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| 25. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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- Friberg, Danielle, et al.
(författare)
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Sibling risk of pediatric obstructive sleep apnea syndrome and adenotonsillar hypertrophy.
- 2009
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Ingår i: Sleep. - : Oxford University Press (OUP). - 0161-8105 .- 1550-9109. ; 32:8, s. 1077-1083
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Tidskriftsartikel (refereegranskat)abstract
- Objectives:To estimate sibling risk of hospitalization for children with sleep disordered breathing (SDB), diagnosed with (1) obstructive sleep apnea syndrome (OSAS), or (2) adenotonsillar hypertrophy in the total Swedish population.Design, Setting, and Participants:Using the MigMed database at the Karolinska Institute, we divided the population of Sweden aged 0–18 years into sibling groups based on a shared mother and father and presence of a primary hospital diagnosis of OSAS or adenotonsillar hypertrophy for each individual born between 1978 and 1986, during the follow-up period 1997–2004. Individuals with at least one affected sibling were identified and the incidence rates were computed, using standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). Reference groups were boys and girls with unaffected siblings of 2 or more.Results:After accounting for socioeconomic status, age, and geographic region, boys with at least one sibling with OSAS had an increased risk of having OSAS (SIR, 33.2; 95% CI, 16.5–64.8), and in girls the SIR was 40.5 (19.4–81.4). For hypertrophy of the tonsils or hypertrophy of the adenoids and tonsils the corresponding SIRs were 4.53 (3.0–6.8) for boys and 4.94 (3.3–7.4) for girls.Conclusions:The study indicate an increased sibling risk of sleep disordered breathing in children, which may be due to heritable genes and/or shared environment such as increased awareness among family members or referring doctors. Caregivers should ask parents if siblings have similar symptoms, and thus offer them early treatment.
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| 27. |
- Försti, A, et al.
(författare)
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Polymorphisms in the genes of the urokinase plasminogen activation system in relation to colorectal cancer
- 2007
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Ingår i: Annals of Oncology. - : Oxford University Press. - 0923-7534 .- 1569-8041. ; 18:12, s. 1990-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background: Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor cancer prognosis. We examined four single nucleotide polymorphisms (SNPs) with a potential effect on expression of genes in the uPA system for their role in colorectal cancer susceptibility and prognosis.Patients and methods: We genotyped the SNPs in 308 Swedish incident colorectal cancer patients with up to 16 years of follow-up and in 585 age- and sex-matched controls. We evaluated the associations between genotypes and colorectal cancer and Dukes' stage. Survival probabilities were compared between different subgroups.Results: Patients with PAI-1 –675 5G/5G genotype had better survival than patients with 4G/4G or 4G/5G genotypes when they had Dukes' stage A or B tumors (P = 0.023 and P = 0.015, respectively). No statistically significant association was observed between the SNPs and the risk of colorectal cancer or Dukes' stage.Conclusions: Our results suggest a role for the PAI-1 genotype in colorectal cancer prognosis, but further studies are needed to evaluate the impact of our finding in the clinic.
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| 28. |
- Golusinski, W, et al.
(författare)
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Alteration of p53 gene structure and function in laryngeal squamous cell cancer
- 1997
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Ingår i: European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. - 0937-4477. ; 254254 Suppl 1, s. S133-S137
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Tidskriftsartikel (refereegranskat)
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