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1. Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

Author

Cenit, M.C., Simeon, C.P., Vonk, M.C., Callejas-Rubio, J.L., Espinosa, G., Carreira, P., Blanco, F.J., Narvaez, J., Tolosa, C., Roman-Ivorra, J.A., Gomez-Garcia, I., Garcia-Hernandez, F.J., Gallego, M., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Garcia de la Pena, P., Lopez-Longo, F.J., Gonzalez-Gay, M.A., The Spanish Scleroderma, G., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Fonseca, C., Denton, C., Nordin, A., Palm, O., Laar, J.M. van, Hunzelmann, N., Distler, J.H., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Martin, J., Cenit, M.C., Simeon, C.P., Vonk, M.C., Callejas-Rubio, J.L., Espinosa, G., Carreira, P., Blanco, F.J., Narvaez, J., Tolosa, C., Roman-Ivorra, J.A., Gomez-Garcia, I., Garcia-Hernandez, F.J., Gallego, M., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Garcia de la Pena, P., Lopez-Longo, F.J., Gonzalez-Gay, M.A., The Spanish Scleroderma, G., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Fonseca, C., Denton, C., Nordin, A., Palm, O., Laar, J.M. van, Hunzelmann, N., Distler, J.H., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 108354.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan((R)) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.

Published
2012

2. The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis.

Author

Martin, J.E., Carmona, F.D., Broen, J.C.A., Simeon, C.P., Vonk, M.C., Carreira, P., Rios-Fernandez, R., Espinosa, G., Vicente-Rabaneda, E., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Fonollosa, V., Gonzalez-Gay, M.A., Saez-Comet, L., Portales, R.G., Pena, P.G. de la, Fernandez-Castro, M., Diaz, B., Martinez-Estupinan, L., Coenen, M.J., Voskuyl, A.E., Schuerwegh, A.J., Vanthuyne, M., Houssiau, F., Smith, V., Keyser, F. de, Langhe, E. De, Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Palm, O., Chee, M.M., Laar, J.M. van, Denton, C., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Fonseca, C., Martin, J.E., Carmona, F.D., Broen, J.C.A., Simeon, C.P., Vonk, M.C., Carreira, P., Rios-Fernandez, R., Espinosa, G., Vicente-Rabaneda, E., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Fonollosa, V., Gonzalez-Gay, M.A., Saez-Comet, L., Portales, R.G., Pena, P.G. de la, Fernandez-Castro, M., Diaz, B., Martinez-Estupinan, L., Coenen, M.J., Voskuyl, A.E., Schuerwegh, A.J., Vanthuyne, M., Houssiau, F., Smith, V., Keyser, F. de, Langhe, E. De, Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Palm, O., Chee, M.M., Laar, J.M. van, Denton, C., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Fonseca, C.

Abstract

1 februari 2012, Contains fulltext : 109760.pdf (publisher's version ) (Closed access), Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor alpha (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 x 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.

Published
2012

3. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.

Author

Bossini-Castillo, L., Martin, J.E., Broen, J., Gorlova, O., Simeon, C.P., Beretta, L., Vonk, M.C., Callejas, J.L., Castellvi, I., Carreira, P., Garcia-Hernandez, F.J., Fernandez Castro, M., Coenen, M.J.H., Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Distler, J.H., Koeleman, B.P., Voskuyl, A.E., Schuerwegh, A.J., Palm, O., Hesselstrand, R., Nordin, A., Airo, P., Lunardi, C., Scorza, R., Shiels, P., Laar, J.M. van, Herrick, A., Worthington, J., Denton, C., Tan, F.K., Arnett, F.C., Agarwal, S.K., Assassi, S., Fonseca, C., Mayes, M.D., Radstake, T.R.D.J., Martin, J., Bossini-Castillo, L., Martin, J.E., Broen, J., Gorlova, O., Simeon, C.P., Beretta, L., Vonk, M.C., Callejas, J.L., Castellvi, I., Carreira, P., Garcia-Hernandez, F.J., Fernandez Castro, M., Coenen, M.J.H., Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Distler, J.H., Koeleman, B.P., Voskuyl, A.E., Schuerwegh, A.J., Palm, O., Hesselstrand, R., Nordin, A., Airo, P., Lunardi, C., Scorza, R., Shiels, P., Laar, J.M. van, Herrick, A., Worthington, J., Denton, C., Tan, F.K., Arnett, F.C., Agarwal, S.K., Assassi, S., Fonseca, C., Mayes, M.D., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 109480.pdf (publisher's version ) (Closed access), A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 x 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 x 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(chi2) = 2.82 x 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 x 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

Published
2012

4. Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

Author

Cenit, M.C., Simeon, C.P., Vonk, M.C., Callejas-Rubio, J.L., Espinosa, G., Carreira, P., Blanco, F.J., Narvaez, J., Tolosa, C., Roman-Ivorra, J.A., Gomez-Garcia, I., Garcia-Hernandez, F.J., Gallego, M., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Garcia de la Pena, P., Lopez-Longo, F.J., Gonzalez-Gay, M.A., The Spanish Scleroderma, G., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Fonseca, C., Denton, C., Nordin, A., Palm, O., Laar, J.M. van, Hunzelmann, N., Distler, J.H., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Martin, J., Cenit, M.C., Simeon, C.P., Vonk, M.C., Callejas-Rubio, J.L., Espinosa, G., Carreira, P., Blanco, F.J., Narvaez, J., Tolosa, C., Roman-Ivorra, J.A., Gomez-Garcia, I., Garcia-Hernandez, F.J., Gallego, M., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Garcia de la Pena, P., Lopez-Longo, F.J., Gonzalez-Gay, M.A., The Spanish Scleroderma, G., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Fonseca, C., Denton, C., Nordin, A., Palm, O., Laar, J.M. van, Hunzelmann, N., Distler, J.H., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 108354.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan((R)) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.

Published
2012

5. The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis.

Author

Martin, J.E., Carmona, F.D., Broen, J.C.A., Simeon, C.P., Vonk, M.C., Carreira, P., Rios-Fernandez, R., Espinosa, G., Vicente-Rabaneda, E., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Fonollosa, V., Gonzalez-Gay, M.A., Saez-Comet, L., Portales, R.G., Pena, P.G. de la, Fernandez-Castro, M., Diaz, B., Martinez-Estupinan, L., Coenen, M.J., Voskuyl, A.E., Schuerwegh, A.J., Vanthuyne, M., Houssiau, F., Smith, V., Keyser, F. de, Langhe, E. De, Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Palm, O., Chee, M.M., Laar, J.M. van, Denton, C., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Fonseca, C., Martin, J., Martin, J.E., Carmona, F.D., Broen, J.C.A., Simeon, C.P., Vonk, M.C., Carreira, P., Rios-Fernandez, R., Espinosa, G., Vicente-Rabaneda, E., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Fonollosa, V., Gonzalez-Gay, M.A., Saez-Comet, L., Portales, R.G., Pena, P.G. de la, Fernandez-Castro, M., Diaz, B., Martinez-Estupinan, L., Coenen, M.J., Voskuyl, A.E., Schuerwegh, A.J., Vanthuyne, M., Houssiau, F., Smith, V., Keyser, F. de, Langhe, E. De, Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Palm, O., Chee, M.M., Laar, J.M. van, Denton, C., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Fonseca, C., and Martin, J.

Abstract

01 februari 2012, Contains fulltext : 109760.pdf (publisher's version ) (Closed access), Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor alpha (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 x 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.

Published
2012

6. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.

Author

Bossini-Castillo, L., Martin, J.E., Broen, J., Gorlova, O., Simeon, C.P., Beretta, L., Vonk, M.C., Callejas, J.L., Castellvi, I., Carreira, P., Garcia-Hernandez, F.J., Fernandez Castro, M., Coenen, M.J.H., Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Distler, J.H., Koeleman, B.P., Voskuyl, A.E., Schuerwegh, A.J., Palm, O., Hesselstrand, R., Nordin, A., Airo, P., Lunardi, C., Scorza, R., Shiels, P., Laar, J.M. van, Herrick, A., Worthington, J., Denton, C., Tan, F.K., Arnett, F.C., Agarwal, S.K., Assassi, S., Fonseca, C., Mayes, M.D., Radstake, T.R.D.J., Martin, J., Bossini-Castillo, L., Martin, J.E., Broen, J., Gorlova, O., Simeon, C.P., Beretta, L., Vonk, M.C., Callejas, J.L., Castellvi, I., Carreira, P., Garcia-Hernandez, F.J., Fernandez Castro, M., Coenen, M.J.H., Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Distler, J.H., Koeleman, B.P., Voskuyl, A.E., Schuerwegh, A.J., Palm, O., Hesselstrand, R., Nordin, A., Airo, P., Lunardi, C., Scorza, R., Shiels, P., Laar, J.M. van, Herrick, A., Worthington, J., Denton, C., Tan, F.K., Arnett, F.C., Agarwal, S.K., Assassi, S., Fonseca, C., Mayes, M.D., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 109480.pdf (publisher's version ) (Closed access), A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 x 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 x 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(chi2) = 2.82 x 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 x 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

Published
2012

7. Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

Author

Cenit, M.C., Simeon, C.P., Vonk, M.C., Callejas-Rubio, J.L., Espinosa, G., Carreira, P., Blanco, F.J., Narvaez, J., Tolosa, C., Roman-Ivorra, J.A., Gomez-Garcia, I., Garcia-Hernandez, F.J., Gallego, M., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Garcia de la Pena, P., Lopez-Longo, F.J., Gonzalez-Gay, M.A., The Spanish Scleroderma, G., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Fonseca, C., Denton, C., Nordin, A., Palm, O., Laar, J.M. van, Hunzelmann, N., Distler, J.H., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Martin, J., Cenit, M.C., Simeon, C.P., Vonk, M.C., Callejas-Rubio, J.L., Espinosa, G., Carreira, P., Blanco, F.J., Narvaez, J., Tolosa, C., Roman-Ivorra, J.A., Gomez-Garcia, I., Garcia-Hernandez, F.J., Gallego, M., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Garcia de la Pena, P., Lopez-Longo, F.J., Gonzalez-Gay, M.A., The Spanish Scleroderma, G., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Fonseca, C., Denton, C., Nordin, A., Palm, O., Laar, J.M. van, Hunzelmann, N., Distler, J.H., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 108354.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan((R)) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.

Published
2012

8. The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis.

Author

Martin, J.E., Carmona, F.D., Broen, J.C.A., Simeon, C.P., Vonk, M.C., Carreira, P., Rios-Fernandez, R., Espinosa, G., Vicente-Rabaneda, E., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Fonollosa, V., Gonzalez-Gay, M.A., Saez-Comet, L., Portales, R.G., Pena, P.G. de la, Fernandez-Castro, M., Diaz, B., Martinez-Estupinan, L., Coenen, M.J., Voskuyl, A.E., Schuerwegh, A.J., Vanthuyne, M., Houssiau, F., Smith, V., Keyser, F. de, Langhe, E. De, Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Palm, O., Chee, M.M., Laar, J.M. van, Denton, C., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Fonseca, C., Martin, J., Martin, J.E., Carmona, F.D., Broen, J.C.A., Simeon, C.P., Vonk, M.C., Carreira, P., Rios-Fernandez, R., Espinosa, G., Vicente-Rabaneda, E., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Fonollosa, V., Gonzalez-Gay, M.A., Saez-Comet, L., Portales, R.G., Pena, P.G. de la, Fernandez-Castro, M., Diaz, B., Martinez-Estupinan, L., Coenen, M.J., Voskuyl, A.E., Schuerwegh, A.J., Vanthuyne, M., Houssiau, F., Smith, V., Keyser, F. de, Langhe, E. De, Riemekasten, G., Witte, T.J.M. de, Hunzelmann, N., Kreuter, A., Palm, O., Chee, M.M., Laar, J.M. van, Denton, C., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Fonseca, C., and Martin, J.

Abstract

01 februari 2012, Contains fulltext : 109760.pdf (publisher's version ) (Closed access), Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor alpha (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 x 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.

Published
2012

9. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort

Author

Bossini-Castillo, L., Broen, J.C.A., Simeon, C.P., Beretta, L., Vonk, M.C., Ortego-Centeno, N., Espinosa, G., Carreira, P., Camps, M.T., Navarrete, N., Gonzalez-Escribano, M.F., Vicente-Rabaneda, E., Rodriguez, L., Tolosa, C., Roman-Ivorra, J.A., Gomez-Gracia, I., Garcia-Hernandez, F.J., Castellvi, I., Gallego, M., Fernandez-Nebro, A., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Pena, P.G. de la, Pros, A., Gonzalez-Gay, M.A., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Coenen, M.J.H., Koeleman, B.P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. De, Voskuyl, A.E., Schuerwegh, A.J., Chee, M.M., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Claes, K., Padykov, L., Nordin, A., Palm, O., Lie, B.A., Airo, P., Scorza, R., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Radstake, T.R.D.J., Martin, J., Rueda, B., Bossini-Castillo, L., Broen, J.C.A., Simeon, C.P., Beretta, L., Vonk, M.C., Ortego-Centeno, N., Espinosa, G., Carreira, P., Camps, M.T., Navarrete, N., Gonzalez-Escribano, M.F., Vicente-Rabaneda, E., Rodriguez, L., Tolosa, C., Roman-Ivorra, J.A., Gomez-Gracia, I., Garcia-Hernandez, F.J., Castellvi, I., Gallego, M., Fernandez-Nebro, A., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Pena, P.G. de la, Pros, A., Gonzalez-Gay, M.A., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Coenen, M.J.H., Koeleman, B.P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. De, Voskuyl, A.E., Schuerwegh, A.J., Chee, M.M., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Claes, K., Padykov, L., Nordin, A., Palm, O., Lie, B.A., Airo, P., Scorza, R., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Radstake, T.R.D.J., Martin, J., and Rueda, B.

Abstract

Contains fulltext : 96595.pdf (publisher's version ) (Closed access), OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

Published
2011

10. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

Author

Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C.A., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L. van, Vanthuyne, M., Slot, R. van 't, Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T.J.M. de, Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., Martin, J., Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C.A., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L. van, Vanthuyne, M., Slot, R. van 't, Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T.J.M. de, Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., and Martin, J.

Abstract

Contains fulltext : 97006.pdf (publisher's version ) (Open Access), The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Published
2011

11. Association of a non-synonymous functional variant of the ITGAM gene with systemic sclerosis

Author

Carmona, F.D., Simeon, C.P., Beretta, L., Carreira, P., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Navarrete, N., Vicente-Rabaneda, E., Rodriguez-Rodriguez, L., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Egurbide, M.V., Fonollosa, V., Gonzalez-Gay, M.A., Rodriguez-Carballeira, M., Diaz-Gonzalez, F., Saez-Comet, L., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Nordin, A., Palm, O., Hoffmann-Vold, A.M., Airo, P., Scorza, R., Lunardi, C., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Martin, J., Carmona, F.D., Simeon, C.P., Beretta, L., Carreira, P., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Navarrete, N., Vicente-Rabaneda, E., Rodriguez-Rodriguez, L., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Egurbide, M.V., Fonollosa, V., Gonzalez-Gay, M.A., Rodriguez-Carballeira, M., Diaz-Gonzalez, F., Saez-Comet, L., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Nordin, A., Palm, O., Hoffmann-Vold, A.M., Airo, P., Scorza, R., Lunardi, C., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 97656.pdf (publisher's version ) (Closed access)

Published
2011

12. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort

Author

Bossini-Castillo, L., Broen, J.C.A., Simeon, C.P., Beretta, L., Vonk, M.C., Ortego-Centeno, N., Espinosa, G., Carreira, P., Camps, M.T., Navarrete, N., Gonzalez-Escribano, M.F., Vicente-Rabaneda, E., Rodriguez, L., Tolosa, C., Roman-Ivorra, J.A., Gomez-Gracia, I., Garcia-Hernandez, F.J., Castellvi, I., Gallego, M., Fernandez-Nebro, A., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Pena, P.G. de la, Pros, A., Gonzalez-Gay, M.A., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Coenen, M.J.H., Koeleman, B.P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. De, Voskuyl, A.E., Schuerwegh, A.J., Chee, M.M., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Claes, K., Padykov, L., Nordin, A., Palm, O., Lie, B.A., Airo, P., Scorza, R., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Radstake, T.R.D.J., Martin, J., Rueda, B., Bossini-Castillo, L., Broen, J.C.A., Simeon, C.P., Beretta, L., Vonk, M.C., Ortego-Centeno, N., Espinosa, G., Carreira, P., Camps, M.T., Navarrete, N., Gonzalez-Escribano, M.F., Vicente-Rabaneda, E., Rodriguez, L., Tolosa, C., Roman-Ivorra, J.A., Gomez-Gracia, I., Garcia-Hernandez, F.J., Castellvi, I., Gallego, M., Fernandez-Nebro, A., Garcia-Portales, R., Egurbide, M.V., Fonollosa, V., Pena, P.G. de la, Pros, A., Gonzalez-Gay, M.A., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Coenen, M.J.H., Koeleman, B.P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. De, Voskuyl, A.E., Schuerwegh, A.J., Chee, M.M., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Claes, K., Padykov, L., Nordin, A., Palm, O., Lie, B.A., Airo, P., Scorza, R., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Radstake, T.R.D.J., Martin, J., and Rueda, B.

Abstract

Contains fulltext : 96595.pdf (publisher's version ) (Closed access), OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

Published
2011

13. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

Author

Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C.A., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L. van, Vanthuyne, M., Slot, R. van 't, Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T.J.M. de, Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., Martin, J., Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C.A., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L. van, Vanthuyne, M., Slot, R. van 't, Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T.J.M. de, Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., and Martin, J.

Abstract

Contains fulltext : 97006.pdf (publisher's version ) (Open Access), The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Published
2011

14. Association of a non-synonymous functional variant of the ITGAM gene with systemic sclerosis

Author

Carmona, F.D., Simeon, C.P., Beretta, L., Carreira, P., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Navarrete, N., Vicente-Rabaneda, E., Rodriguez-Rodriguez, L., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Egurbide, M.V., Fonollosa, V., Gonzalez-Gay, M.A., Rodriguez-Carballeira, M., Diaz-Gonzalez, F., Saez-Comet, L., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Nordin, A., Palm, O., Hoffmann-Vold, A.M., Airo, P., Scorza, R., Lunardi, C., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Martin, J., Carmona, F.D., Simeon, C.P., Beretta, L., Carreira, P., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Navarrete, N., Vicente-Rabaneda, E., Rodriguez-Rodriguez, L., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Egurbide, M.V., Fonollosa, V., Gonzalez-Gay, M.A., Rodriguez-Carballeira, M., Diaz-Gonzalez, F., Saez-Comet, L., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Nordin, A., Palm, O., Hoffmann-Vold, A.M., Airo, P., Scorza, R., Lunardi, C., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 97656.pdf (publisher's version ) (Closed access)

Published
2011

15. Association of a non-synonymous functional variant of the ITGAM gene with systemic sclerosis

Author

Carmona, F.D., Simeon, C.P., Beretta, L., Carreira, P., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Navarrete, N., Vicente-Rabaneda, E., Rodriguez-Rodriguez, L., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Egurbide, M.V., Fonollosa, V., Gonzalez-Gay, M.A., Rodriguez-Carballeira, M., Diaz-Gonzalez, F., Saez-Comet, L., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Nordin, A., Palm, O., Hoffmann-Vold, A.M., Airo, P., Scorza, R., Lunardi, C., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., Martin, J., Carmona, F.D., Simeon, C.P., Beretta, L., Carreira, P., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Navarrete, N., Vicente-Rabaneda, E., Rodriguez-Rodriguez, L., Tolosa, C., Garcia-Hernandez, F.J., Castellvi, I., Egurbide, M.V., Fonollosa, V., Gonzalez-Gay, M.A., Rodriguez-Carballeira, M., Diaz-Gonzalez, F., Saez-Comet, L., Hesselstrand, R., Riemekasten, G., Witte, T.J.M. de, Voskuyl, A.E., Schuerwegh, A.J., Madhok, R., Shiels, P., Fonseca, C., Denton, C., Nordin, A., Palm, O., Hoffmann-Vold, A.M., Airo, P., Scorza, R., Lunardi, C., Laar, J.M. van, Hunzelmann, N., Kreuter, A., Herrick, A., Worthington, J., Koeleman, B.P., Radstake, T.R.D.J., and Martin, J.

Abstract

Contains fulltext : 97656.pdf (publisher's version ) (Closed access)

Published
2011

16. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

Author

Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C.A., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L. van, Vanthuyne, M., Slot, R. van 't, Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T.J.M. de, Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., Martin, J., Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C.A., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L. van, Vanthuyne, M., Slot, R. van 't, Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T.J.M. de, Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., and Martin, J.

Abstract

Contains fulltext : 97006.pdf (publisher's version ) (Open Access), The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Published
2011

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