Frida Emanuelsson1, Børge G Nordestgaard2, Anne Tybjærg-Hansen3, Marianne Benn4. 1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Electronic address: https://twitter.com/Frida_Emanuel. 2. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen City Heart Study, Frederiksberg and Bispebjerg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark. 3. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen City Heart Study, Frederiksberg and Bispebjerg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark. 4. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Electronic address: marianne.benn@regionh.dk.
Abstract
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown. OBJECTIVES: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population. METHODS: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed. RESULTS: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy. CONCLUSIONS: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases.
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown. OBJECTIVES: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population. METHODS: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed. RESULTS: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy. CONCLUSIONS: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases.
Authors: Jie Zheng; Yuemiao Zhang; Humaira Rasheed; Venexia Walker; Yuka Sugawara; Jiachen Li; Yue Leng; Benjamin Elsworth; Robyn E Wootton; Si Fang; Qian Yang; Stephen Burgess; Philip C Haycock; Maria Carolina Borges; Yoonsu Cho; Rebecca Carnegie; Amy Howell; Jamie Robinson; Laurent F Thomas; Ben Michael Brumpton; Kristian Hveem; Stein Hallan; Nora Franceschini; Andrew P Morris; Anna Köttgen; Cristian Pattaro; Matthias Wuttke; Masayuki Yamamoto; Naoki Kashihara; Masato Akiyama; Masahiro Kanai; Koichi Matsuda; Yoichiro Kamatani; Yukinori Okada; Robin Walters; Iona Y Millwood; Zhengming Chen; George Davey Smith; Sean Barbour; Canqing Yu; Bjørn Olav Åsvold; Hong Zhang; Tom R Gaunt Journal: Int J Epidemiol Date: 2021-10-20 Impact factor: 7.196
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