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

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 l... Full description

Journal Title: Science (New York N.Y.), March 11, 2016, Vol.351(6278), pp.1166-1171
Main Author: Zanoni, Paolo
Other Authors: Khetarpal, Sumeet A , Larach, Daniel B , Hancock-Cerutti, William F , Millar, John S , Cuchel, Marina , Derohannessian, Stephanie , Kontush, Anatol , Surendran, Praveen , Saleheen, Danish , Trompet, Stella , Jukema, J Wouter , De Craen, Anton , Deloukas, Panos , Sattar, Naveed , Ford, Ian , Packard, Chris , Majumder, Abdullah Al Shafi , Alam, Dewan S , Di Angelantonio, Emanuele , Abecasis, Goncalo , Chowdhury, Rajiv , Erdmann, Jeanette , Nordestgaard, Børge G , Nielsen, Sune F , Tybjærg-Hansen, Anne , Schmidt, Ruth Frikke , Kuulasmaa, Kari , Liu, Dajiang J , Perola, Markus , Blankenberg, Stefan , Salomaa, Veikko , Männistö, Satu , Amouyel, Philippe , Arveiler, Dominique , Ferrieres, Jean , Müller-Nurasyid, Martina , Ferrario, Marco , Kee, Frank , Willer, Cristen J , Samani, Nilesh , Schunkert, Heribert , Butterworth, Adam S , Howson, Joanna M M , Peloso, Gina M , Stitziel, Nathan O , Danesh, John , Kathiresan, Sekar , Rader, Daniel J , Zanoni, Paolo , Watson, Sarah , Schmidt, Ellen M
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1095-9203 ; DOI: 10.1126/science.aad3517
Link: http://search.proquest.com/docview/1772834189/?pq-origsite=primo
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title: Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
format: Article
creator:
  • Zanoni, Paolo
  • Khetarpal, Sumeet A
  • Larach, Daniel B
  • Hancock-Cerutti, William F
  • Millar, John S
  • Cuchel, Marina
  • Derohannessian, Stephanie
  • Kontush, Anatol
  • Surendran, Praveen
  • Saleheen, Danish
  • Trompet, Stella
  • Jukema, J Wouter
  • De Craen, Anton
  • Deloukas, Panos
  • Sattar, Naveed
  • Ford, Ian
  • Packard, Chris
  • Majumder, Abdullah Al Shafi
  • Alam, Dewan S
  • Di Angelantonio, Emanuele
  • Abecasis, Goncalo
  • Chowdhury, Rajiv
  • Erdmann, Jeanette
  • Nordestgaard, Børge G
  • Nielsen, Sune F
  • Tybjærg-Hansen, Anne
  • Schmidt, Ruth Frikke
  • Kuulasmaa, Kari
  • Liu, Dajiang J
  • Perola, Markus
  • Blankenberg, Stefan
  • Salomaa, Veikko
  • Männistö, Satu
  • Amouyel, Philippe
  • Arveiler, Dominique
  • Ferrieres, Jean
  • Müller-Nurasyid, Martina
  • Ferrario, Marco
  • Kee, Frank
  • Willer, Cristen J
  • Samani, Nilesh
  • Schunkert, Heribert
  • Butterworth, Adam S
  • Howson, Joanna M M
  • Peloso, Gina M
  • Stitziel, Nathan O
  • Danesh, John
  • Kathiresan, Sekar
  • Rader, Daniel J
  • Zanoni, Paolo
  • Watson, Sarah
  • Schmidt, Ellen M
subjects:
  • Aged–Blood
  • Amino Acid Substitution–Blood
  • Animals–Genetics
  • Cholesterol, HDL–Genetics
  • Coronary Disease–Genetics
  • DNA Mutational Analysis–Genetics
  • Female–Metabolism
  • Genetic Variation–Metabolism
  • Heterozygote–Metabolism
  • Homozygote–Metabolism
  • Humans–Metabolism
  • Leucine–Metabolism
  • Male–Metabolism
  • Mice–Metabolism
  • Middle Aged–Metabolism
  • Proline–Metabolism
  • Protein Processing, Post-Translational–Metabolism
  • Risk–Metabolism
  • Scavenger Receptors, Class B–Metabolism
  • Cholesterol, HDL
  • Scarb1 Protein, Human
  • Scavenger Receptors, Class B
  • Proline
  • Leucine
ispartof: Science (New York, N.Y.), March 11, 2016, Vol.351(6278), pp.1166-1171
description: 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). 10.1126/science.aad3517
language: eng
source:
identifier: E-ISSN: 1095-9203 ; DOI: 10.1126/science.aad3517
fulltext: no_fulltext
issn:
  • 10959203
  • 1095-9203
url: Link


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titleRare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
creatorZanoni, Paolo ; Khetarpal, Sumeet A ; Larach, Daniel B ; Hancock-Cerutti, William F ; Millar, John S ; Cuchel, Marina ; Derohannessian, Stephanie ; Kontush, Anatol ; Surendran, Praveen ; Saleheen, Danish ; Trompet, Stella ; Jukema, J Wouter ; De Craen, Anton ; Deloukas, Panos ; Sattar, Naveed ; Ford, Ian ; Packard, Chris ; Majumder, Abdullah Al Shafi ; Alam, Dewan S ; Di Angelantonio, Emanuele ; Abecasis, Goncalo ; Chowdhury, Rajiv ; Erdmann, Jeanette ; Nordestgaard, Børge G ; Nielsen, Sune F ; Tybjærg-Hansen, Anne ; Schmidt, Ruth Frikke ; Kuulasmaa, Kari ; Liu, Dajiang J ; Perola, Markus ; Blankenberg, Stefan ; Salomaa, Veikko ; Männistö, Satu ; Amouyel, Philippe ; Arveiler, Dominique ; Ferrieres, Jean ; Müller-Nurasyid, Martina ; Ferrario, Marco ; Kee, Frank ; Willer, Cristen J ; Samani, Nilesh ; Schunkert, Heribert ; Butterworth, Adam S ; Howson, Joanna M M ; Peloso, Gina M ; Stitziel, Nathan O ; Danesh, John ; Kathiresan, Sekar ; Rader, Daniel J ; Zanoni, Paolo ; Watson, Sarah ; Schmidt, Ellen M
contributorSengupta, Sebanti (correspondence author) ; Gustafsson, Stefan (record owner) ; Kanoni, Stavroula ; Ganna, Andrea ; Chen, Jin ; Buchkovich, Martin L ; Mora, Samia ; Beckmann, Jacques S ; Bragg-Gresham, Jennifer L ; Chang, Hsing-Yi ; Demirkan, Ayşe ; Den Hertog, Heleen M ; Do, Ron ; Donnelly, Louise A ; Ehret, Georg B ; Esko, Tõnu ; Feitosa, Mary F ; Ferreira, Teresa ; Fischer, Krista ; Fontanillas, Pierre ; Fraser, Ross M ; Freitag, Daniel F ; Gurdasani, Deepti ; Heikkilä, Kauko ; Hyppönen, Elina ; Isaacs, Aaron ; Jackson, Anne U ; Johansson, Åsa ; Johnson, Toby ; Kaakinen, Marika ; Kettunen, Johannes ; Kleber, Marcus E ; Li, Xiaohui ; Luan, Jian'an ; Lyytikäinen, Leo-Pekka ; Magnusson, Patrik K E ; Mangino, Massimo ; Mihailov, Evelin ; Montasser, May E ; Nolte, Ilja M ; O'Connell, Jeffrey R ; Palmer, Cameron D ; Petersen, Ann-Kristin ; Sanna, Serena ; Saxena, Richa ; Service, Susan K ; Shah, Sonia ; Shungin, Dmitry ; Sidore, Carlo ; Song, Ci ; Strawbridge, Rona J ; Surakka, Ida ; Tanaka, Toshiko ; Teslovich, Tanya M ; Thorleifsson, Gudmar ; Van Den Herik, Evita G ; Voight, Benjamin F ; Volcik, Kelly A ; Waite, Lindsay L ; Wong, Andrew ; Wu, Ying ; Zhang, Weihua ; Absher, Devin ; Asiki, Gershim ; Barroso, Inês ; Been, Latonya F ; Bolton, Jennifer L ; Bonnycastle, Lori L ; Brambilla, Paolo ; Burnett, Mary S ; Cesana, Giancarlo ; Dimitriou, Maria ; Doney, Alex S F ; Döring, Angela ; Elliott, Paul ; Epstein, Stephen E ; Eyjolfsson, Gudmundur Ingi ; Gigante, Bruna ; Goodarzi, Mark O ; Grallert, Harald ; Gravito, Martha L ; Groves, Christopher J ; Hallmans, Göran ; Hartikainen, Anna-Liisa ; Hayward, Caroline ; Hernandez, Dena ; Hicks, Andrew A ; Holm, Hilma ; Hung, Yi-Jen ; Illig, Thomas ; Jones, Michelle R ; Kaleebu, Pontiano ; Kastelein, John J P ; Khaw, Kay-Tee ; Kim, Eric ; Klopp, Norman ; Komulainen, Pirjo ; Kumari, Meena ; Langenberg, Claudia ; Lehtimäki, Terho ; Lin, Shih-Yi ; Lindström, Jaana ; Loos, Ruth J F ; Mach, François ; Mcardle, Wendy L ; Meisinger, Christa ; Mitchell, Braxton D ; Müller, Gabrielle ; Nagaraja, Ramaiah ; Narisu, Narisu ; Nieminen, Tuomo V M ; Nsubuga, Rebecca N ; Olafsson, Isleifur ; Ong, Ken K ; Palotie, Aarno ; Papamarkou, Theodore ; Pomilla, Cristina ; Pouta, Anneli ; Reilly, Muredach P ; Ridker, Paul M ; Rivadeneira, Fernando ; Rudan, Igor ; Ruokonen, Aimo ; Scharnagl, Hubert ; Seeley, Janet ; Silander, Kaisa ; Stancáková, Alena ; Stirrups, Kathleen ; Swift, Amy J ; Tiret, Laurence ; Uitterlinden, Andre G ; van Pelt, L J ; Vedantam, Sailaja ; Wainwright, Nicholas ; Wijmenga, Cisca ; Wild, Sarah H ; Willemsen, Gonneke ; Wilsgaard, Tom ; Wilson, James F ; Young, Elizabeth H ; Zhao, Jing Hua ; Adair, Linda S ; Arveiler, Dominique ; Assimes, Themistocles L ; Bandinelli, Stefania ; Bennett, Franklyn ; Bochud, Murielle ; Boehm, Bernhard O ; Boomsma, Dorret I ; Borecki, Ingrid B ; Bornstein, Stefan R ; Bovet, Pascal ; Burnier, Michel ; Campbell, Harry ; Chakravarti, Aravinda ; Chambers, John C ; Chen, Yii-Der Ida ; Collins, Francis S ; Cooper, Richard S ; Dedoussis, George ; de Faire, Ulf ; Feranil, Alan B ; Ferrucci, Luigi ; Freimer, Nelson B ; Gieger, Christian ; Groop, Leif C ; Gudnason, Vilmundur ; Gyllensten, Ulf ; Hamsten, Anders ; Harris, Tamara B ; Hingorani, Aroon ; Hirschhorn, Joel N ; Hofman, Albert ; Hovingh, G Kees ; Hsiung, Chao Agnes ; Humphries, Steve E ; Hunt, Steven C ; Hveem, Kristian ; Iribarren, Carlos ; Järvelin, Marjo-Riitta ; Jula, Antti ; Kähönen, Mika ; Kaprio, Jaakko ; Kesäniemi, Antero ; Kivimaki, Mika ; Kooner, Jaspal S ; Koudstaal, Peter J ; Krauss, Ronald M ; Kuh, Diana ; Kuusisto, Johanna ; Kyvik, Kirsten O ; Laakso, Markku ; Lakka, Timo A ; Lind, Lars ; Lindgren, Cecilia M ; Martin, Nicholas G ; März, Winfried ; Mccarthy, Mark I
ispartofScience (New York, N.Y.), March 11, 2016, Vol.351(6278), pp.1166-1171
identifierE-ISSN: 1095-9203 ; DOI: 10.1126/science.aad3517
subjectAged–Blood ; Amino Acid Substitution–Blood ; Animals–Genetics ; Cholesterol, HDL–Genetics ; Coronary Disease–Genetics ; DNA Mutational Analysis–Genetics ; Female–Metabolism ; Genetic Variation–Metabolism ; Heterozygote–Metabolism ; Homozygote–Metabolism ; Humans–Metabolism ; Leucine–Metabolism ; Male–Metabolism ; Mice–Metabolism ; Middle Aged–Metabolism ; Proline–Metabolism ; Protein Processing, Post-Translational–Metabolism ; Risk–Metabolism ; Scavenger Receptors, Class B–Metabolism ; Cholesterol, HDL ; Scarb1 Protein, Human ; Scavenger Receptors, Class B ; Proline ; Leucine
languageeng
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descriptionScavenger 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). 10.1126/science.aad3517
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0Zanoni, Paolo
1Khetarpal, Sumeet A
2Larach, Daniel B
3Hancock-Cerutti, William F
4Millar, John S
5Cuchel, Marina
6Derohannessian, Stephanie
7Kontush, Anatol
8Surendran, Praveen
9Saleheen, Danish
10Trompet, Stella
11Jukema, J Wouter
12De Craen, Anton
13Deloukas, Panos
14Sattar, Naveed
15Ford, Ian
16Packard, Chris
17Majumder, Abdullah Al Shafi
18Alam, Dewan S
19Di Angelantonio, Emanuele
20Abecasis, Goncalo
21Chowdhury, Rajiv
22Erdmann, Jeanette
23Nordestgaard, Børge G
24Nielsen, Sune F
25Tybjærg-Hansen, Anne
26Schmidt, Ruth Frikke
27Kuulasmaa, Kari
28Liu, Dajiang J
29Perola, Markus
30Blankenberg, Stefan
31Salomaa, Veikko
32Männistö, Satu
33Amouyel, Philippe
34Arveiler, Dominique
35Ferrieres, Jean
36Müller-Nurasyid, Martina
37Ferrario, Marco
38Kee, Frank
39Willer, Cristen J
40Samani, Nilesh
41Schunkert, Heribert
42Butterworth, Adam S
43Howson, Joanna M M
44Peloso, Gina M
45Stitziel, Nathan O
46Danesh, John
47Kathiresan, Sekar
48Rader, Daniel J
49Watson, Sarah
50Schmidt, Ellen M
titleRare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
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0Aged–Blood
1Amino Acid Substitution–Blood
2Animals–Genetics
3Cholesterol, HDL–Genetics
4Coronary Disease–Genetics
5DNA Mutational Analysis–Genetics
6Female–Metabolism
7Genetic Variation–Metabolism
8Heterozygote–Metabolism
9Homozygote–Metabolism
10Humans–Metabolism
11Leucine–Metabolism
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1Gustafsson, Stefan
2Kanoni, Stavroula
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4Chen, Jin
5Buchkovich, Martin L
6Mora, Samia
7Beckmann, Jacques S
8Bragg-Gresham, Jennifer L
9Chang, Hsing-Yi
10Demirkan, Ayşe
11Den Hertog, Heleen M
12Do, Ron
13Donnelly, Louise A
14Ehret, Georg B
15Esko, Tõnu
16Feitosa, Mary F
17Ferreira, Teresa
18Fischer, Krista
19Fontanillas, Pierre
20Fraser, Ross M
21Freitag, Daniel F
22Gurdasani, Deepti
23Heikkilä, Kauko
24Hyppönen, Elina
25Isaacs, Aaron
26Jackson, Anne U
27Johansson, Åsa
28Johnson, Toby
29Kaakinen, Marika
30Kettunen, Johannes
31Kleber, Marcus E
32Li, Xiaohui
33Luan, Jian'an
34Lyytikäinen, Leo-Pekka
35Magnusson, Patrik K E
36Mangino, Massimo
37Mihailov, Evelin
38Montasser, May E
39Nolte, Ilja M
40O'Connell, Jeffrey R
41Palmer, Cameron D
42Petersen, Ann-Kristin
43Sanna, Serena
44Saxena, Richa
45Service, Susan K
46Shah, Sonia
47Shungin, Dmitry
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52Tanaka, Toshiko
53Teslovich, Tanya M
54Thorleifsson, Gudmar
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56Voight, Benjamin F
57Volcik, Kelly A
58Waite, Lindsay L
59Wong, Andrew
60Wu, Ying
61Zhang, Weihua
62Absher, Devin
63Asiki, Gershim
64Barroso, Inês
65Been, Latonya F
66Bolton, Jennifer L
67Bonnycastle, Lori L
68Brambilla, Paolo
69Burnett, Mary S
70Cesana, Giancarlo
71Dimitriou, Maria
72Doney, Alex S F
73Döring, Angela
74Elliott, Paul
75Epstein, Stephen E
76Eyjolfsson, Gudmundur Ingi
77Gigante, Bruna
78Goodarzi, Mark O
79Grallert, Harald
80Gravito, Martha L
81Groves, Christopher J
82Hallmans, Göran
83Hartikainen, Anna-Liisa
84Hayward, Caroline
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95Klopp, Norman
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titleRare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
authorZanoni, Paolo ; Khetarpal, Sumeet A ; Larach, Daniel B ; Hancock-Cerutti, William F ; Millar, John S ; Cuchel, Marina ; Derohannessian, Stephanie ; Kontush, Anatol ; Surendran, Praveen ; Saleheen, Danish ; Trompet, Stella ; Jukema, J Wouter ; De Craen, Anton ; Deloukas, Panos ; Sattar, Naveed ; Ford,...
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1Amino Acid Substitution–Blood
2Animals–Genetics
3Cholesterol, HDL–Genetics
4Coronary Disease–Genetics
5DNA Mutational Analysis–Genetics
6Female–Metabolism
7Genetic Variation–Metabolism
8Heterozygote–Metabolism
9Homozygote–Metabolism
10Humans–Metabolism
11Leucine–Metabolism
12Male–Metabolism...
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7Kontush, Anatol
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16Packard, Chris
17Majumder, Abdullah Al Shafi
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22Erdmann, Jeanette
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27Kuulasmaa, Kari
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30Blankenberg, Stefan
31Salomaa, Veikko
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33Amouyel, Philippe
34Arveiler, Dominique
35Ferrieres, Jean
36Müller-Nurasyid, Martina
37Ferrario, Marco
38Kee, Frank
39Willer, Cristen J
40Samani, Nilesh
41Schunkert, Heribert
42Butterworth, Adam S
43Howson, Joanna M M
44Peloso, Gina M
45Stitziel, Nathan O
46Danesh, John
47Kathiresan, Sekar
48Rader, Daniel J
49Watson, Sarah
50Schmidt, Ellen M
51Sengupta, Sebanti
52Gustafsson, Stefan
53Kanoni, Stavroula
54Ganna, Andrea
55Chen, Jin
56Buchkovich, Martin L
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58Beckmann, Jacques S
59Bragg-Gresham, Jennifer L
60Chang, Hsing-Yi
61Demirkan, Ayşe
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63Do, Ron
64Donnelly, Louise A
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70Fontanillas, Pierre
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73Gurdasani, Deepti
74Heikkilä, Kauko
75Hyppönen, Elina
76Isaacs, Aaron
77Jackson, Anne U
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93Petersen, Ann-Kristin
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22Jeanette
23Børge G
24Sune F
25Anne
26Ruth Frikke
27Kari
28Dajiang J
29Markus
30Stefan
31Veikko
32Satu
33Philippe
34Dominique
35Jean
36Martina
37Marco
38Frank
39Cristen J
40Nilesh
41Heribert
42Adam S
43Joanna M M
44Gina M
45Nathan O
46John
47Sekar
48Daniel J
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3Hancock-Cerutti, William F
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8Surendran, Praveen
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29Perola, Markus
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31Salomaa, Veikko
32Männistö, Satu
33Amouyel, Philippe
34Arveiler, Dominique
35Ferrieres, Jean
36Müller-Nurasyid, Martina
37Ferrario, Marco
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atitleRare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
jtitleScience (New York, N.Y.)
risdate20160311
volume351
issue6278
spage1166
epage1171
pages1166-1171
eissn1095-9203
formatjournal
genrearticle
ristypeJOUR
doi10.1126/science.aad3517
urlhttp://search.proquest.com/docview/1772834189/
issn00368075
date2016-03-11