Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

GM Peloso; PL Auer; JC Bis; A Voorman; AC Morrison; NO Stitziel; JA Brody; SA Khetarpal; JR Crosby; M Fomage; Aaron Isaacs; J Jakobsdottir; MF Feitosa; G Davies; JE Huffman; A Manichaikul; B Davis; K Lohman; AY (Aaron) Joon; AV Smith; ML Grove; P Zanoni; V Redon; S Demissie; K Lawson; U Peters; C Carlson; RD Jackson; KK Ryckman; RH Mackey; JG Robinson; DS Siscovick; PJ Schreiner; JC Mychaleckyj; JS Pankow; A Holman; André Uitterlinden; TB Harris; KD Taylor; JM Stafford; LM Reynolds; RE Marioni; Abbas Dehghan; OH Franco Duran; AP Patele; YC Lu; G Hindy; O Gottesman; EP Bottinger; O Melander; M Orho-Melander; RJF Loos; S Duga; PA Merlini; M Farrall; A Goel; R Asselta; D Girelli; N Martinelli; SH Shah; WE Kraus; MY Li; DJ Rader; MP Reilly; R McPherson; H Watkins; D Ardissino; QY Zhang; JD Wang; MY Tsai; HA Taylor; A Correa; ME Griswold; LA Lange; JM Starr; I Rudan; G Eiriksdottir; LJ (Lenore) Launer; JM Ordovas; D Levy; YDI Chen; AP Reiner; C Hayward; O Polasek; IJ Deary; IB Borecki; YM Liu; V Gudnason; JG Wilson; Cornelia Duijn; C Kooperberg; SS Rich; BM Psaty; JI Rotter; CJ O'Donnell; K Rice; E Boerwinkle; S Kathiresan; LA Cupples

doi:10.1016/j.ajhg.2014.01.009

Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

GM Peloso, PL Auer, JC Bis, A Voorman, AC Morrison, NO Stitziel, JA Brody, SA Khetarpal, JR Crosby, M Fomage, Aaron Isaacs, J Jakobsdottir, MF Feitosa, G Davies, JE Huffman, A Manichaikul, B Davis, K Lohman, AY (Aaron) Joon, AV SmithML Grove, P Zanoni, V Redon, S Demissie, K Lawson, U Peters, C Carlson, RD Jackson, KK Ryckman, RH Mackey, JG Robinson, DS Siscovick, PJ Schreiner, JC Mychaleckyj, JS Pankow, A Holman, André Uitterlinden, TB Harris, KD Taylor, JM Stafford, LM Reynolds, RE Marioni, Abbas Dehghan, OH Franco Duran, AP Patele, YC Lu, G Hindy, O Gottesman, EP Bottinger, O Melander, M Orho-Melander, RJF Loos, S Duga, PA Merlini, M Farrall, A Goel, R Asselta, D Girelli, N Martinelli, SH Shah, WE Kraus, MY Li, DJ Rader, MP Reilly, R McPherson, H Watkins, D Ardissino, QY Zhang, JD Wang, MY Tsai, HA Taylor, A Correa, ME Griswold, LA Lange, JM Starr, I Rudan, G Eiriksdottir, LJ (Lenore) Launer, JM Ordovas, D Levy, YDI Chen, AP Reiner, C Hayward, O Polasek, IJ Deary, IB Borecki, YM Liu, V Gudnason, JG Wilson, Cornelia Duijn, C Kooperberg, SS Rich, BM Psaty, JI Rotter, CJ O'Donnell, K Rice, E Boerwinkle, S Kathiresan, LA Cupples

External organisation

Research output: Contribution to journal › Article › Academic › peer-review

269 Citations (Scopus)

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Original language	Undefined/Unknown
Pages (from-to)	223-232
Number of pages	10
Journal	American Journal of Human Genetics
Volume	94
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2014.01.009
Publication status	Published - 2014

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-01

Access to Document

10.1016/j.ajhg.2014.01.009

Cite this

Peloso, GM., Auer, PL., Bis, JC., Voorman, A., Morrison, AC., Stitziel, NO., Brody, JA., Khetarpal, SA., Crosby, JR., Fomage, M., Isaacs, A., Jakobsdottir, J., Feitosa, MF., Davies, G., Huffman, JE., Manichaikul, A., Davis, B., Lohman, K., Joon, AY., ... Cupples, LA. (2014). Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks. American Journal of Human Genetics, 94(2), 223-232. https://doi.org/10.1016/j.ajhg.2014.01.009

@article{739fff8e9e684f48813559578800826f,

title = "Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks",

abstract = "Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the {"}Exome Array{"} to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1\% and 2\%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.",

author = "GM Peloso and PL Auer and JC Bis and A Voorman and AC Morrison and NO Stitziel and JA Brody and SA Khetarpal and JR Crosby and M Fomage and Aaron Isaacs and J Jakobsdottir and MF Feitosa and G Davies and JE Huffman and A Manichaikul and B Davis and K Lohman and Joon, \{AY (Aaron)\} and AV Smith and ML Grove and P Zanoni and V Redon and S Demissie and K Lawson and U Peters and C Carlson and RD Jackson and KK Ryckman and RH Mackey and JG Robinson and DS Siscovick and PJ Schreiner and JC Mychaleckyj and JS Pankow and A Holman and Andr{\'e} Uitterlinden and TB Harris and KD Taylor and JM Stafford and LM Reynolds and RE Marioni and Abbas Dehghan and \{Franco Duran\}, OH and AP Patele and YC Lu and G Hindy and O Gottesman and EP Bottinger and O Melander and M Orho-Melander and RJF Loos and S Duga and PA Merlini and M Farrall and A Goel and R Asselta and D Girelli and N Martinelli and SH Shah and WE Kraus and MY Li and DJ Rader and MP Reilly and R McPherson and H Watkins and D Ardissino and QY Zhang and JD Wang and MY Tsai and HA Taylor and A Correa and ME Griswold and LA Lange and JM Starr and I Rudan and G Eiriksdottir and Launer, \{LJ (Lenore)\} and JM Ordovas and D Levy and YDI Chen and AP Reiner and C Hayward and O Polasek and IJ Deary and IB Borecki and YM Liu and V Gudnason and JG Wilson and Cornelia Duijn and C Kooperberg and SS Rich and BM Psaty and JI Rotter and CJ O'Donnell and K Rice and E Boerwinkle and S Kathiresan and LA Cupples",

year = "2014",

doi = "10.1016/j.ajhg.2014.01.009",

language = "Undefined/Unknown",

volume = "94",

pages = "223--232",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Peloso, GM, Auer, PL, Bis, JC, Voorman, A, Morrison, AC, Stitziel, NO, Brody, JA, Khetarpal, SA, Crosby, JR, Fomage, M, Isaacs, A, Jakobsdottir, J, Feitosa, MF, Davies, G, Huffman, JE, Manichaikul, A, Davis, B, Lohman, K, Joon, AY, Smith, AV, Grove, ML, Zanoni, P, Redon, V, Demissie, S, Lawson, K, Peters, U, Carlson, C, Jackson, RD, Ryckman, KK, Mackey, RH, Robinson, JG, Siscovick, DS, Schreiner, PJ, Mychaleckyj, JC, Pankow, JS, Holman, A, Uitterlinden, A, Harris, TB, Taylor, KD, Stafford, JM, Reynolds, LM, Marioni, RE, Dehghan, A, Franco Duran, OH, Patele, AP, Lu, YC, Hindy, G, Gottesman, O, Bottinger, EP, Melander, O, Orho-Melander, M, Loos, RJF, Duga, S, Merlini, PA, Farrall, M, Goel, A, Asselta, R, Girelli, D, Martinelli, N, Shah, SH, Kraus, WE, Li, MY, Rader, DJ, Reilly, MP, McPherson, R, Watkins, H, Ardissino, D, Zhang, QY, Wang, JD, Tsai, MY, Taylor, HA, Correa, A, Griswold, ME, Lange, LA, Starr, JM, Rudan, I, Eiriksdottir, G, Launer, LJ, Ordovas, JM, Levy, D, Chen, YDI, Reiner, AP, Hayward, C, Polasek, O, Deary, IJ, Borecki, IB, Liu, YM, Gudnason, V, Wilson, JG, Duijn, C, Kooperberg, C, Rich, SS, Psaty, BM, Rotter, JI, O'Donnell, CJ, Rice, K, Boerwinkle, E, Kathiresan, S & Cupples, LA 2014, 'Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks', American Journal of Human Genetics, vol. 94, no. 2, pp. 223-232. https://doi.org/10.1016/j.ajhg.2014.01.009

TY - JOUR

T1 - Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

AU - Peloso, GM

AU - Auer, PL

AU - Bis, JC

AU - Voorman, A

AU - Morrison, AC

AU - Stitziel, NO

AU - Brody, JA

AU - Khetarpal, SA

AU - Crosby, JR

AU - Fomage, M

AU - Isaacs, Aaron

AU - Jakobsdottir, J

AU - Feitosa, MF

AU - Davies, G

AU - Huffman, JE

AU - Manichaikul, A

AU - Davis, B

AU - Lohman, K

AU - Joon, AY (Aaron)

AU - Smith, AV

AU - Grove, ML

AU - Zanoni, P

AU - Redon, V

AU - Demissie, S

AU - Lawson, K

AU - Peters, U

AU - Carlson, C

AU - Jackson, RD

AU - Ryckman, KK

AU - Mackey, RH

AU - Robinson, JG

AU - Siscovick, DS

AU - Schreiner, PJ

AU - Mychaleckyj, JC

AU - Pankow, JS

AU - Holman, A

AU - Uitterlinden, André

AU - Harris, TB

AU - Taylor, KD

AU - Stafford, JM

AU - Reynolds, LM

AU - Marioni, RE

AU - Dehghan, Abbas

AU - Franco Duran, OH

AU - Patele, AP

AU - Lu, YC

AU - Hindy, G

AU - Gottesman, O

AU - Bottinger, EP

AU - Melander, O

AU - Orho-Melander, M

AU - Loos, RJF

AU - Duga, S

AU - Merlini, PA

AU - Farrall, M

AU - Goel, A

AU - Asselta, R

AU - Girelli, D

AU - Martinelli, N

AU - Shah, SH

AU - Kraus, WE

AU - Li, MY

AU - Rader, DJ

AU - Reilly, MP

AU - McPherson, R

AU - Watkins, H

AU - Ardissino, D

AU - Zhang, QY

AU - Wang, JD

AU - Tsai, MY

AU - Taylor, HA

AU - Correa, A

AU - Griswold, ME

AU - Lange, LA

AU - Starr, JM

AU - Rudan, I

AU - Eiriksdottir, G

AU - Launer, LJ (Lenore)

AU - Ordovas, JM

AU - Levy, D

AU - Chen, YDI

AU - Reiner, AP

AU - Hayward, C

AU - Polasek, O

AU - Deary, IJ

AU - Borecki, IB

AU - Liu, YM

AU - Gudnason, V

AU - Wilson, JG

AU - Duijn, Cornelia

AU - Kooperberg, C

AU - Rich, SS

AU - Psaty, BM

AU - Rotter, JI

AU - O'Donnell, CJ

AU - Rice, K

AU - Boerwinkle, E

AU - Kathiresan, S

AU - Cupples, LA

PY - 2014

Y1 - 2014

N2 - Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

AB - Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

U2 - 10.1016/j.ajhg.2014.01.009

DO - 10.1016/j.ajhg.2014.01.009

M3 - Article

C2 - 24507774

SN - 0002-9297

VL - 94

SP - 223

EP - 232

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -