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Fine mapping and co...
Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein
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- Delgado-Vega, Angélica M. (author)
- Uppsala universitet,Genomik
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Dozmorov, Mikhail G. (author)
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Bernal Quiros, Manuel (author)
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Wu, Ying-Yu (author)
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Martinez-Garcia, Belen (author)
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- Kozyrev, Sergey V. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Frostegård, Johan (author)
- Karolinska Institutet
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- Truedsson, Lennart (author)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine
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de Ramon, Enrique (author)
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Gonzalez-Escribano, Maria F. (author)
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Ortego-Centeno, Norberto (author)
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Pons-Estel, Bernardo A. (author)
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D'Alfonso, Sandra (author)
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Sebastiani, Gian Domenico (author)
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Witte, Torsten (author)
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Lauwerys, Bernard R. (author)
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Endreffy, Emoke (author)
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Kovacs, Laszlo (author)
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Vasconcelos, Carlos (author)
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da Silva, Berta Martins (author)
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Wren, Jonathan D. (author)
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Martin, Javier (author)
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Castillejo-Lopez, Casimiro (author)
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Alarcon-Riquelme, Marta E. (author)
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(creator_code:org_t)
- 2012-06-13
- 2012
- English.
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:7, s. 1219-1226
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https://ard.bmj.com/...
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http://dx.doi.org/10...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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http://kipublication...
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Abstract
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- ObjectivesTo perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE).MethodsGenotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor. B (NFkB) binding.ResultsFine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NF kappa B-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR = 2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life.ConclusionsThese results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Delgado-Vega, An ...
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Dozmorov, Mikhai ...
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Bernal Quiros, M ...
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Wu, Ying-Yu
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Martinez-Garcia, ...
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Kozyrev, Sergey ...
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show more...
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Frostegård, Joha ...
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Truedsson, Lenna ...
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de Ramon, Enriqu ...
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Gonzalez-Escriba ...
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Ortego-Centeno, ...
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Pons-Estel, Bern ...
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D'Alfonso, Sandr ...
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Sebastiani, Gian ...
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Witte, Torsten
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Lauwerys, Bernar ...
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Endreffy, Emoke
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Kovacs, Laszlo
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Vasconcelos, Car ...
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da Silva, Berta ...
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Wren, Jonathan D ...
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Martin, Javier
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Castillejo-Lopez ...
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Alarcon-Riquelme ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
- Articles in the publication
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Annals of the Rh ...
- By the university
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Uppsala University
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Lund University
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Karolinska Institutet