Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

John B. Harley; Marta E. Alarcón-Riquelme; Lindsey A. Criswell; Chaim O. Jacob; Robert P. Kimberly; Kathy L. Moser; Betty P. Tsao; Timothy J. Vyse; Carl D. Langefeld; Swapan K. Nath; Joel M. Guthridge; Beth L. Cobb; Daniel B. Mirel; Miranda C. Marion; Adrienne H. Williams; Jasmin Divers; Wei Wang; Summer G. Frank; Bahram Namjou; Stacey B. Gabriel; Annette T. Lee; Peter K. Gregersen; Timothy W. Behrens; Kimberly E. Taylor; Michelle Fernando; Raphael Zidovetzki; Patrick M. Gaffney; Jeffrey C. Edberg; John D. Rioux; Joshua O. Ojwang; Judith A. James; Joan T. Merrill; Gary S. Gilkeson; Michael F. Seldin; Hong Yin; Emily C. Baechler; Quan Zhen Li; Edward K. Wakeland; Gail R. Bruner; Kenneth M. Kaufman; Jennifer A. Kelly

doi:10.1038/ng.81

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

John B. Harley, Marta E. Alarcón-Riquelme, Lindsey A. Criswell, Chaim O. Jacob, Robert P. Kimberly, Kathy L. Moser, Betty P. Tsao, Timothy J. Vyse, Carl D. Langefeld, Swapan K. Nath, Joel M. Guthridge, Beth L. Cobb, Daniel B. Mirel, Miranda C. Marion, Adrienne H. Williams, Jasmin Divers, Wei Wang, Summer G. Frank, Bahram Namjou, Stacey B. GabrielAnnette T. Lee, Peter K. Gregersen, Timothy W. Behrens, Kimberly E. Taylor, Michelle Fernando, Raphael Zidovetzki, Patrick M. Gaffney, Jeffrey C. Edberg, John D. Rioux, Joshua O. Ojwang, Judith A. James, Joan T. Merrill, Gary S. Gilkeson, Michael F. Seldin, Hong Yin, Emily C. Baechler, Quan Zhen Li, Edward K. Wakeland, Gail R. Bruner, Kenneth M. Kaufman, Jennifer A. Kelly

Medicine - Rheumatic and Autoimmune

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

1125 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λ_S = ∼30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10^-7 < P _overall < 1.6 × 10^-23; odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10 ^-5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10^-7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

Original language	English (US)
Pages (from-to)	204-210
Number of pages	7
Journal	Nature Genetics
Volume	40
Issue number	2
DOIs	https://doi.org/10.1038/ng.81
State	Published - Feb 2008

Bibliographical note

Funding Information:
SLEGEN appreciates the financial support of the Alliance for Lupus Research. Other support was obtained individually from the Alliance for Lupus Research (J.B.H., K.L.M., C.O.J.), the US National Institutes of Health (grants RR020278 (S.B.G.), AR62277 (J.B.H.), RR020143 (J.B.H.), AR24260 (J.B.H.), AI24717 (J.B.H.), AR22804 (L.A.C.), AR02175 (L.A.C.), AR052300 (L.A.C.), AR43815 (C.O.J.), AR49084 (R.P.K.), AR33062 (R.P.K.), AR43247 (K.L.M.) and AR43814 (B.P.T.)), the Mary Kirkland Awards (J.B.H., L.A.C.), the US Department of Veterans Affairs (J.B.H.), the Lupus Foundation of Minnesota (K.L.M.), the Knut and Alice Wallenberg Foundation (M.E.A.-R.), the Torsten & Ragnar Söderbergs Foundation (M.E.A.-R.), the Swedish Research Council (M.E.A.-R.) and a Wellcome Trust Senior Fellowship (T.J.V.). Additional acknowledgments are listed in the Supplementary Note online.

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Harley, J. B., Alarcón-Riquelme, M. E., Criswell, L. A., Jacob, C. O., Kimberly, R. P., Moser, K. L., Tsao, B. P., Vyse, T. J., Langefeld, C. D., Nath, S. K., Guthridge, J. M., Cobb, B. L., Mirel, D. B., Marion, M. C., Williams, A. H., Divers, J., Wang, W., Frank, S. G., Namjou, B., ... Kelly, J. A. (2008). Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nature Genetics, 40(2), 204-210. https://doi.org/10.1038/ng.81

Harley, JB, Alarcón-Riquelme, ME, Criswell, LA, Jacob, CO, Kimberly, RP, Moser, KL, Tsao, BP, Vyse, TJ, Langefeld, CD, Nath, SK, Guthridge, JM, Cobb, BL, Mirel, DB, Marion, MC, Williams, AH, Divers, J, Wang, W, Frank, SG, Namjou, B, Gabriel, SB, Lee, AT, Gregersen, PK, Behrens, TW, Taylor, KE, Fernando, M, Zidovetzki, R, Gaffney, PM, Edberg, JC, Rioux, JD, Ojwang, JO, James, JA, Merrill, JT, Gilkeson, GS, Seldin, MF, Yin, H, Baechler, EC, Li, QZ, Wakeland, EK, Bruner, GR, Kaufman, KM & Kelly, JA 2008, 'Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci', Nature Genetics, vol. 40, no. 2, pp. 204-210. https://doi.org/10.1038/ng.81

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title = "Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci",

abstract = "Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ∼30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10-7 < P overall < 1.6 × 10-23; odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10 -5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10-7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.",

author = "Harley, {John B.} and Alarc{\'o}n-Riquelme, {Marta E.} and Criswell, {Lindsey A.} and Jacob, {Chaim O.} and Kimberly, {Robert P.} and Moser, {Kathy L.} and Tsao, {Betty P.} and Vyse, {Timothy J.} and Langefeld, {Carl D.} and Nath, {Swapan K.} and Guthridge, {Joel M.} and Cobb, {Beth L.} and Mirel, {Daniel B.} and Marion, {Miranda C.} and Williams, {Adrienne H.} and Jasmin Divers and Wei Wang and Frank, {Summer G.} and Bahram Namjou and Gabriel, {Stacey B.} and Lee, {Annette T.} and Gregersen, {Peter K.} and Behrens, {Timothy W.} and Taylor, {Kimberly E.} and Michelle Fernando and Raphael Zidovetzki and Gaffney, {Patrick M.} and Edberg, {Jeffrey C.} and Rioux, {John D.} and Ojwang, {Joshua O.} and James, {Judith A.} and Merrill, {Joan T.} and Gilkeson, {Gary S.} and Seldin, {Michael F.} and Hong Yin and Baechler, {Emily C.} and Li, {Quan Zhen} and Wakeland, {Edward K.} and Bruner, {Gail R.} and Kaufman, {Kenneth M.} and Kelly, {Jennifer A.}",

note = "Funding Information: SLEGEN appreciates the financial support of the Alliance for Lupus Research. Other support was obtained individually from the Alliance for Lupus Research (J.B.H., K.L.M., C.O.J.), the US National Institutes of Health (grants RR020278 (S.B.G.), AR62277 (J.B.H.), RR020143 (J.B.H.), AR24260 (J.B.H.), AI24717 (J.B.H.), AR22804 (L.A.C.), AR02175 (L.A.C.), AR052300 (L.A.C.), AR43815 (C.O.J.), AR49084 (R.P.K.), AR33062 (R.P.K.), AR43247 (K.L.M.) and AR43814 (B.P.T.)), the Mary Kirkland Awards (J.B.H., L.A.C.), the US Department of Veterans Affairs (J.B.H.), the Lupus Foundation of Minnesota (K.L.M.), the Knut and Alice Wallenberg Foundation (M.E.A.-R.), the Torsten & Ragnar S{\"o}derbergs Foundation (M.E.A.-R.), the Swedish Research Council (M.E.A.-R.) and a Wellcome Trust Senior Fellowship (T.J.V.). Additional acknowledgments are listed in the Supplementary Note online.",

year = "2008",

month = feb,

doi = "10.1038/ng.81",

language = "English (US)",

volume = "40",

pages = "204--210",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

AU - Harley, John B.

AU - Alarcón-Riquelme, Marta E.

AU - Criswell, Lindsey A.

AU - Jacob, Chaim O.

AU - Kimberly, Robert P.

AU - Moser, Kathy L.

AU - Tsao, Betty P.

AU - Vyse, Timothy J.

AU - Langefeld, Carl D.

AU - Nath, Swapan K.

AU - Guthridge, Joel M.

AU - Cobb, Beth L.

AU - Mirel, Daniel B.

AU - Marion, Miranda C.

AU - Williams, Adrienne H.

AU - Divers, Jasmin

AU - Wang, Wei

AU - Frank, Summer G.

AU - Namjou, Bahram

AU - Gabriel, Stacey B.

AU - Lee, Annette T.

AU - Gregersen, Peter K.

AU - Behrens, Timothy W.

AU - Taylor, Kimberly E.

AU - Fernando, Michelle

AU - Zidovetzki, Raphael

AU - Gaffney, Patrick M.

AU - Edberg, Jeffrey C.

AU - Rioux, John D.

AU - Ojwang, Joshua O.

AU - James, Judith A.

AU - Merrill, Joan T.

AU - Gilkeson, Gary S.

AU - Seldin, Michael F.

AU - Yin, Hong

AU - Baechler, Emily C.

AU - Li, Quan Zhen

AU - Wakeland, Edward K.

AU - Bruner, Gail R.

AU - Kaufman, Kenneth M.

AU - Kelly, Jennifer A.

N1 - Funding Information: SLEGEN appreciates the financial support of the Alliance for Lupus Research. Other support was obtained individually from the Alliance for Lupus Research (J.B.H., K.L.M., C.O.J.), the US National Institutes of Health (grants RR020278 (S.B.G.), AR62277 (J.B.H.), RR020143 (J.B.H.), AR24260 (J.B.H.), AI24717 (J.B.H.), AR22804 (L.A.C.), AR02175 (L.A.C.), AR052300 (L.A.C.), AR43815 (C.O.J.), AR49084 (R.P.K.), AR33062 (R.P.K.), AR43247 (K.L.M.) and AR43814 (B.P.T.)), the Mary Kirkland Awards (J.B.H., L.A.C.), the US Department of Veterans Affairs (J.B.H.), the Lupus Foundation of Minnesota (K.L.M.), the Knut and Alice Wallenberg Foundation (M.E.A.-R.), the Torsten & Ragnar Söderbergs Foundation (M.E.A.-R.), the Swedish Research Council (M.E.A.-R.) and a Wellcome Trust Senior Fellowship (T.J.V.). Additional acknowledgments are listed in the Supplementary Note online.

PY - 2008/2

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N2 - Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ∼30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10-7 < P overall < 1.6 × 10-23; odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10 -5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10-7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

AB - Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ∼30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10-7 < P overall < 1.6 × 10-23; odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10 -5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10-7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

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Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

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