Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort

B. Namjou, P. H. Kothari, J. A. Kelly, S. B. Glenn, J. O. Ojwang, A. Adler, M. E. Alarcón-Riquelme, C. J. Gallant, S. A. Boackle, L. A. Criswell, R. P. Kimberly, E. Brown, J. Edberg, A. M. Stevens, C. O. Jacob, B. P. Tsao, G. S. Gilkeson, D. L. Kamen, J. T. Merrill, M. Petri & 20 otros R. R. Goldman, L. M. Vila, J. M. Anaya, T. B. Niewold, J. Martin, B. A. Pons-Estel, J. M. Sabio, J. L. Callejas, T. J. Vyse, S. C. Bae, F. W. Perrino, B. I. Freedman, R. H. Scofield, K. L. Moser, P. M. Gaffney, J. A. James, C. D. Langefeld, K. M. Kaufman, J. B. Harley, J. P. Atkinson

Resultado de la investigación: Contribución a RevistaArtículo

150 Citas (Scopus)

Resumen

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3′-5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi- Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in 8370 patients with SLE and 7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P0.0008, OR1.73, 95% CI1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P2.99E13, OR5.2, 95% CI3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis. © 2011 Macmillan Publishers Limited All rights reserved.
Idioma originalEnglish (US)
Páginas (desde-hasta)270-279
Número de páginas10
PublicaciónGenes and Immunity
DOI
EstadoPublished - jun 1 2011

Huella dactilar

Systemic Lupus Erythematosus
Mutation
Genes
Mutation Rate
Single Nucleotide Polymorphism
Exonucleases
Brain Diseases
Neurologic Manifestations
Gene Frequency
Quality Control
Autoantibodies
Haplotypes
Population
Seizures
Odds Ratio
Genotype
Confidence Intervals
Pediatrics

Citar esto

Namjou, B., Kothari, P. H., Kelly, J. A., Glenn, S. B., Ojwang, J. O., Adler, A., ... Atkinson, J. P. (2011). Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes and Immunity, 270-279. https://doi.org/10.1038/gene.2010.73
Namjou, B. ; Kothari, P. H. ; Kelly, J. A. ; Glenn, S. B. ; Ojwang, J. O. ; Adler, A. ; Alarcón-Riquelme, M. E. ; Gallant, C. J. ; Boackle, S. A. ; Criswell, L. A. ; Kimberly, R. P. ; Brown, E. ; Edberg, J. ; Stevens, A. M. ; Jacob, C. O. ; Tsao, B. P. ; Gilkeson, G. S. ; Kamen, D. L. ; Merrill, J. T. ; Petri, M. ; Goldman, R. R. ; Vila, L. M. ; Anaya, J. M. ; Niewold, T. B. ; Martin, J. ; Pons-Estel, B. A. ; Sabio, J. M. ; Callejas, J. L. ; Vyse, T. J. ; Bae, S. C. ; Perrino, F. W. ; Freedman, B. I. ; Scofield, R. H. ; Moser, K. L. ; Gaffney, P. M. ; James, J. A. ; Langefeld, C. D. ; Kaufman, K. M. ; Harley, J. B. ; Atkinson, J. P. / Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. En: Genes and Immunity. 2011 ; pp. 270-279.
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title = "Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort",
abstract = "Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3′-5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi- Gouti{\`e}res syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in 8370 patients with SLE and 7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95{\%} confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5{\%}. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)10{\%}) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58{\%} in lupus cases compared with 45{\%} in normal controls (P0.0008, OR1.73, 95{\%} CI1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P2.99E13, OR5.2, 95{\%} CI3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis. {\circledC} 2011 Macmillan Publishers Limited All rights reserved.",
author = "B. Namjou and Kothari, {P. H.} and Kelly, {J. A.} and Glenn, {S. B.} and Ojwang, {J. O.} and A. Adler and Alarc{\'o}n-Riquelme, {M. E.} and Gallant, {C. J.} and Boackle, {S. A.} and Criswell, {L. A.} and Kimberly, {R. P.} and E. Brown and J. Edberg and Stevens, {A. M.} and Jacob, {C. O.} and Tsao, {B. P.} and Gilkeson, {G. S.} and Kamen, {D. L.} and Merrill, {J. T.} and M. Petri and Goldman, {R. R.} and Vila, {L. M.} and Anaya, {J. M.} and Niewold, {T. B.} and J. Martin and Pons-Estel, {B. A.} and Sabio, {J. M.} and Callejas, {J. L.} and Vyse, {T. J.} and Bae, {S. C.} and Perrino, {F. W.} and Freedman, {B. I.} and Scofield, {R. H.} and Moser, {K. L.} and Gaffney, {P. M.} and James, {J. A.} and Langefeld, {C. D.} and Kaufman, {K. M.} and Harley, {J. B.} and Atkinson, {J. P.}",
year = "2011",
month = "6",
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doi = "10.1038/gene.2010.73",
language = "English (US)",
pages = "270--279",
journal = "Genes and Immunity",
issn = "1466-4879",
publisher = "Nature Publishing Group",

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Namjou, B, Kothari, PH, Kelly, JA, Glenn, SB, Ojwang, JO, Adler, A, Alarcón-Riquelme, ME, Gallant, CJ, Boackle, SA, Criswell, LA, Kimberly, RP, Brown, E, Edberg, J, Stevens, AM, Jacob, CO, Tsao, BP, Gilkeson, GS, Kamen, DL, Merrill, JT, Petri, M, Goldman, RR, Vila, LM, Anaya, JM, Niewold, TB, Martin, J, Pons-Estel, BA, Sabio, JM, Callejas, JL, Vyse, TJ, Bae, SC, Perrino, FW, Freedman, BI, Scofield, RH, Moser, KL, Gaffney, PM, James, JA, Langefeld, CD, Kaufman, KM, Harley, JB & Atkinson, JP 2011, 'Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort', Genes and Immunity, pp. 270-279. https://doi.org/10.1038/gene.2010.73

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. / Namjou, B.; Kothari, P. H.; Kelly, J. A.; Glenn, S. B.; Ojwang, J. O.; Adler, A.; Alarcón-Riquelme, M. E.; Gallant, C. J.; Boackle, S. A.; Criswell, L. A.; Kimberly, R. P.; Brown, E.; Edberg, J.; Stevens, A. M.; Jacob, C. O.; Tsao, B. P.; Gilkeson, G. S.; Kamen, D. L.; Merrill, J. T.; Petri, M.; Goldman, R. R.; Vila, L. M.; Anaya, J. M.; Niewold, T. B.; Martin, J.; Pons-Estel, B. A.; Sabio, J. M.; Callejas, J. L.; Vyse, T. J.; Bae, S. C.; Perrino, F. W.; Freedman, B. I.; Scofield, R. H.; Moser, K. L.; Gaffney, P. M.; James, J. A.; Langefeld, C. D.; Kaufman, K. M.; Harley, J. B.; Atkinson, J. P.

En: Genes and Immunity, 01.06.2011, p. 270-279.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort

AU - Namjou, B.

AU - Kothari, P. H.

AU - Kelly, J. A.

AU - Glenn, S. B.

AU - Ojwang, J. O.

AU - Adler, A.

AU - Alarcón-Riquelme, M. E.

AU - Gallant, C. J.

AU - Boackle, S. A.

AU - Criswell, L. A.

AU - Kimberly, R. P.

AU - Brown, E.

AU - Edberg, J.

AU - Stevens, A. M.

AU - Jacob, C. O.

AU - Tsao, B. P.

AU - Gilkeson, G. S.

AU - Kamen, D. L.

AU - Merrill, J. T.

AU - Petri, M.

AU - Goldman, R. R.

AU - Vila, L. M.

AU - Anaya, J. M.

AU - Niewold, T. B.

AU - Martin, J.

AU - Pons-Estel, B. A.

AU - Sabio, J. M.

AU - Callejas, J. L.

AU - Vyse, T. J.

AU - Bae, S. C.

AU - Perrino, F. W.

AU - Freedman, B. I.

AU - Scofield, R. H.

AU - Moser, K. L.

AU - Gaffney, P. M.

AU - James, J. A.

AU - Langefeld, C. D.

AU - Kaufman, K. M.

AU - Harley, J. B.

AU - Atkinson, J. P.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3′-5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi- Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in 8370 patients with SLE and 7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P0.0008, OR1.73, 95% CI1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P2.99E13, OR5.2, 95% CI3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis. © 2011 Macmillan Publishers Limited All rights reserved.

AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3′-5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi- Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in 8370 patients with SLE and 7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P0.0008, OR1.73, 95% CI1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P2.99E13, OR5.2, 95% CI3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis. © 2011 Macmillan Publishers Limited All rights reserved.

U2 - 10.1038/gene.2010.73

DO - 10.1038/gene.2010.73

M3 - Article

SP - 270

EP - 279

JO - Genes and Immunity

JF - Genes and Immunity

SN - 1466-4879

ER -

Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A y otros. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes and Immunity. 2011 jun 1;270-279. https://doi.org/10.1038/gene.2010.73