A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases

Damini Jawaheer, Michael F. Seldin, Christopher I. Amos, Wei V. Chen, Russell Shigeta, Joanita Monteiro, Marlene Kern, Lindsey A. Criswell, Salvatore Albani, J. Lee Nelson, Daniel O. Clegg, Richard Pope, Harry W. Schroeder, S. Louis Bridges, David S. Pisetsky, Ryk Ward, Daniel L. Kastner, Ronald L. Wilder, Theodore Pincus, Leigh F. Callahan & 3 others Donald Flemming, Mark H. Wener, Peter K. Gregersen

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Abstract

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with λHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P < .005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement insignificance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Original languageEnglish (US)
Pages (from-to)927-936
Number of pages10
JournalAmerican Journal of Human Genetics
Volume68
Issue number4
DOIs
StatePublished - Jan 1 2001

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Autoimmune Diseases
Rheumatoid Arthritis
Chromosomes, Human, Pair 1
Ankylosing Spondylitis
Inflammatory Bowel Diseases
Systemic Lupus Erythematosus
Microsatellite Repeats
Multiple Sclerosis
Alleles
Genome
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Jawaheer, D., Seldin, M. F., Amos, C. I., Chen, W. V., Shigeta, R., Monteiro, J., ... Gregersen, P. K. (2001). A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. American Journal of Human Genetics, 68(4), 927-936. https://doi.org/10.1086/319518
Jawaheer, Damini ; Seldin, Michael F. ; Amos, Christopher I. ; Chen, Wei V. ; Shigeta, Russell ; Monteiro, Joanita ; Kern, Marlene ; Criswell, Lindsey A. ; Albani, Salvatore ; Nelson, J. Lee ; Clegg, Daniel O. ; Pope, Richard ; Schroeder, Harry W. ; Bridges, S. Louis ; Pisetsky, David S. ; Ward, Ryk ; Kastner, Daniel L. ; Wilder, Ronald L. ; Pincus, Theodore ; Callahan, Leigh F. ; Flemming, Donald ; Wener, Mark H. ; Gregersen, Peter K. / A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. In: American Journal of Human Genetics. 2001 ; Vol. 68, No. 4. pp. 927-936.
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abstract = "Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with λHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P < .005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement insignificance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.",
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Jawaheer, D, Seldin, MF, Amos, CI, Chen, WV, Shigeta, R, Monteiro, J, Kern, M, Criswell, LA, Albani, S, Nelson, JL, Clegg, DO, Pope, R, Schroeder, HW, Bridges, SL, Pisetsky, DS, Ward, R, Kastner, DL, Wilder, RL, Pincus, T, Callahan, LF, Flemming, D, Wener, MH & Gregersen, PK 2001, 'A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases', American Journal of Human Genetics, vol. 68, no. 4, pp. 927-936. https://doi.org/10.1086/319518

A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. / Jawaheer, Damini; Seldin, Michael F.; Amos, Christopher I.; Chen, Wei V.; Shigeta, Russell; Monteiro, Joanita; Kern, Marlene; Criswell, Lindsey A.; Albani, Salvatore; Nelson, J. Lee; Clegg, Daniel O.; Pope, Richard; Schroeder, Harry W.; Bridges, S. Louis; Pisetsky, David S.; Ward, Ryk; Kastner, Daniel L.; Wilder, Ronald L.; Pincus, Theodore; Callahan, Leigh F.; Flemming, Donald; Wener, Mark H.; Gregersen, Peter K.

In: American Journal of Human Genetics, Vol. 68, No. 4, 01.01.2001, p. 927-936.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases

AU - Jawaheer, Damini

AU - Seldin, Michael F.

AU - Amos, Christopher I.

AU - Chen, Wei V.

AU - Shigeta, Russell

AU - Monteiro, Joanita

AU - Kern, Marlene

AU - Criswell, Lindsey A.

AU - Albani, Salvatore

AU - Nelson, J. Lee

AU - Clegg, Daniel O.

AU - Pope, Richard

AU - Schroeder, Harry W.

AU - Bridges, S. Louis

AU - Pisetsky, David S.

AU - Ward, Ryk

AU - Kastner, Daniel L.

AU - Wilder, Ronald L.

AU - Pincus, Theodore

AU - Callahan, Leigh F.

AU - Flemming, Donald

AU - Wener, Mark H.

AU - Gregersen, Peter K.

PY - 2001/1/1

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N2 - Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with λHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P < .005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement insignificance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

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