Genetic studies in familial ankylosing spondylitis susceptibility

Ge Zhang, Jingchun Luo, Jane Bruckel, Michael A. Weisman, H. Ralph Schumacher, Muhammad A. Khan, Robert D. Inman, Maren Mahowald, Walter P. Maksymowych, Tammy Martin, David T Y Yu, Millicent Stone, James (Jim) Rosenbaum, Patricia Newman, Juwon Lee, Jo A. McClain, O. Clark West, Li Jin, John D. Reveille

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

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-DRBI locus (NPL score 8.720, ASM LOD score 20.49; P = 6.3 × 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 × 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 × 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.

Original languageEnglish (US)
Pages (from-to)2246-2254
Number of pages9
JournalArthritis and Rheumatism
Volume50
Issue number7
DOIs
StatePublished - Jul 2004

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Ankylosing Spondylitis
Major Histocompatibility Complex
Alleles
Chromosomes
HLA-DRB1 Chains
Chromosomes, Human, Pair 6
HLA-B Antigens
Pedigree
Genetic Predisposition to Disease
Nonparametric Statistics
Genetic Markers
Software
Genome
Genes

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Zhang, G., Luo, J., Bruckel, J., Weisman, M. A., Schumacher, H. R., Khan, M. A., ... Reveille, J. D. (2004). Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis and Rheumatism, 50(7), 2246-2254. https://doi.org/10.1002/art.20308

Genetic studies in familial ankylosing spondylitis susceptibility. / Zhang, Ge; Luo, Jingchun; Bruckel, Jane; Weisman, Michael A.; Schumacher, H. Ralph; Khan, Muhammad A.; Inman, Robert D.; Mahowald, Maren; Maksymowych, Walter P.; Martin, Tammy; Yu, David T Y; Stone, Millicent; Rosenbaum, James (Jim); Newman, Patricia; Lee, Juwon; McClain, Jo A.; West, O. Clark; Jin, Li; Reveille, John D.

In: Arthritis and Rheumatism, Vol. 50, No. 7, 07.2004, p. 2246-2254.

Research output: Contribution to journalArticle

Zhang, G, Luo, J, Bruckel, J, Weisman, MA, Schumacher, HR, Khan, MA, Inman, RD, Mahowald, M, Maksymowych, WP, Martin, T, Yu, DTY, Stone, M, Rosenbaum, JJ, Newman, P, Lee, J, McClain, JA, West, OC, Jin, L & Reveille, JD 2004, 'Genetic studies in familial ankylosing spondylitis susceptibility', Arthritis and Rheumatism, vol. 50, no. 7, pp. 2246-2254. https://doi.org/10.1002/art.20308
Zhang G, Luo J, Bruckel J, Weisman MA, Schumacher HR, Khan MA et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis and Rheumatism. 2004 Jul;50(7):2246-2254. https://doi.org/10.1002/art.20308
Zhang, Ge ; Luo, Jingchun ; Bruckel, Jane ; Weisman, Michael A. ; Schumacher, H. Ralph ; Khan, Muhammad A. ; Inman, Robert D. ; Mahowald, Maren ; Maksymowych, Walter P. ; Martin, Tammy ; Yu, David T Y ; Stone, Millicent ; Rosenbaum, James (Jim) ; Newman, Patricia ; Lee, Juwon ; McClain, Jo A. ; West, O. Clark ; Jin, Li ; Reveille, John D. / Genetic studies in familial ankylosing spondylitis susceptibility. In: Arthritis and Rheumatism. 2004 ; Vol. 50, No. 7. pp. 2246-2254.
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abstract = "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-DRBI locus (NPL score 8.720, ASM LOD score 20.49; P = 6.3 × 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 × 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 × 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.",
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AU - Zhang, Ge

AU - Luo, Jingchun

AU - Bruckel, Jane

AU - Weisman, Michael A.

AU - Schumacher, H. Ralph

AU - Khan, Muhammad A.

AU - Inman, Robert D.

AU - Mahowald, Maren

AU - Maksymowych, Walter P.

AU - Martin, Tammy

AU - Yu, David T Y

AU - Stone, Millicent

AU - Rosenbaum, James (Jim)

AU - Newman, Patricia

AU - Lee, Juwon

AU - McClain, Jo A.

AU - West, O. Clark

AU - Jin, Li

AU - Reveille, John D.

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N2 - 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-DRBI locus (NPL score 8.720, ASM LOD score 20.49; P = 6.3 × 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 × 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 × 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.

AB - 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-DRBI locus (NPL score 8.720, ASM LOD score 20.49; P = 6.3 × 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 × 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 × 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.

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