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PMID: 11254450 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

American journal of human genetics ·Vol. 68 ·No. 4 ·2001-04-00 ·Pages 927-36

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

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 lambdaHLA = 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 in significance 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.

MeSH Terms
Alleles Arthritis, Rheumatoid/genetics Autoimmune Diseases/genetics Chromosome Mapping Chromosomes, Human/genetics Female Genetic Predisposition to Disease/genetics Genetic Testing Genome, Human HLA Antigens/genetics Humans Lod Score Male Matched-Pair Analysis Microsatellite Repeats/genetics Middle Aged Nuclear Family Software Statistics, Nonparametric United States Whites/genetics X Chromosome/genetics
Chemicals
HLA Antigens
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Jawaheer D
Division of Biology and Human Genetics, North Shore University Hospital, Manhasset, NY 11030, USA.
Seldin M F
Amos C I
Chen W V
Shigeta R
Monteiro J
Kern M
Criswell L A
Albani S
Nelson J L
Clegg D O
Pope R
Schroeder H W
Bridges S L
Pisetsky D S
Ward R
Kastner D L
Wilder R L
Pincus T
Callahan L F
Flemming D
Wener M H
Gregersen P K
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/319518
Published
2001-04-00
Epub
2001-00-09
Pages
927-36
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1275647
Subset
IM
Grants
NCRR NIH HHS · M01 RR000079 · United States
NCRR NIH HHS · P41 RR003655 · United States
NCRR NIH HHS · 5 M01 RR-00079 · United States
NIAMS NIH HHS · R01 AR044422 · United States
NCRR NIH HHS · 1 P41 RR03655 · United States
NIAMS NIH HHS · R01 AR44222 · United States
NIAMS NIH HHS · N01-AR-7-2232 · United States
External Links
PubMed source DOI: 10.1086/319518 PMC Full Text View journal details
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