Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

Travis Hughes; Adam Adler; Joan T. Merrill; Jennifer A. Kelly; Kenneth M. Kaufman; Adrienne Williams; Carl D. Langefeld; Gary S. Gilkeson; Elena Sanchez; Javier Martin; Susan A. Boackle; Anne M. Stevens; Graciela S. Alarcón; Timothy B. Niewold; Elizabeth E. Brown; Robert P. Kimberly; Jeffrey C. Edberg; Rosalind Ramsey-Goldman; Michelle Petri; John D. Reveille; Lindsey A. Criswell; Luis M. Vilá; Chaim O. Jacob; Patrick M. Gaffney; Kathy L. Moser; Timothy J. Vyse; Marta E. Alarcón-Riquelme; Judith A. James; Betty P. Tsao; R. Hal Scofield; John B. Harley; Bruce C. Richardson; Amr H. Sawalha; Johan Frostegård; Lennart Truedsson; Enrique De Ramón; José M. Sabio; María F. González-Escribano; Norberto Ortego-Centeno; José Luis Callejas; Julio Sánchez-Román; Sandra D'Alfonso; Sergio Migliarese; Gian Domenico Sebastiani; Mauro Galeazzi; Torsten Witte; Bernard R. Lauwerys; Emoke Endreffy; László Kovács; Carlos Vasconcelos; Berta Martins Da Silva

doi:10.1136/annrheumdis-2011-200385

Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

Travis Hughes, Adam Adler, Joan T. Merrill, Jennifer A. Kelly, Kenneth M. Kaufman, Adrienne Williams, Carl D. Langefeld, Gary S. Gilkeson, Elena Sanchez, Javier Martin, Susan A. Boackle, Anne M. Stevens, Graciela S. Alarcón, Timothy B. Niewold, Elizabeth E. Brown, Robert P. Kimberly, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, Michelle Petri, John D. ReveilleLindsey A. Criswell, Luis M. Vilá, Chaim O. Jacob, Patrick M. Gaffney, Kathy L. Moser, Timothy J. Vyse, Marta E. Alarcón-Riquelme, Judith A. James, Betty P. Tsao, R. Hal Scofield, John B. Harley, Bruce C. Richardson, Amr H. Sawalha, Johan Frostegård, Lennart Truedsson, Enrique De Ramón, José M. Sabio, María F. González-Escribano, Norberto Ortego-Centeno, José Luis Callejas, Julio Sánchez-Román, Sandra D'Alfonso, Sergio Migliarese, Gian Domenico Sebastiani, Mauro Galeazzi, Torsten Witte, Bernard R. Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins Da Silva

School of Medicine

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

56 Scopus citations

Abstract

Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 ^-8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Original language	English (US)
Pages (from-to)	694-699
Number of pages	6
Journal	Annals of the rheumatic diseases
Volume	71
Issue number	5
DOIs	https://doi.org/10.1136/annrheumdis-2011-200385
State	Published - May 2012

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology
Biochemistry, Genetics and Molecular Biology(all)

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10.1136/annrheumdis-2011-200385

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Hughes, T., Adler, A., Merrill, J. T., Kelly, J. A., Kaufman, K. M., Williams, A., Langefeld, C. D., Gilkeson, G. S., Sanchez, E., Martin, J., Boackle, S. A., Stevens, A. M., Alarcón, G. S., Niewold, T. B., Brown, E. E., Kimberly, R. P., Edberg, J. C., Ramsey-Goldman, R., Petri, M., ... Da Silva, B. M. (2012). Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Annals of the rheumatic diseases, 71(5), 694-699. https://doi.org/10.1136/annrheumdis-2011-200385

Hughes, T, Adler, A, Merrill, JT, Kelly, JA, Kaufman, KM, Williams, A, Langefeld, CD, Gilkeson, GS, Sanchez, E, Martin, J, Boackle, SA, Stevens, AM, Alarcón, GS, Niewold, TB, Brown, EE, Kimberly, RP, Edberg, JC, Ramsey-Goldman, R, Petri, M, Reveille, JD, Criswell, LA, Vilá, LM, Jacob, CO, Gaffney, PM, Moser, KL, Vyse, TJ, Alarcón-Riquelme, ME, James, JA, Tsao, BP, Scofield, RH, Harley, JB, Richardson, BC, Sawalha, AH, Frostegård, J, Truedsson, L, De Ramón, E, Sabio, JM, González-Escribano, MF, Ortego-Centeno, N, Callejas, JL, Sánchez-Román, J, D'Alfonso, S, Migliarese, S, Sebastiani, GD, Galeazzi, M, Witte, T, Lauwerys, BR, Endreffy, E, Kovács, L, Vasconcelos, C & Da Silva, BM 2012, 'Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus', Annals of the rheumatic diseases, vol. 71, no. 5, pp. 694-699. https://doi.org/10.1136/annrheumdis-2011-200385

@article{10d9e0d06ef942f7802304d9fa0395a1,

title = "Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus",

abstract = "Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.",

author = "Travis Hughes and Adam Adler and Merrill, {Joan T.} and Kelly, {Jennifer A.} and Kaufman, {Kenneth M.} and Adrienne Williams and Langefeld, {Carl D.} and Gilkeson, {Gary S.} and Elena Sanchez and Javier Martin and Boackle, {Susan A.} and Stevens, {Anne M.} and Alarc{\'o}n, {Graciela S.} and Niewold, {Timothy B.} and Brown, {Elizabeth E.} and Kimberly, {Robert P.} and Edberg, {Jeffrey C.} and Rosalind Ramsey-Goldman and Michelle Petri and Reveille, {John D.} and Criswell, {Lindsey A.} and Vil{\'a}, {Luis M.} and Jacob, {Chaim O.} and Gaffney, {Patrick M.} and Moser, {Kathy L.} and Vyse, {Timothy J.} and Alarc{\'o}n-Riquelme, {Marta E.} and James, {Judith A.} and Tsao, {Betty P.} and Scofield, {R. Hal} and Harley, {John B.} and Richardson, {Bruce C.} and Sawalha, {Amr H.} and Johan Frosteg{\aa}rd and Lennart Truedsson and {De Ram{\'o}n}, Enrique and Sabio, {Jos{\'e} M.} and Gonz{\'a}lez-Escribano, {Mar{\'i}a F.} and Norberto Ortego-Centeno and Callejas, {Jos{\'e} Luis} and Julio S{\'a}nchez-Rom{\'a}n and Sandra D'Alfonso and Sergio Migliarese and Sebastiani, {Gian Domenico} and Mauro Galeazzi and Torsten Witte and Lauwerys, {Bernard R.} and Emoke Endreffy and L{\'a}szl{\'o} Kov{\'a}cs and Carlos Vasconcelos and {Da Silva}, {Berta Martins}",

year = "2012",

month = may,

doi = "10.1136/annrheumdis-2011-200385",

language = "English (US)",

volume = "71",

pages = "694--699",

journal = "Annals of the rheumatic diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "5",

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TY - JOUR

T1 - Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

AU - Hughes, Travis

AU - Adler, Adam

AU - Merrill, Joan T.

AU - Kelly, Jennifer A.

AU - Kaufman, Kenneth M.

AU - Williams, Adrienne

AU - Langefeld, Carl D.

AU - Gilkeson, Gary S.

AU - Sanchez, Elena

AU - Martin, Javier

AU - Boackle, Susan A.

AU - Stevens, Anne M.

AU - Alarcón, Graciela S.

AU - Niewold, Timothy B.

AU - Brown, Elizabeth E.

AU - Kimberly, Robert P.

AU - Edberg, Jeffrey C.

AU - Ramsey-Goldman, Rosalind

AU - Petri, Michelle

AU - Reveille, John D.

AU - Criswell, Lindsey A.

AU - Vilá, Luis M.

AU - Jacob, Chaim O.

AU - Gaffney, Patrick M.

AU - Moser, Kathy L.

AU - Vyse, Timothy J.

AU - Alarcón-Riquelme, Marta E.

AU - James, Judith A.

AU - Tsao, Betty P.

AU - Scofield, R. Hal

AU - Harley, John B.

AU - Richardson, Bruce C.

AU - Sawalha, Amr H.

AU - Frostegård, Johan

AU - Truedsson, Lennart

AU - De Ramón, Enrique

AU - Sabio, José M.

AU - González-Escribano, María F.

AU - Ortego-Centeno, Norberto

AU - Callejas, José Luis

AU - Sánchez-Román, Julio

AU - D'Alfonso, Sandra

AU - Migliarese, Sergio

AU - Sebastiani, Gian Domenico

AU - Galeazzi, Mauro

AU - Witte, Torsten

AU - Lauwerys, Bernard R.

AU - Endreffy, Emoke

AU - Kovács, László

AU - Vasconcelos, Carlos

AU - Da Silva, Berta Martins

PY - 2012/5

Y1 - 2012/5

N2 - Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

AB - Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

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Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

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