Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

P. S. Ramos; J. A. Kelly; C. Gray-McGuire; G. R. Bruner; A. N. Leiran; Carolyn M Meyer; B. Namjou; K. J. Espe; W. A. Ortmann; M. Reichlin; C. D. Langefeld; J. A. James; P. M. Gaffney; T. W. Behrens; J. B. Harley; K. L. Moser

doi:10.1038/sj.gene.6364316

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

P. S. Ramos, J. A. Kelly, C. Gray-McGuire, G. R. Bruner, A. N. Leiran, Carolyn M Meyer, B. Namjou, K. J. Espe, W. A. Ortmann, M. Reichlin, C. D. Langefeld, J. A. James, P. M. Gaffney, T. W. Behrens, J. B. Harley, K. L. Moser

Pediatrics - Blood/Marrow Transplant

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 × 10^-6), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 × 10^-6), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 × 10^-4) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 × 10^-4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

Original language	English (US)
Pages (from-to)	417-432
Number of pages	16
Journal	Genes and Immunity
Volume	7
Issue number	5
DOIs	https://doi.org/10.1038/sj.gene.6364316
State	Published - Jul 2006

Bibliographical note

Funding Information:
We thank the families and their referring physicians for their participation in this study. We gratefully acknowledge Dr Jane Olson for making a substantial contribution to the study design and statistical analyses, as well as insightful discussions. Some of the results in this report were obtained using the program package SAGE, which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. Some pedigrees (cohorts A, B, C and D) were obtained from the Lupus Multiplex Registry and Repository (http://omrf.ouhsc.edu/lupus), supported by NIH contract N01 AR12253. PSR was supported by a fellowship from the Fundac¸ão para a Ciência e Tecnologia (SFRH/BD/1090/2000). This study was supported by NIH Grants AI24717, AI31584, AI053747, AR42460, AR048940, RR020143 (to JBH) and AR46405 (to KLM).

Access

10.1038/sj.gene.6364316

OpenUrl availability

Full text

Cite this

Ramos, P. S., Kelly, J. A., Gray-McGuire, C., Bruner, G. R., Leiran, A. N., Meyer, C. M., Namjou, B., Espe, K. J., Ortmann, W. A., Reichlin, M., Langefeld, C. D., James, J. A., Gaffney, P. M., Behrens, T. W., Harley, J. B., & Moser, K. L. (2006). Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus. Genes and Immunity, 7(5), 417-432. https://doi.org/10.1038/sj.gene.6364316

Ramos, PS, Kelly, JA, Gray-McGuire, C, Bruner, GR, Leiran, AN, Meyer, CM, Namjou, B, Espe, KJ, Ortmann, WA, Reichlin, M, Langefeld, CD, James, JA, Gaffney, PM, Behrens, TW, Harley, JB & Moser, KL 2006, 'Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus', Genes and Immunity, vol. 7, no. 5, pp. 417-432. https://doi.org/10.1038/sj.gene.6364316

@article{017d86b4e2e74f19a2fc2999b5b062c3,

title = "Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus",

abstract = "Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 × 10-6), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 × 10-6), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 × 10-4) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 × 10-4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.",

author = "Ramos, {P. S.} and Kelly, {J. A.} and C. Gray-McGuire and Bruner, {G. R.} and Leiran, {A. N.} and Meyer, {Carolyn M} and B. Namjou and Espe, {K. J.} and Ortmann, {W. A.} and M. Reichlin and Langefeld, {C. D.} and James, {J. A.} and Gaffney, {P. M.} and Behrens, {T. W.} and Harley, {J. B.} and Moser, {K. L.}",

note = "Funding Information: We thank the families and their referring physicians for their participation in this study. We gratefully acknowledge Dr Jane Olson for making a substantial contribution to the study design and statistical analyses, as well as insightful discussions. Some of the results in this report were obtained using the program package SAGE, which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. Some pedigrees (cohorts A, B, C and D) were obtained from the Lupus Multiplex Registry and Repository (http://omrf.ouhsc.edu/lupus), supported by NIH contract N01 AR12253. PSR was supported by a fellowship from the Fundac¸{\~a}o para a Ci{\^e}ncia e Tecnologia (SFRH/BD/1090/2000). This study was supported by NIH Grants AI24717, AI31584, AI053747, AR42460, AR048940, RR020143 (to JBH) and AR46405 (to KLM).",

year = "2006",

month = jul,

doi = "10.1038/sj.gene.6364316",

language = "English (US)",

volume = "7",

pages = "417--432",

journal = "Genes and Immunity",

issn = "1466-4879",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

AU - Ramos, P. S.

AU - Kelly, J. A.

AU - Gray-McGuire, C.

AU - Bruner, G. R.

AU - Leiran, A. N.

AU - Meyer, Carolyn M

AU - Namjou, B.

AU - Espe, K. J.

AU - Ortmann, W. A.

AU - Reichlin, M.

AU - Langefeld, C. D.

AU - James, J. A.

AU - Gaffney, P. M.

AU - Behrens, T. W.

AU - Harley, J. B.

AU - Moser, K. L.

N1 - Funding Information: We thank the families and their referring physicians for their participation in this study. We gratefully acknowledge Dr Jane Olson for making a substantial contribution to the study design and statistical analyses, as well as insightful discussions. Some of the results in this report were obtained using the program package SAGE, which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. Some pedigrees (cohorts A, B, C and D) were obtained from the Lupus Multiplex Registry and Repository (http://omrf.ouhsc.edu/lupus), supported by NIH contract N01 AR12253. PSR was supported by a fellowship from the Fundac¸ão para a Ciência e Tecnologia (SFRH/BD/1090/2000). This study was supported by NIH Grants AI24717, AI31584, AI053747, AR42460, AR048940, RR020143 (to JBH) and AR46405 (to KLM).

PY - 2006/7

Y1 - 2006/7

N2 - Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 × 10-6), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 × 10-6), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 × 10-4) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 × 10-4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

AB - Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 × 10-6), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 × 10-6), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 × 10-4) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 × 10-4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

UR - http://www.scopus.com/inward/record.url?scp=33746333273&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746333273&partnerID=8YFLogxK

U2 - 10.1038/sj.gene.6364316

DO - 10.1038/sj.gene.6364316

M3 - Article

C2 - 16775618

AN - SCOPUS:33746333273

SN - 1466-4879

VL - 7

SP - 417

EP - 432

JO - Genes and Immunity

JF - Genes and Immunity

IS - 5

ER -

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

Abstract

Bibliographical note

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this