X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased 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 Kumar; Jacen 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 Alarcon-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

doi:10.1002/art.39560

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased 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 Alarcon-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

Immunology and Immunotherapy

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

63 Citations (Scopus)

Abstract

OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.

METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).

RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.

CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.

Original language	English
Journal	Arthritis & Rheumatology (Hoboken)
Early online date	29 Dec 2015
DOIs	https://doi.org/10.1002/art.39560
Publication status	Published - May 2016

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Liu, K., Kurien, B. T., Zimmerman, S. L., Kaufman, K. M., Taft, D. H., Kottyan, L. C., Lazaro, S., Weaver, C. A., Ice, J. A., Adler, A. J., Chodosh, J., Radfar, L., Rasmussen, A., Stone, D. U., Lewis, D. M., Li, S., Koelsch, K. A., Igoe, A., Talsania, M., ... Scofield, R. H. (2016). X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis & Rheumatology (Hoboken). https://doi.org/10.1002/art.39560

@article{b399ec2ff8ad482db4e7129d35576923,

title = "X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased 47,XXX in Systemic Lupus Erythematosus and Sj{\"o}gren's Syndrome",

abstract = "OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sj{\"o}gren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.",

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 Jacques-Eric Gottenberg and Juan-Manuel Anaya 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 Wan-Fai Ng 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 Alarcon-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 McCune, {W Joseph} 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 Scofield, {R Hal}",

note = "{\textcopyright} 2015, American College of Rheumatology.",

year = "2016",

month = may,

doi = "10.1002/art.39560",

language = "English",

journal = "Arthritis & Rheumatology (Hoboken)",

issn = "2326-5191",

publisher = "Wiley",

}

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, J-E, Anaya, J-M, Cunninghame-Graham, DS, Huang, AJW, Brennan, MT, Hughes, P, Illei, GG, Miceli-Richard, C, Keystone, EC, Bykerk, VP, Hirschfield, G, Xie, G, Ng, W-F, Nordmark, G, Eriksson, P, Omdal, R, Rhodus, NL, Rischmueller, M, Rohrer, M, Segal, BM, Vyse, TJ, Wahren-Herlenius, M, Witte, T, Pons-Estel, B, Alarcon-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, McCune, WJ, Salmon, JE, Merrill, JT, Weisman, MH, Wallace, DJ, Utset, TO, Bottinger, EP, Amos, CI, Siminovitch, KA, Mariette, X, Sivils, KL, Harley, JB & Scofield, RH 2016, 'X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome', Arthritis & Rheumatology (Hoboken). https://doi.org/10.1002/art.39560

TY - JOUR

T1 - X Chromosome Dose and Sex Bias in Autoimmune Diseases

T2 - Increased 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 - Alarcon-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 - McCune, W Joseph

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 - Scofield, R Hal

PY - 2016/5

Y1 - 2016/5

N2 - OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.

AB - OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.

U2 - 10.1002/art.39560

DO - 10.1002/art.39560

M3 - Article

C2 - 26713507

JO - Arthritis & Rheumatology (Hoboken)

JF - Arthritis & Rheumatology (Hoboken)

SN - 2326-5191

ER -

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

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