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- Gaziano, Liam, et al.
(författare)
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Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
- 2022
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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| 2. |
- Erdélyi, Máté, 1975-
(författare)
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Towards the Development of Photoswitchable β-Hairpin Mimetics
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogeneous peptides with new physicochemical and pharmacological properties. The β-hairpin motif has been shown to be involved in numerous physiological processes, among others in regulation of eucariotic gene transcription. This thesis addresses the design, synthesis and conformational analysis of photoswitchable β-hairpin mimetics.The developmental work included the establishment of an improved procedure for cross coupling of aryl halides with terminal alkynes. Microwave mediated Sonogashira couplings in closed vessels were optimized under homogeneous and solid-phase conditions furnishing excellent yields for a large variety of substrates within 5 – 25 minutes. In addition, microwave heating was shown not to have any non-conventional effect on the reaction rate.Furthermore, the most important factors affecting β-hairpin stability were evaluated. Studies of tetrapeptide and decapeptide analogues revealed the essential role of the β-turn in initiation of hairpin folding. Moreover, hydrogen bonding was shown to be the main interchain stabilizing force, whereas hydrophobic interactions were found to be relatively weak. Nevertheless, hydrophobic packing appears to provide an important contribution to the thermodynamic stability of β-hairpins.Photoswitchable peptidomimetics were prepared by incorporation of various stilbene moieties into tetra- and decapeptides. Synthesis, photochemical isomerisation and spectroscopic conformational analysis of the compounds were performed.
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