Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM

Amit K. Maiti, Xana Kim-Howard, Prasenjeet Motghare, Vandana Pradhan, Kek Heng Chua, Celi Sun, María Teresa Arango-Guerrero, Kanjaksha Ghosh, Timothy B. Niewold, John B. Harley, Juan Manual Anaya, Loren L. Looger, Swapan K. Nath

Resultado de la investigación: Contribución a RevistaArtículo

14 Citas (Scopus)

Resumen

Integrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' <'AG' <'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. © The Author 2014. Published by Oxford University Press. All rights reserved.
Idioma originalEnglish (US)
Páginas (desde-hasta)4161-4176
Número de páginas16
PublicaciónHuman Molecular Genetics
DOI
EstadoPublished - ene 1 2014

Huella dactilar

Nucleic Acids
CD11b Antigens
Alleles
Systemic Lupus Erythematosus
Proteins
Macrophage-1 Antigen
RNA
Vitronectin
Mutant Proteins
Phagocytosis
Hispanic Americans
Fibrinogen
Chromatin
Monocytes
Immune System
Membrane Proteins
Leukocytes
Transcription Factors
Odds Ratio
Genotype

Citar esto

Maiti, A. K., Kim-Howard, X., Motghare, P., Pradhan, V., Chua, K. H., Sun, C., ... Nath, S. K. (2014). Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM. Human Molecular Genetics, 4161-4176. https://doi.org/10.1093/hmg/ddu106
Maiti, Amit K. ; Kim-Howard, Xana ; Motghare, Prasenjeet ; Pradhan, Vandana ; Chua, Kek Heng ; Sun, Celi ; Arango-Guerrero, María Teresa ; Ghosh, Kanjaksha ; Niewold, Timothy B. ; Harley, John B. ; Anaya, Juan Manual ; Looger, Loren L. ; Nath, Swapan K. / Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM. En: Human Molecular Genetics. 2014 ; pp. 4161-4176.
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title = "Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM",
abstract = "Integrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' <'AG' <'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. {\circledC} The Author 2014. Published by Oxford University Press. All rights reserved.",
author = "Maiti, {Amit K.} and Xana Kim-Howard and Prasenjeet Motghare and Vandana Pradhan and Chua, {Kek Heng} and Celi Sun and Arango-Guerrero, {Mar{\'i}a Teresa} and Kanjaksha Ghosh and Niewold, {Timothy B.} and Harley, {John B.} and Anaya, {Juan Manual} and Looger, {Loren L.} and Nath, {Swapan K.}",
year = "2014",
month = "1",
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doi = "10.1093/hmg/ddu106",
language = "English (US)",
pages = "4161--4176",
journal = "Human Molecular Genetics",
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Maiti, AK, Kim-Howard, X, Motghare, P, Pradhan, V, Chua, KH, Sun, C, Arango-Guerrero, MT, Ghosh, K, Niewold, TB, Harley, JB, Anaya, JM, Looger, LL & Nath, SK 2014, 'Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM', Human Molecular Genetics, pp. 4161-4176. https://doi.org/10.1093/hmg/ddu106

Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM. / Maiti, Amit K.; Kim-Howard, Xana; Motghare, Prasenjeet; Pradhan, Vandana; Chua, Kek Heng; Sun, Celi; Arango-Guerrero, María Teresa; Ghosh, Kanjaksha; Niewold, Timothy B.; Harley, John B.; Anaya, Juan Manual; Looger, Loren L.; Nath, Swapan K.

En: Human Molecular Genetics, 01.01.2014, p. 4161-4176.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM

AU - Maiti, Amit K.

AU - Kim-Howard, Xana

AU - Motghare, Prasenjeet

AU - Pradhan, Vandana

AU - Chua, Kek Heng

AU - Sun, Celi

AU - Arango-Guerrero, María Teresa

AU - Ghosh, Kanjaksha

AU - Niewold, Timothy B.

AU - Harley, John B.

AU - Anaya, Juan Manual

AU - Looger, Loren L.

AU - Nath, Swapan K.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Integrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' <'AG' <'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. © The Author 2014. Published by Oxford University Press. All rights reserved.

AB - Integrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' <'AG' <'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. © The Author 2014. Published by Oxford University Press. All rights reserved.

U2 - 10.1093/hmg/ddu106

DO - 10.1093/hmg/ddu106

M3 - Article

SP - 4161

EP - 4176

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

ER -