{"id":262,"date":"2023-01-01T00:00:00","date_gmt":"2022-12-30T23:04:21","guid":{"rendered":"https:\/\/cushlamckinney.wordpress.com\/?p=262"},"modified":"2025-01-06T09:43:00","modified_gmt":"2025-01-05T20:43:00","slug":"262","status":"publish","type":"post","link":"https:\/\/cushla.spooky-possum.org\/wordpress\/index.php\/2023\/01\/01\/262\/","title":{"rendered":"First author\/co-author publications"},"content":{"rendered":"\n

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout<\/strong><\/h2>\n\n\n\n

McKinney C., Stamp L.K., Dalbeth N., et al. Arthritis Res. Ther<\/em>. 17<\/strong>(1):1 (2015)<\/p>\n\n\n\n

Introduction<\/strong> The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1\u03b2 (IL-1\u03b2) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1\u03b2 axis for association with gout. Methods<\/strong> 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (M\u0101ori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. Results<\/strong> Eleven SNPs were tested in the TLR2<\/em>, CD14<\/em>, IL1B<\/em>, CARD8<\/em>, NLRP3<\/em>, MYD88<\/em>, P2RX7<\/em>, DAPK1<\/em> and TNXIP<\/em> genes. Nominally significant (P<\/em>\u2009<\u20090.05) associations with gout were detected at CARD8 rs2043211<\/em> (OR\u2009=\u20091.12, P\u2009=<\/em>\u20090.007), IL1B rs1143623<\/em> (OR\u2009=\u20091.10, P<\/em>\u2009=\u20090.020) and CD14 rs2569190<\/em> (OR\u2009=\u20091.08; P<\/em>\u2009=\u20090.036).<\/em> There was significant multiplicative interaction between CARD8<\/em> and IL1B<\/em> (P<\/em>\u2009=\u20090.005), with the IL1B<\/em> risk genotype amplifying the risk effect of CARD8.<\/em> Conclusion <\/strong>There is evidence for association of gout with functional variants in CARD8, IL1B<\/em> and CD14<\/em>. The gout-associated allele of IL1B<\/em> increases expression of IL-1\u03b2 \u2013 the multiplicative interaction with CARD8<\/em> would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1\u03b2 expression leading to increased production of mature IL-1\u03b2 in gout.<\/p>\n\n\n\n

https:\/\/link.springer.com\/article\/10.1186\/s13075-015-0802-3<\/a><\/p>\n\n\n\n

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis<\/strong><\/h2>\n\n\n\n

McKinney, C<\/strong>., Broen, J., Vonk, M. et al.<\/em> Genes Immun<\/em> 13<\/strong>, 458\u2013460 (2012)<\/p>\n\n\n\n

There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B<\/em>) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B<\/em> CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B<\/em> deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B<\/em> CN and disease susceptibility. CN of \u2a7d1 was a significant risk factor for SSc (OR=1.55 (1.13\u20132.14), P<\/em>=0.007) relative to CN\u2a7e2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B<\/em> deficiency contributes to the pathology of SSc, and FCGR3B<\/em> CN variation is a common risk factor for systemic autoimmunity.<\/p>\n\n\n\n

https:\/\/doi.org\/10.1038\/gene.2012.15<\/a><\/p>\n\n\n\n

Meta-analysis confirms a role for deletion in FcgR3B in autoimmune phenotypes. <\/strong><\/h2>\n\n\n\n

McKinney, C<\/strong>., and Merriman T.R. Hum Mol. Genet<\/em>. 21<\/strong>(10):2370-2376 (2012).<\/p>\n\n\n\n

Although deletion in the low-affinity IgG receptor gene FCGR3B<\/em> has repeatedly been implicated in systemic autoimmune disease, the role of FCGR3B<\/em> copy number variation (CNV) in autoimmunity still remains unclear. Factors such as study size, ethnicity, specific disease phenotype and experimental methodology may explain these conflicting results. Here we aimed at using meta-analysis to assess the role for FCGR3B<\/em> CNV in autoimmunity. We excluded studies using SybrGreen-based genotyping and found strong evidence for association between low (<2) FCGR3B<\/em> CN and systemic lupus erythematosus [OR = 1.59 (1.32\u20131.92), P<\/em>meta<\/sub>=<\/em>9.1 \u00d7 10\u22127<\/sup>], but not for rheumatoid arthritis [OR = 1.36 (0.89\u20132.06), P<\/em>= 0.15]. However, a combined autoimmune phenotype analysis supports the deletion of FCGR3B<\/em> as a risk factor for non-organ-specific autoimmunity [OR = 1.44 (1.28\u20131.62), P<\/em>meta<\/sub>= 2.9 \u00d7 10\u22129<\/sup>]. This meta-analysis implicates the clearance of immune complex in the etiology of non-organ-specific autoimmune disease.<\/p>\n\n\n\n

https:\/\/doi.org\/10.1093\/hmg\/dds039<\/a><\/p>\n\n\n\n

Association of variation in Fc {gamma}receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples<\/strong><\/h2>\n\n\n\n

McKinney C<\/strong>., Merriman M.E., Chapman P.T., et al. Ann Rheum<\/em> Dis.<\/em> 67<\/strong>(3):109-13 (2008).<\/p>\n\n\n\n

There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1<\/em>) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by \u03b2-chemokines is a feature of autoimmunity, and that the CCR5\u039432 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1<\/em> copy-number influences susceptibility to RA and type 1 diabetes (T1D). Methods<\/strong> We measured CCL3L1<\/em> copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. Results<\/strong> A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08\u20131.66, p\u200a=\u200a0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75\u20131.60, p\u200a=\u200a0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98\u20132.20, p\u200a=\u200a0.064) and in the combined RA\/T1D cohort (OR 1.30, 95% CI 1.00\u20131.54, p\u200a=\u200a0.003). Genetic interaction between CCL3L1<\/em> dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1<\/em> copy-number was ablated by a dysfunctional CCR5<\/em> (CCR5<\/em>\u039432<\/em>). Conclusion<\/strong> These data suggest that increased CCL3L1<\/em> expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5<\/em>\u039432<\/em> protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.<\/p>\n\n\n\n

http:\/\/dx.doi.org\/10.1136\/ard.2007.075028<\/a><\/p>\n\n\n\n

The human genome and understanding of common disease:present and future technologies<\/strong><\/h2>\n\n\n\n

McKinney C<\/strong>., and Merriman T.R. Cell. Mol. Life Sci.<\/em> 64<\/strong>:961-78 (2007)<\/a>.<\/p>\n\n\n\n

The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate power and insufficient information on genetic variation in candidate genes. The unavailability of high throughput and low-cost genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual\u2019s disease still remains a challenge.<\/p>\n\n\n\n

https:\/\/doi.org\/10.1007\/s00018-007-6405-7<\/a><\/p>\n\n\n\n

An update on the genetic causes of hyperuricaeia and gout<\/strong><\/h2>\n\n\n\n

Merriman T.R., and McKinney C<\/strong>. In Gout (pp. 54-69) N. Dalbeth, F. Perez-Ruiz, & N Schlesinger (Eds.). London, UK: Future Medicine (2013).<\/p>\n\n\n\n

Gout results from an innate immune reaction to monosodium urate crystals deposited in the joints of individuals with elevated serum urate levels (hyperuricaemia). Urate, the primary cause of gout, is a metabolite with beneficial properties. The use of genome\u2010wide association scanning has identified 28 loci that control serum urate levels. Predominant among these are loci containing uric acid transporter genes involved in renal and gut excretion of uric acid. The SLC2A9 (GLUT9) and ABCG2 genes have particularly strong effects on serum urate and risk of gout. In contrast to serum urate, the genetic control of inflammatory gout is very poorly understood, largely because no genome\u2010wide association scan has been conducted using clinically ascertained gout cases<\/p>\n\n\n\n

https:\/\/doi.org\/10.2217\/ebo.12.256<\/a><\/p>\n\n\n\n

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