0056, USA.

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.

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.

PMID: 15248224

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