Dataset Information

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

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.

SUBMITTER: Gaziano L

PROVIDER: S-EPMC9662821 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

Gaziano Liam L Sun Luanluan L Arnold Matthew M Bell Steven S Cho Kelly K Kaptoge Stephen K SK Song Rebecca J RJ Burgess Stephen S Posner Daniel C DC Mosconi Katja K Robinson-Cohen Cassianne C Mason Amy M AM Bolton Thomas R TR Tao Ran R Allara Elias E Schubert Petra P Chen Lingyan L Staley James R JR Staplin Natalie N Altay Servet S Amiano Pilar P Arndt Volker V Ärnlöv Johan J Barr Elizabeth L M ELM Björkelund Cecilia C Boer Jolanda M A JMA Brenner Hermann H Casiglia Edoardo E Chiodini Paolo P Cooper Jackie A JA Coresh Josef J Cushman Mary M Dankner Rachel R Davidson Karina W KW de Jongh Renate T RT Donfrancesco Chiara C Engström Gunnar G Freisling Heinz H de la Cámara Agustín Gómez AG Gudnason Vilmundur V Hankey Graeme J GJ Hansson Per-Olof PO Heath Alicia K AK Hoorn Ewout J EJ Imano Hironori H Jassal Simerjot K SK Kaaks Rudolf R Katzke Verena V Kauhanen Jussi J Kiechl Stefan S Koenig Wolfgang W Kronmal Richard A RA Kyrø Cecilie C Lawlor Deborah A DA Ljungberg Börje B MacDonald Conor C Masala Giovanna G Meisinger Christa C Melander Olle O Moreno Iribas Conchi C Ninomiya Toshiharu T Nitsch Dorothea D Nordestgaard Børge G BG Onland-Moret Charlotte C Palmieri Luigi L Petrova Dafina D Garcia Jose Ramón Quirós JRQ Rosengren Annika A Sacerdote Carlotta C Sakurai Masaru M Santiuste Carmen C Schulze Matthias B MB Sieri Sabina S Sundström Johan J Tikhonoff Valérie V Tjønneland Anne A Tong Tammy T Tumino Rosario R Tzoulaki Ioanna I van der Schouw Yvonne T YT Monique Verschuren W M WM Völzke Henry H Wallace Robert B RB Wannamethee S Goya SG Weiderpass Elisabete E Willeit Peter P Woodward Mark M Yamagishi Kazumasa K Zamora-Ros Raul R Akwo Elvis A EA Pyarajan Saiju S Gagnon David R DR Tsao Philip S PS Muralidhar Sumitra S Edwards Todd L TL Damrauer Scott M SM Joseph Jacob J Pennells Lisa L Wilson Peter W F PWF Harrison Seamus S Gaziano Thomas A TA Inouye Michael M Baigent Colin C Casas Juan P JP Langenberg Claudia C Wareham Nick N Riboli Elio E Gaziano J Michael JM Danesh John J Hung Adriana M AM Butterworth Adam S AS Wood Angela M AM Di Angelantonio Emanuele E

Circulation 20221031 20

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 36314129

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Project description:BackgroundHigh levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach.MethodsFor observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays.ResultsMajority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = -5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = -8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/L, Z = -1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, χ = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN.ConclusionsBy observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.

Project description:BackgroundBrain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits.Methods and findingsObservational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR). Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the "Snap" card game. Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never drinkers comprised 2.7% of the sample. Alcohol consumption was associated with markers of higher iron (χ) in putamen (β = 0.08 standard deviation (SD) [95% confidence interval (CI) 0.06 to 0.09], p < 0.001), caudate (β = 0.05 [0.04 to 0.07], p < 0.001), and substantia nigra (β = 0.03 [0.02 to 0.05], p < 0.001) and lower iron in the thalami (β = -0.06 [-0.07 to -0.04], p < 0.001). Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly. MR analyses provided weak evidence these relationships are causal. Genetically predicted alcoholic drinks weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections. Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction. Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f. <7 units (56 g). Systemic iron levels partially mediated associations of alcohol intake with brain iron. Markers of higher basal ganglia iron associated with slower executive function, lower fluid intelligence, and slower reaction times. The main limitations of the study include that χ and T2* can reflect changes in myelin as well as iron, alcohol use was self-reported, and MR estimates can be influenced by genetic pleiotropy.ConclusionsTo the best of our knowledge, this study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline.

Dataset Information

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

Background

Methods

Results

Conclusions

Publications

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

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