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1.  Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus 
Nature genetics  2015;47(12):1457-1464.
Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including 10 novel associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n=16) of transcription factors among SLE susceptibility genes. This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.
PMCID: PMC4668589  PMID: 26502338
2.  Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome 
Nature genetics  2013;45(11):10.1038/ng.2792.
Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.
PMCID: PMC3867192  PMID: 24097067
3.  CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B cell signaling and activation 
Nature genetics  2012;44(11):1227-1230.
C-src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of Csk with systemic lupus erythematosus (SLE) and refined its location to an intronic polymorphism rs34933034 (OR 1.32, p = 1.04 × 10−9). The risk allele is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, B cell receptor (BCR)-mediated activation of mature B cells, as well as plasma IgM, are increased. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele compared to non-risk haplotypes due to an expansion of the late transitional cells, a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points of B cells.
PMCID: PMC3715052  PMID: 23042117
4.  Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation 
Human molecular genetics  2006;16(6):579-591.
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 × 10−4) and rs3807306 (P = 4.9 × 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 × 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 × 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.
PMCID: PMC3706933  PMID: 17189288
5.  Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus 
Human molecular genetics  2003;13(1):137-147.
Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk.
PMCID: PMC3707088  PMID: 14645206
6.  Genetic Analyses of Interferon Pathway-Related Genes Reveals Multiple New Loci Associated with Systemic Lupus Erythematosus (SLE) 
Arthritis and rheumatism  2011;63(7):2049-2057.
The overexpression of interferon (IFN)-inducible genes is a prominent feature of SLE, serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. The genetic variations responsible for sustained activation of IFN responsive genes are unknown.
We systematically evaluated association of SLE with a total of 1,754 IFN-pathway related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We performed a three-stage design where two cohorts (total n=939 SLE cases, 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons.
A total of 16,137 SNPs passed all quality control filters of which 316 demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including the transmembrane receptor CD44 (rs507230, P = 3.98×10−12), cytokine pleiotrophin (PTN) (rs919581, P = 5.38×10−04), the heat-shock DNAJA1 (rs10971259, P = 6.31×10−03), and the nuclear import protein karyopherin alpha 1 (KPNA1) (rs6810306, P = 4.91×10−02).
This study expands the number of candidate genes associated with SLE and highlights the potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.
PMCID: PMC3128183  PMID: 21437871
7.  Genetic Variants Near TNFAIP3 on 6q23 are Associated with Systemic Lupus Erythematosus (SLE) 
Nature genetics  2008;40(9):1059-1061.
SLE is an autoimmune disease influenced by genetic and environmental components. We performed a genome-wide association scan (GWAS) and observed novel association evidence with a variant inTNFAIP3(rs5029939, P = 2.89×10−12, OR = 2.29). We also found evidence of two independent signals of association to SLE risk, including one described in Rheumatoid Arthritis. These results establish that genetic variation inTNFAIP3contributes to differential risk for SLE and RA.
PMCID: PMC2772171  PMID: 19165918
8.  FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity 
Nature genetics  2007;39(6):721-723.
Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 × 10-8), microscopic polyangiitis (P = 2.9 × 10-4) and Wegener’s granulomatosis in two independent cohorts from the UK (P = 3 × 10-3) and France (P = 1.1 × 10-4). We did not observe this association in the organ-specific Graves’ disease or Addison’s disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity.
PMCID: PMC2742197  PMID: 17529978

Results 1-8 (8)