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ABSTRACT: To evaluate FCGR3B copy number variation (CNV) in African and European populations and to determine if FCGR3B copy number is associated with SLE and SLE nephritis risk in Afro-Caribbeans, adjusting for African genetic ancestry.
We estimated FCGR3B to determine if there were ethnic variations in CNV (unrelated unadmixed Europeans and Africans). We then examined CNV at FCGR3B in relation to SLE and SLE nephritis within a case-control collection of 134 cases of SLE (37 with SLE nephritis) and 589 population controls of mainly Afro-Caribbean descent resident in Trinidad.
We found a significant difference in copy number FCGR3B distribution between unadmixed African and European UK cohorts, with 27 (29%) vs 3 (5%) for those with low (0 or 1) copy FCGR3B, respectively, P = 0.002. In a Trinidadian SLE case-control study, low FCGR3B CNV was associated with SLE risk 1.7 (95% CI 1.1, 2.8), P = 0.02, which remained after adjustment for African genetic ancestry; odds ratios (ORs) 1.7 (95% CI 1.0, 2.8), P = 0.04.
Our studies suggest that FCGR3B low copy number is associated with SLE risk in Afro-Caribbean populations independently of CNV due to African ancestry.
Rheumatology (Oxford, England) 02/2011; 50(7):1206-10. · 4.24 Impact Factor
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ABSTRACT: Brachydactyly type A2 (BDA2) is an autosomal dominant disorder. It was recently reported that a 5.9 kb duplication and a 5.5 kb duplication in the region 20p12.2-12.3 are associated with BDA2 in two European families.
To characterise a 6-generation Chinese family with 16 members affected by BDA2 and map the gene to 20p12.2-12.3.
A 4.6 kb duplication downstream of the bone morphogenetic protein 2 (BMP2) was identified in the family. The duplication co-segregated with the phenotype and was absent in unaffected family members and control subjects. Coding and splice-site mutations of all annotated genes in the critical region were also excluded. The duplication partially overlaps with the reported duplications but has a different breakpoint. The most conserved 2.1 kb fragment in the duplication was cloned into the pGL3-promoter vector downstream of the firefly luciferase reporter gene in the 5' to 3' orientation and transfected into osteosarcoma U-2OS and Hela cells. A reduced luciferase activity was observed.
The smallest duplication is described, which partially overlaps the reported duplications but has a different breakpoint, and its association with BDA2 in a Chinese family is confirmed. The results also provide evidence for cis-regulatory sequences in the duplication 3' of BMP2.
Journal of Medical Genetics 02/2011; 48(5):312-6. · 6.36 Impact Factor
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Cushla McKinney,
Manuela Fanciulli,
Marilyn E Merriman,
Amanda Phipps-Green,
Behrooz Z Alizadeh,
Bobby P C Koeleman,
Nicola Dalbeth,
Peter J Gow,
Andrew A Harrison,
John Highton, [......],
Lisa K Stamp,
Sophia Steer,
Pilar Barrera,
Marieke J H Coenen,
Barbara Franke,
Piet L C M van Riel, Tim J Vyse,
Tim J Aitman,
Timothy R D J Radstake,
Tony R Merriman
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ABSTRACT: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA.
FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry.
Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4).
One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required.
Annals of the rheumatic diseases 09/2010; 69(9):1711-6. · 8.11 Impact Factor
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Rheumatology (Oxford, England) 09/2009; 48(12):1616-8. · 4.24 Impact Factor
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Ru Li,
Chao Xue,
Caixia Li,
Tanqi Lou,
Yu Tao,
Youji Li,
Weijun Huang,
Jun Zhang,
Joseph C K Leung,
Man F Lam, Tim J Vyse,
Kar N Lai,
Changyou Wu,
Yiming Wang
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ABSTRACT: The T cell receptor alpha constant gene (TRAC) encodes the constant region of the alpha chain for the T cell receptor, and the association of its gene variants with IgA nephropathy remains controversial. The authors resequenced the gene in 100 patients with IgA nephropathy and 100 controls, tested its linkage disequilibrium pattern, constructed haplotypes, and performed association and functional studies. First, the association between TRAC variants and IgA nephropathy was tested in 704 patients and 704 controls. Next, these 704 patients were divided into two independent datasets--310 with family member(s) and 394 single patients--to test the association separately. Results showed that the gene is located in a recombination hot spot, with nine linkage disequilibrium blocks within a 6.9-kb region. There is a hypervariable region with six single-nucleotide polymorphisms (SNPs) in an 85-bp stretch in intron 1. We identified multiple SNPs and two haplotypes that associate with IgA nephropathy (P = 0.0000013-0.0096 by logistic regression for SNPs; P = 0.0003 and P = 0.0398 for haplotype associations). The family-based study replicated both haplotype findings, and the 394 single-patient case-control study replicated the association with haplotype 1 (P = 0.0033). The overtransmitted/observed haplotypes demonstrated reduced transcription activity compared with the undertransmitted/observed haplotypes. In conclusion, this study suggests an association between TRAC variants and susceptibility to IgA nephropathy.
Journal of the American Society of Nephrology 07/2009; 20(6):1359-67. · 9.66 Impact Factor
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Benjamin Rhodes,
David L Morris,
Lakshman Subrahmanyan,
Cristin Aubin,
Carlos F Mendes de Leon,
Jeremiah F Kelly,
Dennis A Evans,
John C Whittaker,
Jorge R Oksenberg,
Philip L De Jager, Tim J Vyse
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ABSTRACT: Basal levels of C-reactive protein (CRP) have been associated with disease, particularly future cardiovascular events. Twin studies estimate 50% CRP heritability, so the identification of genetic variants influencing CRP expression is important. Existing studies in populations of European ancestry have identified numerous cis-acting variants but leave significant ambiguity over the identity of the key functional polymorphisms. We addressed this issue by typing a dense map of CRP single-nucleotide polymorphisms (SNPs), and quantifying serum CRP in 594 unrelated African Americans. We used Bayesian model choice analysis to select the combination of SNPs best explaining basal CRP and found strong support for triallelic rs3091244 alone, with the T allele acting in an additive manner (Bayes factor > 100 vs. null model), with additional support for a model incorporating both rs3091244 and rs12728740. Admixture analysis suggested SNP rs12728740 segregated with haplotypes predicted to be of recent European origin. Using a cladistic approach we confirmed the importance of rs3091244(T) by demonstrating a significant partition of haplotype effect based on the rs3091244(C/T) mutation (F = 8.91, P = 0.006). We argue that weaker linkage disequilibrium across the African American CRP locus compared with Europeans has allowed us to establish an unambiguous functional role for rs3091244(T), while also recognising the potential for additional functional mutations present in the European genome.
Human Genetics 07/2008; 123(6):633-42. · 5.07 Impact Factor
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Tim J Vyse
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ABSTRACT: In this issue of Immunity, the Coronin-1A gene Coro1a, which regulates cytoskeletal structure, is shown by Haraldsson et al. (2007) to be a surprising disease-susceptibility gene that contributes to the spontaneous systemic autoimmunity in the MRL mouse, a model of systemic lupus erythematosus.
Immunity 02/2008; 28(1):8-10. · 21.64 Impact Factor
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ABSTRACT: Results from two studies have implicated the interferon regulatory gene IRF5 as a susceptibility gene in systemic lupus erythematosus (SLE). In this study, we conducted a family-based association analysis in 380 UK SLE nuclear families. Using a higher density of markers than has hitherto been screened, we show that there is association with two SNPs in the first intron, rs2004640 (P = 3.4 x 10(-4)) and rs3807306 (P = 4.9 x 10(-4)), and the association extends into the 3'-untranslated region (UTR). There is a single haplotype block encompassing IRF5 and we show for the first time that the gene comprises two over-transmitted haplotypes and a single under-transmitted haplotype. The strongest association is with a TCTAACT haplotype (T:U = 1.92, P = 5.8 x 10(-5)), which carries all the over-transmitted alleles from this study. Haplotypes carrying the T alleles of rs2004640 and rs2280714 and the A allele of rs10954213 are over-transmitted in SLE families. The TAT haplotype shows a dose-dependent relationship with mRNA expression. A differential expression pattern was seen between two expression probes located each side of rs10954213 in the 3'-UTR. rs10954213 shows the strongest association with RNA expression levels (P = 1 x 10(-14)). The A allele of rs10954213 creates a functional polyadenylation site and the A genotype correlates with increased expression of a transcript variant containing a shorter 3'-UTR. Expression levels of transcript variants with the shorter or longer 3'-UTRs are inversely correlated. Our data support a new mechanism by which an IRF5 polymorphism controls the expression of alternate transcript variants which may have different effects on interferon signalling.
Human Molecular Genetics 04/2007; 16(6):579-91. · 7.64 Impact Factor
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Paul I W de Bakker,
Gil McVean,
Pardis C Sabeti,
Marcos M Miretti,
Todd Green,
Jonathan Marchini,
Xiayi Ke,
Alienke J Monsuur,
Pamela Whittaker,
Marcos Delgado, [......],
Mark J Daly,
John Trowsdale,
Cisca Wijmenga, Tim J Vyse,
Stephan Beck,
Sarah Shaw Murray,
Mary Carrington,
Simon Gregory,
Panos Deloukas,
John D Rioux
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ABSTRACT: The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.
Nature Genetics 11/2006; 38(10):1166-72. · 35.53 Impact Factor
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ABSTRACT: Autoantibodies produced by differentiated B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). The Toll-like receptor 9 (TLR-9) gene has recently emerged as an important costimulatory molecule for both B cells and dendritic cells that respond to chromatin immune complexes. Genetic variation affecting the function of TLR-9 may therefore increase or decrease the threshold of B cell or dendritic cell activation. This variability in activation threshold may, in turn, affect an individual's susceptibility to SLE. This study assessed the role of genetic variation within the TLR-9 gene in susceptibility to SLE.
We genotyped 362 SLE-affected subject/parent trios for 10 single-nucleotide polymorphisms (SNPs) covering a 68,742-bp genomic segment that contains the TLR-9 gene and approximately 60 kb of flanking sequence. We analyzed the data using the transmission disequilibrium test.
There was no association of susceptibility to SLE with any of the 9 SNPs that generated usable data or the 8 haplotypes found at a frequency of >0.05 in this population. When analyzing the subset of 143 subjects with lupus nephritis, there was also no evidence of association between disease susceptibility and any SNP or haplotype.
These results indicate that there is no evidence that common (frequency higher than 5%) alleles of the TLR-9 gene contribute significantly to the genetic risk involved in susceptibility to SLE or lupus nephritis.
Arthritis & Rheumatism 05/2006; 54(4):1279-82. · 7.87 Impact Factor
