X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

Ke Liu, Biji T. Kurien, Sarah L. Zimmerman, Kenneth M. Kaufman, Diana H. Taft, Leah C. Kottyan, Sara Lazaro, Carrie A. Weaver, John A. Ice, Adam J. Adler, James Chodosh, Lida Radfar, Astrid Rasmussen, Donald U. Stone, David M. Lewis, Shibo Li, Kristi A. Koelsch, Ann Igoe, Mitali Talsania, Jay KumarJacen S. Maier-Moore, Valerie M. Harris, Rajaram Gopalakrishnan, Roland Jonsson, James A. Lessard, Xianglan Lu, Jacques Eric Gottenberg, Juan Manuel Anaya, Deborah S. Cunninghame-Graham, Andrew J W Huang, Michael T. Brennan, Pamela Hughes, Gabor G. Illei, Corinne Miceli-Richard, Edward C. Keystone, Vivian P. Bykerk, Gideon Hirschfield, Gang Xie, Wan Fai Ng, Gunnel Nordmark, Per Eriksson, Roald Omdal, Nelson L. Rhodus, Maureen Rischmueller, Michael Rohrer, Barbara M. Segal, Timothy J. Vyse, Marie Wahren-Herlenius, Torsten Witte, Bernardo Pons-Estel, Marta E. Alarcón-Riquelme, Joel M. Guthridge, Judith A. James, Christopher J. Lessard, Jennifer A. Kelly, Susan D. Thompson, Patrick M. Gaffney, Courtney G. Montgomery, Jeffrey C. Edberg, Robert P. Kimberly, Graciela S. Alarcón, Carl L. Langefeld, Gary S. Gilkeson, Diane L. Kamen, Betty P. Tsao, W. Joseph McCune, Jane E. Salmon, Joan T. Merrill, Michael H. Weisman, Daniel J. Wallace, Tammy O. Utset, Erwin P. Bottinger, Christopher I. Amos, Katherine A. Siminovitch, Xavier Mariette, Kathy L. Sivils, John B. Harley, R. Hal Scofield

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Objective More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. Conclusion The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

Original languageEnglish (US)
Pages (from-to)1290-1300
Number of pages11
JournalArthritis and Rheumatology
Volume68
Issue number5
DOIs
StatePublished - May 1 2016
Externally publishedYes

Fingerprint

Sexism
X Chromosome
Systemic Lupus Erythematosus
Autoimmune Diseases
Biliary Liver Cirrhosis
Rheumatoid Arthritis
Odds Ratio
Confidence Intervals
Live Birth
Sarcoidosis
Fluorescence In Situ Hybridization
Autoimmunity
Single Nucleotide Polymorphism
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Liu, K., Kurien, B. T., Zimmerman, S. L., Kaufman, K. M., Taft, D. H., Kottyan, L. C., ... Hal Scofield, R. (2016). X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis and Rheumatology, 68(5), 1290-1300. https://doi.org/10.1002/art.39560

X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. / Liu, Ke; Kurien, Biji T.; Zimmerman, Sarah L.; Kaufman, Kenneth M.; Taft, Diana H.; Kottyan, Leah C.; Lazaro, Sara; Weaver, Carrie A.; Ice, John A.; Adler, Adam J.; Chodosh, James; Radfar, Lida; Rasmussen, Astrid; Stone, Donald U.; Lewis, David M.; Li, Shibo; Koelsch, Kristi A.; Igoe, Ann; Talsania, Mitali; Kumar, Jay; Maier-Moore, Jacen S.; Harris, Valerie M.; Gopalakrishnan, Rajaram; Jonsson, Roland; Lessard, James A.; Lu, Xianglan; Gottenberg, Jacques Eric; Anaya, Juan Manuel; Cunninghame-Graham, Deborah S.; Huang, Andrew J W; Brennan, Michael T.; Hughes, Pamela; Illei, Gabor G.; Miceli-Richard, Corinne; Keystone, Edward C.; Bykerk, Vivian P.; Hirschfield, Gideon; Xie, Gang; Ng, Wan Fai; Nordmark, Gunnel; Eriksson, Per; Omdal, Roald; Rhodus, Nelson L.; Rischmueller, Maureen; Rohrer, Michael; Segal, Barbara M.; Vyse, Timothy J.; Wahren-Herlenius, Marie; Witte, Torsten; Pons-Estel, Bernardo; Alarcón-Riquelme, Marta E.; Guthridge, Joel M.; James, Judith A.; Lessard, Christopher J.; Kelly, Jennifer A.; Thompson, Susan D.; Gaffney, Patrick M.; Montgomery, Courtney G.; Edberg, Jeffrey C.; Kimberly, Robert P.; Alarcón, Graciela S.; Langefeld, Carl L.; Gilkeson, Gary S.; Kamen, Diane L.; Tsao, Betty P.; Joseph McCune, W.; Salmon, Jane E.; Merrill, Joan T.; Weisman, Michael H.; Wallace, Daniel J.; Utset, Tammy O.; Bottinger, Erwin P.; Amos, Christopher I.; Siminovitch, Katherine A.; Mariette, Xavier; Sivils, Kathy L.; Harley, John B.; Hal Scofield, R.

In: Arthritis and Rheumatology, Vol. 68, No. 5, 01.05.2016, p. 1290-1300.

Research output: Contribution to journalArticle

Liu, K, Kurien, BT, Zimmerman, SL, Kaufman, KM, Taft, DH, Kottyan, LC, Lazaro, S, Weaver, CA, Ice, JA, Adler, AJ, Chodosh, J, Radfar, L, Rasmussen, A, Stone, DU, Lewis, DM, Li, S, Koelsch, KA, Igoe, A, Talsania, M, Kumar, J, Maier-Moore, JS, Harris, VM, Gopalakrishnan, R, Jonsson, R, Lessard, JA, Lu, X, Gottenberg, JE, Anaya, JM, Cunninghame-Graham, DS, Huang, AJW, Brennan, MT, Hughes, P, Illei, GG, Miceli-Richard, C, Keystone, EC, Bykerk, VP, Hirschfield, G, Xie, G, Ng, WF, Nordmark, G, Eriksson, P, Omdal, R, Rhodus, NL, Rischmueller, M, Rohrer, M, Segal, BM, Vyse, TJ, Wahren-Herlenius, M, Witte, T, Pons-Estel, B, Alarcón-Riquelme, ME, Guthridge, JM, James, JA, Lessard, CJ, Kelly, JA, Thompson, SD, Gaffney, PM, Montgomery, CG, Edberg, JC, Kimberly, RP, Alarcón, GS, Langefeld, CL, Gilkeson, GS, Kamen, DL, Tsao, BP, Joseph McCune, W, Salmon, JE, Merrill, JT, Weisman, MH, Wallace, DJ, Utset, TO, Bottinger, EP, Amos, CI, Siminovitch, KA, Mariette, X, Sivils, KL, Harley, JB & Hal Scofield, R 2016, 'X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome', Arthritis and Rheumatology, vol. 68, no. 5, pp. 1290-1300. https://doi.org/10.1002/art.39560
Liu, Ke ; Kurien, Biji T. ; Zimmerman, Sarah L. ; Kaufman, Kenneth M. ; Taft, Diana H. ; Kottyan, Leah C. ; Lazaro, Sara ; Weaver, Carrie A. ; Ice, John A. ; Adler, Adam J. ; Chodosh, James ; Radfar, Lida ; Rasmussen, Astrid ; Stone, Donald U. ; Lewis, David M. ; Li, Shibo ; Koelsch, Kristi A. ; Igoe, Ann ; Talsania, Mitali ; Kumar, Jay ; Maier-Moore, Jacen S. ; Harris, Valerie M. ; Gopalakrishnan, Rajaram ; Jonsson, Roland ; Lessard, James A. ; Lu, Xianglan ; Gottenberg, Jacques Eric ; Anaya, Juan Manuel ; Cunninghame-Graham, Deborah S. ; Huang, Andrew J W ; Brennan, Michael T. ; Hughes, Pamela ; Illei, Gabor G. ; Miceli-Richard, Corinne ; Keystone, Edward C. ; Bykerk, Vivian P. ; Hirschfield, Gideon ; Xie, Gang ; Ng, Wan Fai ; Nordmark, Gunnel ; Eriksson, Per ; Omdal, Roald ; Rhodus, Nelson L. ; Rischmueller, Maureen ; Rohrer, Michael ; Segal, Barbara M. ; Vyse, Timothy J. ; Wahren-Herlenius, Marie ; Witte, Torsten ; Pons-Estel, Bernardo ; Alarcón-Riquelme, Marta E. ; Guthridge, Joel M. ; James, Judith A. ; Lessard, Christopher J. ; Kelly, Jennifer A. ; Thompson, Susan D. ; Gaffney, Patrick M. ; Montgomery, Courtney G. ; Edberg, Jeffrey C. ; Kimberly, Robert P. ; Alarcón, Graciela S. ; Langefeld, Carl L. ; Gilkeson, Gary S. ; Kamen, Diane L. ; Tsao, Betty P. ; Joseph McCune, W. ; Salmon, Jane E. ; Merrill, Joan T. ; Weisman, Michael H. ; Wallace, Daniel J. ; Utset, Tammy O. ; Bottinger, Erwin P. ; Amos, Christopher I. ; Siminovitch, Katherine A. ; Mariette, Xavier ; Sivils, Kathy L. ; Harley, John B. ; Hal Scofield, R. / X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. In: Arthritis and Rheumatology. 2016 ; Vol. 68, No. 5. pp. 1290-1300.
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title = "X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sj{\"o}gren's Syndrome",
abstract = "Objective More than 80{\%} of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sj{\"o}gren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95{\%} confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95{\%} confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. Conclusion The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.",
author = "Ke Liu and Kurien, {Biji T.} and Zimmerman, {Sarah L.} and Kaufman, {Kenneth M.} and Taft, {Diana H.} and Kottyan, {Leah C.} and Sara Lazaro and Weaver, {Carrie A.} and Ice, {John A.} and Adler, {Adam J.} and James Chodosh and Lida Radfar and Astrid Rasmussen and Stone, {Donald U.} and Lewis, {David M.} and Shibo Li and Koelsch, {Kristi A.} and Ann Igoe and Mitali Talsania and Jay Kumar and Maier-Moore, {Jacen S.} and Harris, {Valerie M.} and Rajaram Gopalakrishnan and Roland Jonsson and Lessard, {James A.} and Xianglan Lu and Gottenberg, {Jacques Eric} and Anaya, {Juan Manuel} and Cunninghame-Graham, {Deborah S.} and Huang, {Andrew J W} and Brennan, {Michael T.} and Pamela Hughes and Illei, {Gabor G.} and Corinne Miceli-Richard and Keystone, {Edward C.} and Bykerk, {Vivian P.} and Gideon Hirschfield and Gang Xie and Ng, {Wan Fai} and Gunnel Nordmark and Per Eriksson and Roald Omdal and Rhodus, {Nelson L.} and Maureen Rischmueller and Michael Rohrer and Segal, {Barbara M.} and Vyse, {Timothy J.} and Marie Wahren-Herlenius and Torsten Witte and Bernardo Pons-Estel and Alarc{\'o}n-Riquelme, {Marta E.} and Guthridge, {Joel M.} and James, {Judith A.} and Lessard, {Christopher J.} and Kelly, {Jennifer A.} and Thompson, {Susan D.} and Gaffney, {Patrick M.} and Montgomery, {Courtney G.} and Edberg, {Jeffrey C.} and Kimberly, {Robert P.} and Alarc{\'o}n, {Graciela S.} and Langefeld, {Carl L.} and Gilkeson, {Gary S.} and Kamen, {Diane L.} and Tsao, {Betty P.} and {Joseph McCune}, W. and Salmon, {Jane E.} and Merrill, {Joan T.} and Weisman, {Michael H.} and Wallace, {Daniel J.} and Utset, {Tammy O.} and Bottinger, {Erwin P.} and Amos, {Christopher I.} and Siminovitch, {Katherine A.} and Xavier Mariette and Sivils, {Kathy L.} and Harley, {John B.} and {Hal Scofield}, R.",
year = "2016",
month = "5",
day = "1",
doi = "10.1002/art.39560",
language = "English (US)",
volume = "68",
pages = "1290--1300",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

TY - JOUR

T1 - X Chromosome Dose and Sex Bias in Autoimmune Diseases

T2 - Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

AU - Liu, Ke

AU - Kurien, Biji T.

AU - Zimmerman, Sarah L.

AU - Kaufman, Kenneth M.

AU - Taft, Diana H.

AU - Kottyan, Leah C.

AU - Lazaro, Sara

AU - Weaver, Carrie A.

AU - Ice, John A.

AU - Adler, Adam J.

AU - Chodosh, James

AU - Radfar, Lida

AU - Rasmussen, Astrid

AU - Stone, Donald U.

AU - Lewis, David M.

AU - Li, Shibo

AU - Koelsch, Kristi A.

AU - Igoe, Ann

AU - Talsania, Mitali

AU - Kumar, Jay

AU - Maier-Moore, Jacen S.

AU - Harris, Valerie M.

AU - Gopalakrishnan, Rajaram

AU - Jonsson, Roland

AU - Lessard, James A.

AU - Lu, Xianglan

AU - Gottenberg, Jacques Eric

AU - Anaya, Juan Manuel

AU - Cunninghame-Graham, Deborah S.

AU - Huang, Andrew J W

AU - Brennan, Michael T.

AU - Hughes, Pamela

AU - Illei, Gabor G.

AU - Miceli-Richard, Corinne

AU - Keystone, Edward C.

AU - Bykerk, Vivian P.

AU - Hirschfield, Gideon

AU - Xie, Gang

AU - Ng, Wan Fai

AU - Nordmark, Gunnel

AU - Eriksson, Per

AU - Omdal, Roald

AU - Rhodus, Nelson L.

AU - Rischmueller, Maureen

AU - Rohrer, Michael

AU - Segal, Barbara M.

AU - Vyse, Timothy J.

AU - Wahren-Herlenius, Marie

AU - Witte, Torsten

AU - Pons-Estel, Bernardo

AU - Alarcón-Riquelme, Marta E.

AU - Guthridge, Joel M.

AU - James, Judith A.

AU - Lessard, Christopher J.

AU - Kelly, Jennifer A.

AU - Thompson, Susan D.

AU - Gaffney, Patrick M.

AU - Montgomery, Courtney G.

AU - Edberg, Jeffrey C.

AU - Kimberly, Robert P.

AU - Alarcón, Graciela S.

AU - Langefeld, Carl L.

AU - Gilkeson, Gary S.

AU - Kamen, Diane L.

AU - Tsao, Betty P.

AU - Joseph McCune, W.

AU - Salmon, Jane E.

AU - Merrill, Joan T.

AU - Weisman, Michael H.

AU - Wallace, Daniel J.

AU - Utset, Tammy O.

AU - Bottinger, Erwin P.

AU - Amos, Christopher I.

AU - Siminovitch, Katherine A.

AU - Mariette, Xavier

AU - Sivils, Kathy L.

AU - Harley, John B.

AU - Hal Scofield, R.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Objective More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. Conclusion The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

AB - Objective More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. Conclusion The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

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U2 - 10.1002/art.39560

DO - 10.1002/art.39560

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JO - Arthritis and Rheumatology

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