Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

Damini Jawaheer, Wentian Li, Robert R. Graham, Wei Chen, Aarti Damle, Xiangli Xiao, Joanita Monteiro, Houman Khalili, Annette Lee, Robert Lundsten, Ann Begovich, Teodorica Bugawan, Henry Erlich, James T. Elder, Lindsey A. Criswell, Michael F Seldin, Christopher I. Amos, Timothy W. Behrens, Peter K. Gregersen

Research output: Contribution to journalArticle

148 Citations (Scopus)

Abstract

Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

Original languageEnglish (US)
Pages (from-to)585-594
Number of pages10
JournalAmerican Journal of Human Genetics
Volume71
Issue number3
DOIs
StatePublished - Sep 2002

Fingerprint

HLA Antigens
Rheumatoid Arthritis
Haplotypes
Disease Susceptibility
Major Histocompatibility Complex
Epitopes
Alleles
Population
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Jawaheer, D., Li, W., Graham, R. R., Chen, W., Damle, A., Xiao, X., ... Gregersen, P. K. (2002). Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. American Journal of Human Genetics, 71(3), 585-594. https://doi.org/10.1086/342407

Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. / Jawaheer, Damini; Li, Wentian; Graham, Robert R.; Chen, Wei; Damle, Aarti; Xiao, Xiangli; Monteiro, Joanita; Khalili, Houman; Lee, Annette; Lundsten, Robert; Begovich, Ann; Bugawan, Teodorica; Erlich, Henry; Elder, James T.; Criswell, Lindsey A.; Seldin, Michael F; Amos, Christopher I.; Behrens, Timothy W.; Gregersen, Peter K.

In: American Journal of Human Genetics, Vol. 71, No. 3, 09.2002, p. 585-594.

Research output: Contribution to journalArticle

Jawaheer, D, Li, W, Graham, RR, Chen, W, Damle, A, Xiao, X, Monteiro, J, Khalili, H, Lee, A, Lundsten, R, Begovich, A, Bugawan, T, Erlich, H, Elder, JT, Criswell, LA, Seldin, MF, Amos, CI, Behrens, TW & Gregersen, PK 2002, 'Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis', American Journal of Human Genetics, vol. 71, no. 3, pp. 585-594. https://doi.org/10.1086/342407
Jawaheer, Damini ; Li, Wentian ; Graham, Robert R. ; Chen, Wei ; Damle, Aarti ; Xiao, Xiangli ; Monteiro, Joanita ; Khalili, Houman ; Lee, Annette ; Lundsten, Robert ; Begovich, Ann ; Bugawan, Teodorica ; Erlich, Henry ; Elder, James T. ; Criswell, Lindsey A. ; Seldin, Michael F ; Amos, Christopher I. ; Behrens, Timothy W. ; Gregersen, Peter K. / Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. In: American Journal of Human Genetics. 2002 ; Vol. 71, No. 3. pp. 585-594.
@article{85669689633f4edb9c87f23ab3e231c1,
title = "Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis",
abstract = "Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 {"}shared epitope{"} in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.",
author = "Damini Jawaheer and Wentian Li and Graham, {Robert R.} and Wei Chen and Aarti Damle and Xiangli Xiao and Joanita Monteiro and Houman Khalili and Annette Lee and Robert Lundsten and Ann Begovich and Teodorica Bugawan and Henry Erlich and Elder, {James T.} and Criswell, {Lindsey A.} and Seldin, {Michael F} and Amos, {Christopher I.} and Behrens, {Timothy W.} and Gregersen, {Peter K.}",
year = "2002",
month = "9",
doi = "10.1086/342407",
language = "English (US)",
volume = "71",
pages = "585--594",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

AU - Jawaheer, Damini

AU - Li, Wentian

AU - Graham, Robert R.

AU - Chen, Wei

AU - Damle, Aarti

AU - Xiao, Xiangli

AU - Monteiro, Joanita

AU - Khalili, Houman

AU - Lee, Annette

AU - Lundsten, Robert

AU - Begovich, Ann

AU - Bugawan, Teodorica

AU - Erlich, Henry

AU - Elder, James T.

AU - Criswell, Lindsey A.

AU - Seldin, Michael F

AU - Amos, Christopher I.

AU - Behrens, Timothy W.

AU - Gregersen, Peter K.

PY - 2002/9

Y1 - 2002/9

N2 - Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

AB - Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

UR - http://www.scopus.com/inward/record.url?scp=18544362452&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18544362452&partnerID=8YFLogxK

U2 - 10.1086/342407

DO - 10.1086/342407

M3 - Article

C2 - 12181776

AN - SCOPUS:18544362452

VL - 71

SP - 585

EP - 594

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -