The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Fall, Tove; Hägg, Sara; Mägi, Reedik; Ploner, Alexander; Fischer, Krista; Horikoshi, Momoko; Sarin, Antti‐Pekka; Þorleifsson, Guðmar; Ladenvall, Claes; Kals, Mart; Kuningas, Maris; Draisma, Harmen H.M.; Ried, Janina S.; Zuydam, Natalie R. van; Huikari, Ville; Mangino, Massimo; Sonestedt, Emily; Benyamin, Beben; Nelson, Christopher P.; Rivera, Natalia V.; Kristiansson, Kati; Shen, Huei-Yi; Havulinna, Aki S.; Dehghan, Abbas; Donnelly, Louise A.; Kaakinen, Marika; Nuotio, Marja Liisa; Robertson, Neil; Bruijn, Renée F.A.G. de; Ikram, M. Arfan; Amin, Najaf; Balmforth, Anthony J.; Braund, Peter S.; Doney, Alex S.F.; Döring, Angela; Elliott, Paul; Esko, Tõnu; Franco, Oscar H.; Grétarsdóttir, Sólveig; Hartikainen, Anna-Liisa; Heikkilä, Kauko; Herzig, Karl‐Heinz; Hólm, Hilma; Hottenga, Jouke Jan; Hyppönen, Elina; Illig, Thomas; Isaacs, Aaron; Isomaa, Bo; Karssen, Lennart C.; Kettunen, Johannes; Köenig, Wolfgang; Kuulasmaa, Kari; Laatikainen, Tiina; Laitinen, Jaana; Lindgren, Cecilia M.; Lyssenko, Valeriya; Läärä, Esa; Rayner, Nigel W.; Männistö, Satu; Pouta, A; Rathmann, Wolfgang; Rivadeneira, Fernando; Ruokonen, Aimo; Savolainen, Markku J.; Sijbrands, Eric J.G.; Small, Kerrin S.; Smit, Jan; Steinthórsdóttir, Valgerður; Syvänen, Ann‐Christine; Taanila, Anja; Tobin, Martin D.; Uitterlinden, André G.; Willems, Sara M.; Willemsen, Gonneke; Witteman, Jacqueline C. M.; Perola, Markus; Evans, Alun; Ferrières, Jean; Virtamo, Jarmo; Kee, Frank; Trégouët, David‐Alexandre; Arveiler, Dominique; Amouyel, Philippe; Ferrario, Marco; Brambilla, Paolo; Hall, Alistair S.; Heath, Andrew C.; Madden, Pamela A. F.; Martin, Nicholas; Montgomery, Grant W.; Whitfield, John B.; Jula, Antti; Knekt, Paul; Oostra, Ben A.; Duijn, Cornelia M. van; Penninx, Brenda W. J. H.; Smith, George Davey; Kaprio, Jaakko; Samani, Nilesh J.; Gieger, Christian; Peters, Annette; Wichmann, H‐Erich; Boomsma, Dorret I.; Geus, Eco J. C. de; Tuomi, Tiinamaija; Power, Chris; Hammond, Christopher J; Spector, Tim D.; Lind, Lars; Orho‐Melander, Marju; Palmer, Colin N.A.; Morris, Andrew D.; Groop, Leif; Järvelin, Marjo‐Riitta; Salomaa, Veikko; Vartiainen, Erkki; Hofman, Albert; Ripatti, Samuli; Metspalu, Andres; Þorsteinsdóttir, Unnur; Stefánsson, Kári; Pedersen, Nancy L.; McCarthy, Mark I.; Ingelsson, Erik; Prokopenko, Inga

doi:10.1371/journal.pmed.1001474

Cited by 179 publications

(137 citation statements)

References 44 publications

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“…In total, the genetic variants from the 3 identified loci explained 0.9% variation of plasma PAI‐1 levels in the Framingham Heart Study 28. This strength of IV is in the range of others that have been employed in successful MR studies, suggesting these variants could serve as a potential IV in MR analyses with risk factor, subclinical, and clinical outcomes 26, 29, 30…”

Section: Introductionmentioning

confidence: 82%

“…The causal effect of a per unit change of log‐transformed PAI‐1 on CHD is estimated as the per risk allele change of CHD risk dependent on the per risk allele change of log‐transformed PAI‐1 units. When using 1 SNP as an IV, it is calculated as the ratio estimate of the SNP‐CHD association to the SNP‐PAI‐1, that is, β SNP‐CHD association /β SNP‐PAI‐1 association 26. When using multiple SNPs as an IV, the combined causal effect was evaluated as the inverse‐variance weighted estimate of the causal ratio when using each SNP alone as an IV 25.…”

Section: Methodsmentioning

confidence: 99%

“…This method is referred to as the Mendelian randomization (MR) approach 25. Given that genotypes are assigned randomly from parents to offspring during meiosis, the causal effect of PAI‐1 on CHD risk can be estimated by the ratio of a SNP(IV)‐PAI‐1 association to SNP(IV)‐CHD association 25, 26. Using the MR method, a previous study suggested a causal association of PAI‐1 with myocardial infarction and blood triglycerides 27.…”

Section: Introductionmentioning

confidence: 99%

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Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Song

Burgess

Eicher

et al. 2017

JAHA

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BackgroundPlasminogen activator inhibitor type 1 (PAI‐1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI‐1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI‐1 on CHD risk.Methods and ResultsTo evaluate the association between PAI‐1 and CHD, we applied a 3‐step strategy. First, we investigated the observational association between PAI‐1 and CHD incidence using a systematic review based on a literature search for PAI‐1 and CHD studies. Second, we explored the causal association between PAI‐1 and CHD using a Mendelian randomization approach using summary statistics from large genome‐wide association studies. Finally, we explored the causal effect of PAI‐1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta‐analysis, the highest quantile of blood PAI‐1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age‐ and sex‐adjusted model. The effect size was reduced in studies using a multivariable‐adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI‐1 level on CHD risk (odds ratio=1.22 per unit increase of log‐transformed PAI‐1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI‐1 on elevating blood glucose and high‐density lipoprotein cholesterol.ConclusionsOur study indicates a causal effect of elevated PAI‐1 level on CHD risk, which may be mediated by glucose dysfunction.

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Section: Introductionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

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Burgess

Eicher

et al. 2017

JAHA

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“…Therefore, the primary aim of our study was to assess the associations of different immunological variables (leucocyte count and levels of three acute-phase proteins, IL-6 and adiponectin) with changes in HbA 1c over a follow-up of 7 years. Since obesity is an important determinant of both subclinical inflammation and glycaemic control [18], the secondary aim of our study was to investigate the extent to which baseline levels of abdominal adiposity and 7 year changes in waist circumference may explain these associations.…”

Section: Introductionmentioning

confidence: 99%

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study

et al. 2015

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Aims/hypothesis The role of biomarkers of subclinical inflammation in the early deterioration of glycaemia before type 2 diabetes is largely unknown. We hypothesised that increased levels of circulating proinflammatory biomarkers and decreased circulating adiponectin would be associated with 7 year increases of HbA 1c in non-diabetic individuals. Methods This study was based on individuals who participated in the prospective Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999)(2000)(2001) and the 7 year follow-up KORA F4 (2006-2008) survey. Individuals with type 2 diabetes at baseline or with a diagnosis of diabetes in the period between both surveys were excluded, which left a sample of 850 men and women. Multivariable linear regression analyses were performed to assess associations among baseline values of leucocyte count and levels of acute-phase proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and fibrinogen), IL-6 and adiponectin with changes in HbA 1c between baseline and follow-up. Results A high leucocyte count and high hsCRP, SAA and IL-6 levels were positively associated with changes in HbA 1c after adjusting for age, sex, lifestyle factors and baseline HbA 1c . In contrast, the adiponectin level was inversely associated with changes in HbA 1c (p value between <0.0001 and 0.020). The associations of leucocyte count and levels of hsCRP and SAA with HbA 1c changes remained significant after additional adjustment for waist circumference and circulating lipids at baseline and for the 7 year change in waist circumference (p value between 0.004 and 0.045).Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3679-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation An elevated leucocyte count and elevated hsCRP and SAA were associated with early deterioration of glycaemia before the diagnosis of type 2 diabetes. These associations were largely independent of baseline abdominal adiposity and increases in waist circumference.

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“…Conclusion. NT-proBNP reveals the patients with early cardial disorders among persons with MS. Метаболический синдром (МС) играет существен-ную роль в ускорении развития и прогрессирования заболеваний, связанных с атеросклерозом, которые, по оценкам ВОЗ, занимают первое место среди причин смертности населения индустриально развитых стран мира [1][2][3]. …”

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Brain Natriuretic Propeptide as a Marker of the Heart Damage in Metabolic Syndrome

Либис¹,

Исаева²,

Вдовенко³

et al. 2015

Ross. kardiol. ž.

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Цель. Изучить связь уровня NT-proBNP c компонентами метаболического синдрома (МС) и показателями диастолической и систолической функции ЛЖ у лиц с МС. Материал и методы. Обследовано 148 человек. Основную группу составили лица с МС (100 человек), контрольную группу -лица без МС (48 человек). Обсле-дуемым производилась антропометрия, измерение АД, определение уровня глюкозы, показателей липидного спектра, уровня NT-proBNP и регистрация ЭКГ и ЭхоКГ. МС и его компоненты определялись по критериям IDF (2005). Результаты. Пациенты с МС имели более высокий уровень NT-proBNP, чем в контрольной группе (246,5±35,3 пг/мл vs 24,33±4,7 пг/мл, р<0,0001). Выяв-лено, что диаметр ЛП (β=0,766, р=0,001), ТМЖП (β=0,29, р=0,04), ОТ (β=-0,217, р=0,039) и уровень ТГ (β=-0,22, р=0,04) являются независимыми факторами, связанными с уровнем NT-proBNP. При увеличении степени тяжести диастоли-ческой дисфункции ЛЖ увеличивался уровень NT-proBNP. заключение. NT-proBNP позволяет выявлять пациентов с ранними кардиаль-ными расстройствами среди лиц, имеющих МС. СН -сердечная недостаточность, ДД ЛЖ -диастолическая дисфункция левого желудочка, ЛЖ -левый желудочек, ОХС -общий холестерин, ТГ -триглицериды, ЛПВП -липопротеиды высокой плотности, ЛПНП -липо-протеиды низкой плотности, ИА -индекс атерогенности, ИР -инсулиноре-зистентность, МС -метаболический синдром, ЭКГ -электрокардиография, ЭхоКГ -эхокардиография, NT-proBNP -мозговой натрийуретический про-пептид, ЛП -размер левого предсердия, ЛА -размер легочной артерии, КДР -конечно-диастолический размер ЛЖ, КДО -конечно-диастоличе-ский объем ЛЖ, КСР -конечно-систолический размер ЛЖ, КСО -конечно-систолический объем ЛЖ, ТМЖП -толщина межжелудочковой перего-родки, ТЗСЛЖ -толщина задней стенки ЛЖ, УО -ударный объем, Р ла сист -систолическое АД в легочной артерии, ФВ -фракция выброса ЛЖ, Е -максимальная скорость кровотока раннего диастолического напол-нения, А -максимальная скорость кровотока во время систолы предсердий, IVRT -время изоволюмического расслабления, АДс -систолическое АД, АДд -диастолическое АД, ОТ -окружность талии, ИМТ -индекс массы тела, ПЖ -правый желудочек. bRAIN NATRIURETIC PROPEPTIDE AS A MARKER OF THE HEART DAMAGE IN METAbOLIC SYNDROMELibis R. A., Isaeva E. N., Vdovenko L. G., Basyrova I. R Aim. To study the relationship of NT-proBNP level with metabolic sindrome (MS) components and values of diastolic and systolic functions of the LV in patients with MS. Material and methods. Totally 148 patients studied. The main group consisted of 100 persons with MS, controls were 48 persons without MS. The participants underwent anthropometry, BP measurement, glucose level measurement, lipid spectrum, NT-proBNP levels and also ECG and EchoCG recording. MS and its components were evaluated according to IDF (2005). Results. MS patients had higher level of NT-proBNP than controls (246,5±35,3 pg/ml vs 24,33±4,7 pg/ml, р<0,0001). It was shown that the diameter of LA (β=0,766, р=0,001), IVST (β=0,29, р=0,04), OT (β=-0,217, р=0,039) and level of TG (β=-0,22, р=0,04) are independent factors related to N...

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The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Abstract: In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design. Please see later in the article for the Editors' Summary

Cited by 179 publications

References 44 publications

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study

Brain Natriuretic Propeptide as a Marker of the Heart Damage in Metabolic Syndrome

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