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1. Systematic review of the prospective association of daily step counts with risk of mortality, cardiovascular disease, and dysglycemia

Author

Fulton, J.E., Carnethon, M.R., Lee, I.-M., Carlson, S.A., Thomas, W.I., Hall, K.S., Omura, J.D., Ekelund, U., Galuska, D.A., Paluch, A.E., Hyde, E.T., Bassett, D.R., Kraus, W.E., Matthews, C.E., and Evenson, K.R.

Abstract

Background: Daily step counts is an intuitive metric that has demonstrated success in motivating physical activity in adults and may hold potential for future public health physical activity recommendations. This review seeks to clarify the pattern of the associations between daily steps and subsequent all-cause mortality, cardiovascular disease (CVD) morbidity and mortality, and dysglycemia, as well as the number of daily steps needed for health outcomes. Methods: A systematic review was conducted to identify prospective studies assessing daily step count measured by pedometer or accelerometer and their associations with all-cause mortality, CVD morbidity or mortality, and dysglycemia (dysglycemia or diabetes incidence, insulin sensitivity, fasting glucose, HbA1c). The search was performed across the Medline, Embase, CINAHL, and the Cochrane Library databases from inception to August 1, 2019. Eligibility criteria included longitudinal design with health outcomes assessed at baseline and subsequent timepoints; defining steps per day as the exposure; reporting all-cause mortality, CVD morbidity or mortality, and/or dysglycemia outcomes; adults ���18 years old; and non-patient populations. Results: Seventeen prospective studies involving over 30,000 adults were identified. Five studies reported on all-cause mortality (follow-up time 4-10 years), four on cardiovascular risk or events (6 months to 6 years), and eight on dysglycemia outcomes (3 months to 5 years). For each 1000 daily step count increase at baseline, risk reductions in all-cause mortality (6-36%) and CVD (5-21%) at follow-up were estimated across a subsample of included studies. There was no evidence of significant interaction by age, sex, health conditions or behaviors (e.g., alcohol use, smoking status, diet) among studies that tested for interactions. Studies examining dysglycemia outcomes report inconsistent findings, partially due to heterogeneity across studies of glycemia-related biomarker outcomes, analytic approaches, and sample characteristics. Conclusions: Evidence from longitudinal data consistently demonstrated that walking an additional 1000 steps per day can help lower the risk of all-cause mortality, and CVD morbidity and mortality in adults, and that health benefits are present below 10,000 steps per day. However, the shape of the dose-response relation is not yet clear. Data are currently lacking to identify a specific minimum threshold of daily step counts needed to obtain overall health benefit.

Published
2020
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5. Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Author

Webb, T.R., Erdmann, J., Stirrups, K.E., Stitziel, N.O., Masca, N.G.D., Jansen, H., Kanoni, S., Nelson, C.P., Ferrario, P.G., Konig, I.R., Eicher, J.D., Johnson, A.D., Hamby, S.E., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., Bjorkegren, J.L.M., Weeke, P.E., Auer, P.L., Schick, U.M., Lu, Y.C., Zhang, H., Dube, M.P., Goel, A., Farrall, M., Peloso, G.M., Won, H.H., R. do, Iperen, E. van, Kruppa, J., Mahajan, A., Scott, R.A., Willenborg, C., Braund, P.S., Capelleveen, J.C. van, Doney, A.S.F., Donnelly, L.A., Asselta, R., Merlini, P.A., Duga, S., Marziliano, N., Denny, J.C., Shaffer, C., El-Mokhtari, N.E., Franke, A., Heilmann, S., Hengstenberg, C., Hoffmann, P., Holmen, O.L., Hveem, K., Jansson, J.H., Jockel, K.H., Kessler, T., Kriebel, J., Laugwitz, K.L., Marouli, E., Martinelli, N., McCarthy, M.I., Zuydam, N.R. van, Meisinger, C., Esko, T., Mihailov, E., Escher, S.A., Alver, M., Moebus, S., Morris, A.D., Virtamo, J., Nikpay, M., Olivieri, O., Provost, S., AlQarawi, A., Robertson, N.R., Akinsansya, K.O., Reilly, D.F., Vogt, T.F., Yin, W., Asselbergs, F.W., Kooperberg, C., Jackson, R.D., Stahl, E., Muller-Nurasyid, M., Strauch, K., Varga, T.V., Waldenberger, M., Zeng, L.Y., Chowdhury, R., Salomaa, V., Ford, I., Jukema, J.W., Amouyel, P., Kontto, J., Nordestgaard, B.G., Ferrieres, J., Saleheen, D., Sattar, N., Surendran, P., Wagner, A., Young, R., Howson, J.M.M., Butterworth, A.S., Danesh, J., Ardissino, D., Bottinger, E.P., Erbel, R., Franks, P.W., Girelli, D., Hall, A.S., Hovingh, G.K., Kastrati, A., Lieb, W., Meitinger, T., Kraus, W.E., Shah, S.H., McPherson, R., Orho-Melander, M., Melander, O., Metspalu, A., Palmer, C.N.A., Peters, A., Rader, D.J., Reilly, M.P., Loos, R.J.F., Reiner, A.P., Roden, D.M., Tardif, J.C., Thompson, J.R., Wareham, N.J., Watkins, H., Willer, C.J., Samani, N.J., Schunkert, H., Deloukas, P., Kathiresan, S., Wellcome Trust Case Control, MORGAM Investigators, and Myocardial Infarction Genetics

Subjects
expression quantitative trait loci, single nucleotide polymorphism, cholesteryl ester transfer protein, genome-wide association, genetics
Abstract

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Published
2017

6. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Author

Dewey, F.E., Gusarova, V., Dunbar, R.L., O'Dushlaine, C., Schurmann, C., Gottesman, O., McCarthy, S., Hout, C.V. van, Bruse, S., Dansky, H.M., Leader, J.B., Murray, M.F., Ritchie, M.D., Kirchner, H.L., Habegger, L., Lopez, A., Penn, J., Zhao, A., Shao, W., Stahl, N., Murphy, A.J., Hamon, S., Bouzelmat, A., Zhang, R., Shumel, B., Pordy, R., Gipe, D., Herman, G.A., Sheu, W.H.H., Lee, I.T., Liang, K.W., Guo, X., Rotter, J.I., Chen, Y.I., Kraus, W.E., Shah, S.H., Damrauer, S., Small, A., Rader, D.J., Wulff, A.B., Nordestgaard, B.G., Tybjærg-Hansen, A., Hoek, A.M. van den, Princen, H.M.G., Ledbetter, D.H., Carey, D.J., Overton, J.D., Reid, J.G., Sasiela, W.J., Banerjee, P., Shuldiner, A.R., Borecki, I.B., Teslovich, T.M., Yancopoulos, G.D., Mellis, S.J., Gromada, J., and Baras, A.

Subjects
Male, Metabolic Health Research, Inbred Strains, Biomedical Innovation, Coronary Artery Disease, Cardiovascular, Medical and Health Sciences, Antibodies, Dose-Response Relationship, Mice, Double-Blind Method, Life, Clinical Research, General & Internal Medicine, Monoclonal, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, Aetiology, Biology, Heart Disease - Coronary Heart Disease, Aged, Dyslipidemias, Angiopoietin-Like Protein 3, Animal, Middle Aged, Atherosclerosis, Lipid Metabolism, Lipids, Angiopoietin-like Proteins, Heart Disease, Good Health and Well Being, Cardiovascular Diseases, Disease Models, Mutation, lipids (amino acids, peptides, and proteins), Female, ELSS - Earth, Life and Social Sciences, Drug, Angiopoietins, Healthy Living
Abstract

Background Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. Methods We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. Results In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. Conclusions Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

Published
2017

7. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author

Zillikens, M.C., Demissie, S., Hsu, Y.H., Yerges-Armstrong, L.M., Chou, W.C., Stolk, L., Livshits, G., Broer, L., Johnson, T., Koller, D.L., Kutalik, Z., Luan, J., Malkin, I., Ried, J.S., Smith, A.V., Thorleifsson, G., Vandenput, L., Hua Zhao, J., Zhang, W., Aghdassi, A., Åkesson, K., Amin, N., Baier, L.J., Barroso, I., Bennett, D.A., Bertram, L., Biffar, R., Bochud, M., Boehnke, M., Borecki, I.B., Buchman, A.S., Byberg, L., Campbell, H., Campos Obanda, N., Cauley, J.A., Cawthon, P.M., Cederberg, H., Chen, Z., Cho, N.H., Jin Choi, H., Claussnitzer, M., Collins, F., Cummings, S.R., De Jager, P.L., Demuth, I., Dhonukshe-Rutten, RAM, Diatchenko, L., Eiriksdottir, G., Enneman, A.W., Erdos, M., Eriksson, J.G., Eriksson, J., Estrada, K., Evans, D.S., Feitosa, M.F., Fu, M., Garcia, M., Gieger, C., Girke, T., Glazer, N.L., Grallert, H., Grewal, J., Han, B.G., Hanson, R.L., Hayward, C., Hofman, A., Hoffman, E.P., Homuth, G., Hsueh, W.C., Hubal, M.J., Hubbard, A., Huffman, K.M., Husted, L.B., Illig, T., Ingelsson, E., Ittermann, T., Jansson, J.O., Jordan, J.M., Jula, A., Karlsson, M., Khaw, K.T., Kilpeläinen, T.O., Klopp, N., Kloth, JSL, Koistinen, H.A., Kraus, W.E., Kritchevsky, S., Kuulasmaa, T., Kuusisto, J., Laakso, M., Lahti, J., Lang, T., Langdahl, B.L., Launer, L.J., Lee, J.Y., Lerch, M.M., Lewis, J.R., Lind, L., Lindgren, C., Liu, Y., Liu, T., Ljunggren, Ö., Lorentzon, M., Luben, R.N., Maixner, W., McGuigan, F.E., Medina-Gomez, C., Meitinger, T., Melhus, H., Mellström, D., Melov, S., Michaëlsson, K., Mitchell, B.D., Morris, A.P., Mosekilde, L., Newman, A., Nielson, C.M., O'Connell, J.R., Oostra, B.A., Orwoll, E.S., Palotie, A., Parker, S., Peacock, M., Perola, M., Peters, A., Polasek, O., Prince, R.L., Räikkönen, K., Ralston, S.H., Ripatti, S., Robbins, J.A., Rotter, J.I., Rudan, I., Salomaa, V., Satterfield, S., Schadt, E.E., Schipf, S., Scott, L., Sehmi, J., Shen, J., Soo Shin, C., Sigurdsson, G., Smith, S., Soranzo, N., Stančáková, A., Steinhagen-Thiessen, E., Streeten, E.A., Styrkarsdottir, U., Swart, KMA, Tan, S.T., Tarnopolsky, M.A., Thompson, P., Thomson, C.A., Thorsteinsdottir, U., Tikkanen, E., Tranah, G.J., Tuomilehto, J., van Schoor, N.M., Verma, A., Vollenweider, P., Völzke, H., Wactawski-Wende, J., Walker, M., Weedon, M.N., Welch, R., Wichmann, H.E., Widen, E., Williams, FMK, Wilson, J.F., Wright, N.C., Xie, W., Yu, L., Zhou, Y., Chambers, J.C., Döring, A., van Duijn, C.M., Econs, M.J., Gudnason, V., Kooner, J.S., Psaty, B.M., Spector, T.D., Stefansson, K., Rivadeneira, F., Uitterlinden, A.G., Wareham, N.J., Ossowski, V., Waterworth, D., Loos, RJF, Karasik, D., Harris, T.B., Ohlsson, C., Kiel, D.P., Zillikens, M.C., Demissie, S., Hsu, Y.H., Yerges-Armstrong, L.M., Chou, W.C., Stolk, L., Livshits, G., Broer, L., Johnson, T., Koller, D.L., Kutalik, Z., Luan, J., Malkin, I., Ried, J.S., Smith, A.V., Thorleifsson, G., Vandenput, L., Hua Zhao, J., Zhang, W., Aghdassi, A., Åkesson, K., Amin, N., Baier, L.J., Barroso, I., Bennett, D.A., Bertram, L., Biffar, R., Bochud, M., Boehnke, M., Borecki, I.B., Buchman, A.S., Byberg, L., Campbell, H., Campos Obanda, N., Cauley, J.A., Cawthon, P.M., Cederberg, H., Chen, Z., Cho, N.H., Jin Choi, H., Claussnitzer, M., Collins, F., Cummings, S.R., De Jager, P.L., Demuth, I., Dhonukshe-Rutten, RAM, Diatchenko, L., Eiriksdottir, G., Enneman, A.W., Erdos, M., Eriksson, J.G., Eriksson, J., Estrada, K., Evans, D.S., Feitosa, M.F., Fu, M., Garcia, M., Gieger, C., Girke, T., Glazer, N.L., Grallert, H., Grewal, J., Han, B.G., Hanson, R.L., Hayward, C., Hofman, A., Hoffman, E.P., Homuth, G., Hsueh, W.C., Hubal, M.J., Hubbard, A., Huffman, K.M., Husted, L.B., Illig, T., Ingelsson, E., Ittermann, T., Jansson, J.O., Jordan, J.M., Jula, A., Karlsson, M., Khaw, K.T., Kilpeläinen, T.O., Klopp, N., Kloth, JSL, Koistinen, H.A., Kraus, W.E., Kritchevsky, S., Kuulasmaa, T., Kuusisto, J., Laakso, M., Lahti, J., Lang, T., Langdahl, B.L., Launer, L.J., Lee, J.Y., Lerch, M.M., Lewis, J.R., Lind, L., Lindgren, C., Liu, Y., Liu, T., Ljunggren, Ö., Lorentzon, M., Luben, R.N., Maixner, W., McGuigan, F.E., Medina-Gomez, C., Meitinger, T., Melhus, H., Mellström, D., Melov, S., Michaëlsson, K., Mitchell, B.D., Morris, A.P., Mosekilde, L., Newman, A., Nielson, C.M., O'Connell, J.R., Oostra, B.A., Orwoll, E.S., Palotie, A., Parker, S., Peacock, M., Perola, M., Peters, A., Polasek, O., Prince, R.L., Räikkönen, K., Ralston, S.H., Ripatti, S., Robbins, J.A., Rotter, J.I., Rudan, I., Salomaa, V., Satterfield, S., Schadt, E.E., Schipf, S., Scott, L., Sehmi, J., Shen, J., Soo Shin, C., Sigurdsson, G., Smith, S., Soranzo, N., Stančáková, A., Steinhagen-Thiessen, E., Streeten, E.A., Styrkarsdottir, U., Swart, KMA, Tan, S.T., Tarnopolsky, M.A., Thompson, P., Thomson, C.A., Thorsteinsdottir, U., Tikkanen, E., Tranah, G.J., Tuomilehto, J., van Schoor, N.M., Verma, A., Vollenweider, P., Völzke, H., Wactawski-Wende, J., Walker, M., Weedon, M.N., Welch, R., Wichmann, H.E., Widen, E., Williams, FMK, Wilson, J.F., Wright, N.C., Xie, W., Yu, L., Zhou, Y., Chambers, J.C., Döring, A., van Duijn, C.M., Econs, M.J., Gudnason, V., Kooner, J.S., Psaty, B.M., Spector, T.D., Stefansson, K., Rivadeneira, F., Uitterlinden, A.G., Wareham, N.J., Ossowski, V., Waterworth, D., Loos, RJF, Karasik, D., Harris, T.B., Ohlsson, C., and Kiel, D.P.

Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10(-8)) or suggestively genome wide (p < 2.3 × 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Published
2017

8. Supplementary Material for: Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization

Author

Wang, H., Pun, P.H., Kwee, L., Craig, D., Haynes, C., Chryst-Ladd, M., Svetkey, L.P., Patel, U.D., Hauser, E.R., Pollak, M.R., Kraus, W.E., and Shah, S.H.

Abstract

Background: While the association between APOL1 genetic variants and chronic kidney disease (CKD) has been established, their association with cardiovascular disease (CVD) is unclear. This study sought to understand CKD and cardiovascular risk conferred by APOL1 variants in a secondary cardiovascular prevention population. Methods: Two risk variants in APOL1 were genotyped in African-Americans (n = 1,641) enrolled in the CATHGEN biorepository, comprised of patients referred for cardiac catheterization at Duke University Hospital, Durham, NC, USA (2001-2010). Individuals were categorized as noncarriers (n = 722), heterozygote (n = 771), or homozygote carriers (n = 231) of APOL1 risk alleles. Multivariable logistic regression and Cox proportional hazards models adjusted for CVD risk factors were used to assess the association between APOL1 risk variants and prevalent and incident CKD, prevalent coronary artery disease (CAD), incident CVD events, and mortality. Results: The previously identified association between APOL1 variants and prevalent CKD was confirmed (OR: 1.85, 95% CI: 1.33-2.57, p = 0.0002). No statistically significant associations were detected between APOL1 variants and incident CKD or prevalent CAD, incident CVD events or mortality. Age, type 2 diabetes, and ejection fraction at baseline were significant clinical factors that predicted the risk of incident CKD in a subgroup analysis of APOL1 homozygous individuals. Conclusion:APOL1 genetic variants are not associated with CAD or incident CVD events in a cohort of individuals with a high burden of cardiometabolic risk factors. In individuals with homozygous APOL1 status, factors that predicted subsequent CKD included age, presence of type 2 diabetes, and ejection fraction at baseline.

Published
2016
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9. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Author

Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A.B., Norddahl, G.L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., Jonsdottir, I., Steinthorsdottir, V., Rafnar, T., Swinkels, D.W., Galesloot, T.E., Grarup, N., Jorgensen, T., Vestergaard, H., Hansen, T., Lauritzen, T., Linneberg, A., Friedrich, N., Krarup, N.T., Fenger, M., Abildgaard, U., Hansen, P.R., Galloe, A.M., Braund, P.S., Nelson, C.P., Hall, A.S., Williams, M.J., Rij, A.M. van, Jones, G.T., Patel, R.S., Levey, A.I., Hayek, S., Shah, S.H., Reilly, M., Eyjolfsson, G.I., Sigurdardottir, O., Olafsson, I., Kiemeney, L.A.L.M., Quyyumi, A.A., Rader, D.J., Kraus, W.E., Samani, N.J., Pedersen, O., Thorgeirsson, G., Masson, G., Holm, H., Gudbjartsson, D., Sulem, P., Thorsteinsdottir, U., Stefansson, K., Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A.B., Norddahl, G.L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., Jonsdottir, I., Steinthorsdottir, V., Rafnar, T., Swinkels, D.W., Galesloot, T.E., Grarup, N., Jorgensen, T., Vestergaard, H., Hansen, T., Lauritzen, T., Linneberg, A., Friedrich, N., Krarup, N.T., Fenger, M., Abildgaard, U., Hansen, P.R., Galloe, A.M., Braund, P.S., Nelson, C.P., Hall, A.S., Williams, M.J., Rij, A.M. van, Jones, G.T., Patel, R.S., Levey, A.I., Hayek, S., Shah, S.H., Reilly, M., Eyjolfsson, G.I., Sigurdardottir, O., Olafsson, I., Kiemeney, L.A.L.M., Quyyumi, A.A., Rader, D.J., Kraus, W.E., Samani, N.J., Pedersen, O., Thorgeirsson, G., Masson, G., Holm, H., Gudbjartsson, D., Sulem, P., Thorsteinsdottir, U., and Stefansson, K.

Abstract

Item does not contain fulltext, BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0x10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0x10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8x10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health

Published
2016

10. Concordance for cardiovascular risk factors in affected sib pairs (ASPs) with early-onset coronary artery disease (CAD)

Author

Hauser, E.R., Mooser, V., Schmidt, S., Crossman, D.C., Haines, J.L., Jones, C., Winkelmann, B., Foster, C., Haynes, C., Dowdy, Z.E., Estabrooks, S.E., Middleton, L.T., Manasco, P., Roses, A.D., Granger, C.B., Kraus, W.E., and Pericak-Vance, M.A.

Subjects
Genetic research -- Analysis, Human genetics -- Research, Cardiovascular diseases -- Genetic aspects, Coronary heart disease -- Genetic aspects, Biological sciences
Published
2000

11. Beta-Blocker Selectivity in Heart Failure (HF) Patients With Chronic Obstructive Pulmonary Disease (COPD): Insights from HF-A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION)

Author

Mentz, R.J., primary, Schulte, P.J., additional, Kitzman, D.W., additional, Fiuzat, M., additional, Kraus, W.E., additional, Pina, I. L., additional, Keteyian, S.J., additional, Fleg, J.L., additional, Ellis, S.J., additional, Whellan, D.J., additional, and O'Connor, C.M., additional

Published
2012
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16. Normal skeletal muscle Na+‐K+pump concentration in patients with chronic heart failure

Author

Green, H.J., Duscha, B.D., Sullivan, M.J., Keteyian, S.J., and Kraus, W.E.

Abstract

Intrinsic changes in skeletal muscle are being increasingly suspected as part of the underlying cause of exercise intolerance in patients with chronic heart failure (CHF). The objective of the present study was to determine whether differences existed between CHF patients and age‐matched healthy controls in the concentration of skeletal muscle Na+‐K+–ATPase (adenosine triphosphatase), a cation pump that functions to restore Na+‐K+gradients and protect membrane excitability. Moreover, given the potency for physical activity in altering long‐term regulation of the pump, an additional objective was to examine the role of activity level in pump expression in CHF patients. Na+‐K+–ATPase concentration (pmol/g wet wt) determined in the vastus lateralis muscle of 27 CHF males (ejection fraction, 23 ± 1.6%), using the vanadate facilitated [3H] ouabain binding technique, was not different (264 ± 10) from 10 sedentary controls (268 ± 19,P> 0.05). Similarly, no differences (P> 0.05) could be found between female patients (228 ± 16, n= 7) and controls (243 ± 13, n= 9). Differences between untrained control (294 ± 20, n= 7), chronically active (251 ± 20, n= 9), and trained (252 ± 16, n= 6) CHF groups in Na+‐K+pump expression were also insignificant. This study indicates that long‐term regulation of Na+‐K+–ATPase concentration is not altered in moderate CHF patients, regardless of the history of regular activity. However, the positive correlations (P< 0.05) that were observed between peak aerobic power (V̇O2peak) and Na+‐K+–ATPase (r= 0.422) and V̇O2peak and maximal citrate synthase activity (r= 0.404) suggests a role for the skeletal muscle in explaining exercise intolerance in CHF patients. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 69–76, 2001

Published
2001
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19. Integration of a three-stage expander into a CO2 refrigeration system

Author

Nickl, J., Will, G., Quack, H., and Kraus, W.E.

Subjects
*CARBON dioxide, *REFRIGERATION & refrigerating machinery, *COMPRESSORS, *TURBOMACHINES
Abstract

Abstract: The inclusion of an expander with work recovery provides two advantages for transcritical CO2 refrigeration cycles: the COP is improved and the exhaust pressure of the main compressor is lowered. Several designs of expanders have been proposed for this application and some prototypes have been tested already. In our laboratory a three-stage expander has been developed, which replaces the throttle valve of the normal refrigeration cycle and expands into the two-phase region. For optimum integration into the overall system it is proposed to install a vapour-liquid separator between the second and third stage of expansion. The vapour is guided back to the third expander stage whereas the liquid is supplied to the cooling stations via thermostatic or electronic expansion valves. [Copyright &y& Elsevier]

Published
2005
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