Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Zanoni, P. et al. (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science, 351(6278), pp. 1166-1171. (doi:10.1126/science.aad3517) (PMID:26965621) (PMCID:PMC4889017)

Zanoni, P. et al. (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science, 351(6278), pp. 1166-1171. (doi:10.1126/science.aad3517) (PMID:26965621) (PMCID:PMC4889017)

[img]
Preview
Text
132144.pdf - Accepted Version

443kB

Abstract

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian and Packard, Professor Chris and Sattar, Professor Naveed and Strawbridge, Dr Rona
Authors: Zanoni, P., Khetarpal, S. A., Larach, D. B., Hancock-Cerutti, W. F., Millar, J. S., Cuchel, M., DerOhannessian, S., Kontush, A., Surendran, P., Saleheen, D., Trompet, S., Jukema, J. W., De Craen, A., Deloukas, P., Sattar, N., Ford, I., Packard, C., Majumder, A. a. S., Alam, D. S., Di Angelantonio, E., Abecasis, G., Chowdhury, R., Erdmann, J., Nordestgaard, B. G., Nielsen, S. F., Tybjaerg-Hansen, A., Schmidt, R. F., Kuulasmaa, K., Liu, D. J., Perola, M., Blankenberg, S., Salomaa, V., Mannisto, S., Amouyel, P., Arveiler, D., Ferrieres, J., Muller-Nurasyid, M., Ferrario, M., Kee, F., Willer, C. J., Samani, N., Schunkert, H., Butterworth, A. S., Howson, J. M.M., Peloso, G. M., Stitziel, N. O., Danesh, J., Kathiresan, S., Rader, D. J., Watson, S., Schmidt, E. M., Sengupta, S., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., Buchkovich, M. L., Mora, S., Beckmann, J. S., Bragg-Gresham, J. L., Chang, H.-Y., Demirkan, A., Den Hertog, H. M., Do, R., Donnelly, L. A., Ehret, G. B., Esko, T., Feitosa, M. F., Ferreira, T., Fischer, K., Fontanillas, P., Fraser, R. M., Freitag, D. F., Gurdasani, D., Heikkila, K., Hypponen, E., Isaacs, A., Jackson, A. U., Johansson, A., Johnson, T., Kaakinen, M., Kettunen, J., Kleber, M. E., Li, X., Luan, J., Lyytikainen, L.-P., Magnusson, P. K. E., Mangino, M., Mihailov, E., Montasser, M. E., Nolte, I. M., OConnell, J. R., Palmer, C. D., Petersen, A.-K., Sanna, S., Saxena, R., Service, S. K., Shah, S., Shungin, D., Sidore, C., Song, C., Strawbridge, R.J., Surakka, I., Tanaka, T., Teslovich, T. M., Thorleifsson, G., Van den Herik, E. G., Voight, B. F., Volcik, K. A., Waite, L. L., Wong, A., Wu, Y., Zhang, W., Absher, D., Asiki, G., Barroso, I., Been, L. F., Bolton, J. L., Bonnycastle, L. L., Brambilla, P., Burnett, M. S., Cesana, G., Dimitriou, M., Doney, A. S. F., Doring, A., Elliott, P., Epstein, S. E., Eyjolfsson, G. I., Gigante, B., Goodarzi, M. O., Grallert, H., Gravito, M. L., Groves, C. J., Hallmans, G., Hartikainen, A.-L., Hayward, C., Hernandez, D., Hicks, A. A., Holm, H., Hung, Y.-J., Illig, T., Jones, M. R., Kaleebu, P., Kastelein, J. J. P., Khaw, K.-T., Kim, E., Klopp, N., Komulainen, P., Kumari, M., Langenberg, C., Lehtimaki, T., Lin, S.-Y., Lindstrom, J., Loos, R. J. F., Mach, F., McArdle, W. L., Meisinger, C., Mitchell, B. D., Muller, G., Nagaraja, R., Narisu, N., Nieminen, T. V. M., Nsubuga, R. N., Olafsson, I., Ong, K. K., Palotie, A., Papamarkou, T., Pomilla, C., Pouta, A., Reilly, M. P., Ridker, P. M., Rivadeneira, F., Rudan, I., Ruokonen, A., Scharnagl, H., Seeley, J., Silander, K., Stancakova, A., Stirrups, K., Swift, A. J., Tiret, L., Uitterlinden, A. G., van Pelt, L. J., Vedantam, S., Wainwright, N., Wijmenga, C., Wild, S. H., Willemsen, G., Wilsgaard, T., Wilson, J. F., Young, E. H., Zhao, J. H., Adair, L. S., Arveiler, D., Assimes, T. L., Bandinelli, S., Bennett, F., Bochud, M., Boehm, B. O., Boomsma, D. I., Borecki, I. B., Bornstein, S. R., Bovet, P., Burnier, M., Campbell, H., Chakravarti, A., Chambers, J. C., Chen, Y.-D. I., Collins, F. S., Cooper, R. S., Dedoussis, G., de Faire, U., Feranil, A. B., Ferrucci, L., Freimer, N. B., Gieger, C., Groop, L. C., Gudnason, V., Gyllensten, U., Hamsten, A., Harris, T. B., Hingorani, A., Hirschhorn, J. N., Hofman, A., Hovingh, G. K., Hsiung, C. A., Humphries, S. E., Hunt, S. C., Hveem, K., Iribarren, C., Jarvelin, M.-R., Jula, A., Kahonen, M., Kaprio, J., Kesaniemi, A., Kivimaki, M., Kooner, J. S., Koudstaal, P. J., Krauss, R. M., Kuh, D., Kuusisto, J., Kyvik, K. O., Laakso, M., Lakka, T. A., Lind, L., Lindgren, C. M., Martin, N. G., Marz, W., McCarthy, M. I., McKenzie, C. A., Meneton, P., Metspalu, A., Moilanen, L., Morris, A. D., Munroe, P. B., Njolstad, I., Pedersen, N. L., Power, C., Pramstaller, P. P., Price, J. F., Psaty, B. M., Quertermous, T., Rauramaa, R., Salomaa, V., Sanghera, D. K., Saramies, J., Schwarz, P. E. H., Sheu, W. H.- H., Shuldiner, A. R., Siegbahn, A., Spector, T. D., Stefansson, K., Strachan, D. P., Tayo, B. O., Tremoli, E., Tuomilehto, J., Uusitupa, M., van Duijn, C. M., Vollenweider, P., Wallentin, L., Wareham, N. J., Whitfield, J. B., Wolffenbuttel, B. H. R., Ordovas, J. M., Boerwinkle, E., Palmer, C. N. A., Thorsteinsdottir, U., Chasman, D. I., Rotter, J. I., Franks, P. W., Riatti, S., Cupples, L. A., Sandhu, M. S., Rich, S. S., Boehnke, M., Deloukas, P., Mohlke, K. L., Ingelsson, E., Gu, D., Roberts, R., Watkins, H., Blankenberg, S., Clarke, R., Collins, R., Kim, B.-J., McPherson, R., Nieminen, M. S., O'Donnell, C., Schreiber, S., Siegbahn, A., and Zalloua, P. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Science
Publisher:American Association for the Advancement of Science
ISSN:0036-8075
ISSN (Online):1095-9203
Copyright Holders:Copyright © 2016 The AuthorsAmerican Association for the Advancement of Science
First Published:First published in Science 351(6278):1166-1171
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record