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- Strawbridge, Rona J., et al.
(author)
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Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
- 2017
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In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 266, s. 196-204
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Journal article (peer-reviewed)abstract
- Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
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| 3. |
- Tan, Lionel K.K., et al.
(author)
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Vaccine-induced, but not natural immunity, against the Streptococcal inhibitor of complement protects against invasive disease
- 2021
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In: npj Vaccines. - : Springer Science and Business Media LLC. - 2059-0105. ; 6
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Journal article (peer-reviewed)abstract
- Highly pathogenic emm1 Streptococcus pyogenes strains secrete the multidomain Streptococcal inhibitor of complement (SIC) that binds and inactivates components of the innate immune response. We aimed to determine if naturally occurring or vaccine-induced antibodies to SIC are protective against invasive S. pyogenes infection. Immunisation with full-length SIC protected mice against systemic bacterial dissemination following intranasal or intramuscular infection with emm1 S. pyogenes. Vaccine-induced rabbit anti-SIC antibodies, but not naturally occurring human anti-SIC antibodies, enhanced bacterial clearance in an ex vivo whole-blood assay. SIC vaccination of both mice and rabbits resulted in antibody recognition of all domains of SIC, whereas naturally occurring human anti-SIC antibodies recognised the proline-rich region of SIC only. We, therefore, propose a model whereby natural infection with S. pyogenes generates non-protective antibodies against the proline-rich region of SIC, while vaccination with full-length SIC permits the development of protective antibodies against all SIC domains.
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| 4. |
- Wanhainen, Anders, et al.
(author)
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Immune-response against Streptococcus pyogenes in the development of abdominal aortic aneurysm - A population-based case-control study
- 2008
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In: Vasa: European Journal of Vascular Medicine. - : Hogrefe Publishing Group. - 0301-1526 .- 1664-2872. ; 37:2, s. 143-149
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Journal article (peer-reviewed)abstract
- Background: In a population -based case-control study the association between antibodies to Streptococcus pyogenes antigens and the development of abdominal aortic aneurysm (AAA) was analysed. Patients and methods: Forty-two patients with screening-detected AAA were compared to 100 age- and sex matched controls with normal aortas. Antibodies against three recently characterized cell wall-attached proteins of S. pyogenes (SclA, ScIB and GRAB) were analysed in plasma samples obtained at screening (current), and in samples obtained from a study conducted 12 years previously on the same population (historical). Results: Historical antibody levels against the S. pyogenes antigen GRAB were significantly higher in AAA patients compared with controls (0.25 vs 0.17, p = 0.021). A similar trend was observed in current GRAB antibody levels (0.23 vs 0. 17, p = 0.072). GRAB-antibody levels at age 60 years retained the association with AAA in a logistic regression model after adjustment for a history of atherosclerosis (OR 20.2, p = 0.022), current smoking (OR 21.4, p = 0.025) and family history of AAA (OR 12.9, p = 0.053). Current and historical antibody levels against ScIA and SclB in AAA patients were similar to those in controls. Conclusions: The results indicate that the immune response against S. pyogenes protein GRAB may be involved in the pathogenesis of AAA.
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