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- Moreno Velásquez, Ilais
(författare)
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The association of inflammatory biomarkers with cardiovascular events : a long and winding path
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims: The overall aim of this thesis was to investigate the association of inflammatory biomarkers with cardiovascular disease (CVD) with the final scope to identify potential novel predictors of incident cardiovascular events (CVE). The specific objectives were: to study the association between levels of IL8 and the genetic variants at the IL8 and IL8 receptor genes with the occurrence of myocardial infarction (MI) and to explore if these genetic variants regulate IL8 levels (Study 1); to identify novel genetic variants associated with IL8 levels (Study II); to study the association of IL8 levels with the risk of CVE (Study III) and, finally, to investigate the association between the levels of soluble IL6 receptors (sIL6R and sgp130) with the occurrence of MI (Study IV). Materials and Methods: Study I, II and IV were based on the Stockholm Heart Epidemiology Program (SHEEP), a population-based case-control study of incident MI performed between 1992 and 1994 at the ten emergency hospitals within the county of Stockholm. Controls were randomly selected from the study base, using density sampling and matching for age, sex and hospital catchment area. The analyses performed in this thesis were restricted to non-fatal cases (n=1213) and matched controls (n=1561), with available biomarkers data. Exposure information was available from questionnaires, anthropometric measurements, blood samples and medical records. Study III was based on a cohort of 60- year-old men and women from Stockholm (60YO), a population-based prospective study performed between 1997 and 1999 in Stockholm County. A total of 4232 individuals (78%) agreed to be enrolled in the study. Participants were followed for an average of 14.5 years for the assessment of CVE and cardiovascular mortality. Up to December 31, 2012, n= 491 cases were recorded. A nested-case control was conducted based on the full enumerated cohort. Controls (n= 981) were randomly selected from the study base having the same sex as the case, being alive, and not been classified as a case at the date of the CVE (+/- 60 days). Results and Conclusions: Circulating levels of IL8 were associated with a reduced occurrence of non-fatal MI in the SHEEP population aged 45-70 years (Study I), whereas no association was observed with the risk of CVE- defined as fatal and non-fatal MI, fatal and non-fatal stroke and hospitalization due to angina pectoris in the 60YO cohort (Study III). Median levels of IL8 did not vary according to IL8 and IL8 receptor genetic variants (Study I). A SNP rs12075 A/G, Asp42Gly, mapping at the Duffy antigen receptor for chemokines (DARC) gene on chromosome 1 was associated with circulating IL8 in serum, but not in plasma. Homozygous carriers of the G allele had lower levels of IL8 (Study II). These findings were replicated in independent populations. SIL6R and sgp130 had opposing associations with MI. Sgp130 was an effect modifier of the association of sIL6R with MI and there was an indication of a possible interaction between high sIL6R and low sgp130 with the risk of MI (Study IV). Our results suggest that differences in baseline characteristics of a study population, genetic predisposition and genetic regulation of biomarkers should be taken into account when interpreting the results of associations of biomarkers with CVD risk. In a broader sense, the role of molecular pathways should be evaluated in studies aimed at analysing the risk associated with complex outcomes rather than applying single biomarker approaches.
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| 2. |
- Velasquez, Ilais Moreno, et al.
(författare)
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Duffy antigen receptor genetic variant and the association with Interleukin 8 levels
- 2015
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 72:2, s. 178-184
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study is to identify loci associated with circulating levels of Interleukin 8 (IL8). We investigated the associations of 121,445 single nucleotide polymorphisms (SNPs) from the Illumina 200K CardioMetabochip with IL8 levels in 1077 controls from the Stockholm Heart Epidemiology Program (SHEEP) study, using linear regression under an additive model of inheritance. Five SNPs (rs12075A/G, rs13179413C/T, rs6907989T/A, rs9352745A/C, rs1779553T/C) reached the predefined threshold of genome-wide significance (p < 1.0 x 10(-5)) and were tested for in silico replication in three independent populations, derived from the PIVUS, MDC-CC and SCARF studies. IL8 was measured in serum (SHEEP, PIVUS) and plasma (MDC-CC, SCARF). The strongest association was found with the SNP rs12075 A/G, Asp42Gly (p = 1.6 x 10(-6)), mapping to the Duffy antigen receptor for chemokines (DARC) gene on chromosome 1. The minor allele G was associated with 15.6% and 10.4% reduction in serum IL8 per copy of the allele in SHEEP and PIVUS studies respectively. No association was observed between rs12075 and plasma IL8. Conclusion: rs12075 was associated with serum levels but not with plasma levels of IL8. It is likely that serum IL8 represents the combination of levels of circulating plasma IL8 and additional chemokine liberated from the erythrocyte DARC reservoir due to clotting. These findings highlight the importance of understanding ILS as a biomarker in cardiometabolic diseases.
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| 3. |
- Velasquez, Ilais Moreno, et al.
(författare)
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Interleukin-8 is associated with increased total mortality in women but not in men-findings from a community-based cohort of elderly
- 2015
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 47:1, s. 28-33
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To elucidate the association among circulating IL-8 and total mortality in a cohort of elderly, and to explore potential sex differences in the observed association. Methods. The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) is a cohort of 70-year-old men and women living in Uppsala, Sweden; baseline period: 2001-2004. IL-8 serum measurements were performed in 1003 participants. Results. In total, 61 men and 40 women died during follow-up (median 7.9 years). Baseline IL-8 concentrations were higher in women than in men (P = 0.03). In a multivariable model adjusting for age, established cardiovascular risk factors, and C-reactive protein, log-transformed standard deviation increments in IL-8 levels were weakly associated with an increased risk for total mortality (hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.02 -1.23, P < 0.05) in the whole cohort. Stratified analysis revealed an association in women (HR 1.18, 95% CI 1.06-1.30, P < 0.01) but not in men (HR 0.98, 95% CI 0.76-1.26). Conclusions. A weak association between IL-8 serum levels and an increased risk for mortality was observed. The prospective data support the role of IL-8 as a biomarker of interest; yet, further studies are warranted to elucidate validity of our finding and the possibility of a sex difference.
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