Abstract
Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
| Original language | English |
|---|---|
| Article number | 240 |
| Journal | BMC Cardiovascular Disorders |
| Volume | 19 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 29 Oct 2019 |
Keywords
- Genetic association studies
- LDL-cholesterol
- Mendelian randomisation
- Phenome-wide association scan
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. / Schmidt, Amand F.; Holmes, Michael V.; Preiss, David; Swerdlow, Daniel I.; Denaxas, Spiros; Fatemifar, Ghazaleh; Faraway, Rupert; Finan, Chris; Valentine, Dennis; Fairhurst-Hunter, Zammy; Hartwig, Fernando Pires; Horta, Bernardo Lessa; Hypponen, Elina; Power, Christine; Moldovan, Max; Van Iperen, Erik; Hovingh, Kees; Demuth, Ilja; Norman, Kristina; Steinhagen-Thiessen, Elisabeth; Demuth, Juri; Bertram, Lars; Lill, Christina M.; Coassin, Stefan; Willeit, Johann; Kiechl, Stefan; Willeit, Karin; Mason, Dan; Wright, John; Morris, Richard; Wanamethee, Goya; Whincup, Peter; Ben-Shlomo, Yoav; McLachlan, Stela; Price, Jackie F.; Kivimaki, Mika; Welch, Catherine; Sanchez-Galvez, Adelaida; Marques-Vidal, Pedro; Nicolaides, Andrew; Panayiotou, Andrie G.; Onland-Moret, N. Charlotte; Van Der Schouw, Yvonne T.; Matullo, Giuseppe; Fiorito, Giovanni; Guarrera, Simonetta; Sacerdote, Carlotta; Wareham, Nicholas J.; Langenberg, Claudia; Scott, Robert A.; Luan, Jian'An; Bobak, Martin; Malyutina, Sofia; Pajak, Andrzej; Kubinova, Ruzena; Tamosiunas, Abdonas; Pikhart, Hynek; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Linneberg, Allan; Jess, Tine; Cooper, Jackie; Humphries, Steve E.; Brilliant, Murray; Kitchner, Terrie; Hakonarson, Hakon; Carrell, David S.; McCarty, Catherine A.; Lester, Kirchner H.; Larson, Eric B.; Crosslin, David R.; De Andrade, Mariza; Roden, Dan M.; Denny, Joshua C.; Carty, Cara; Hancock, Stephen; Attia, John; Holliday, Elizabeth; Scott, Rodney; Schofield, Peter; O'Donnell, Martin; Yusuf, Salim; Chong, Michael; Pare, Guillaume; Van Der Harst, Pim; Said, M. Abdullah; Eppinga, Ruben N.; Verweij, Niek; Snieder, Harold; Christen, Tim; Mook-Kanamori, D. O.; Gustafsson, Stefan; Lind, Lars; Ingelsson, Erik; Pazoki, Raha; Franco, Oscar; Hofman, Albert; Uitterlinden, Andre; Dehghan, Abbas; Teumer, Alexander; Baumeister, Sebastian; Dörr, Marcus; Lerch, Markus M.; Völker, Uwe; Völzke, Henry; Ward, Joey; Pell, Jill P.; Meade, Tom; Christophersen, Ingrid E.; Maitland-Van Der Zee, Anke H.; Baranova, Ekaterina V.; Young, Robin; Ford, Ian; Campbell, Archie; Padmanabhan, Sandosh; Bots, Michiel L.; Grobbee, Diederick E.; Froguel, Philippe; Thuillier, Dorothée; Roussel, Ronan; Bonnefond, Amélie; Cariou, Bertrand; Smart, Melissa; Bao, Yanchun; Kumari, Meena; Mahajan, Anubha; Hopewell, Jemma C.; Seshadri, Sudha; Dale, Caroline; Costa, Rui Providencia E.; Ridker, Paul M.; Chasman, Daniel I.; Reiner, Alex P.; Ritchie, Marylyn D.; Lange, Leslie A.; Cornish, Alex J.; Dobbins, Sara E.; Hemminki, Kari; Kinnersley, Ben; Sanson, Marc; Labreche, Karim; Simon, Matthias; Bondy, Melissa; Law, Philip; Speedy, Helen; Allan, James; Li, Ni; Went, Molly; Weinhold, Niels; Morgan, Gareth; Sonneveld, Pieter; Nilsson, Björn; Goldschmidt, Hartmut; Sud, Amit; Engert, Andreas; Hansson, Markus; Hemingway, Harry; Asselbergs, Folkert W.; Patel, Riyaz S.; Keating, Brendan J.; Sattar, Naveed; Houlston, Richard; Casas, Juan P.; Hingorani, Aroon D.
In: BMC Cardiovascular Disorders, Vol. 19, No. 1, 240, 29.10.2019.Research output: Contribution to journal › Article
TY - JOUR
T1 - Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
AU - Schmidt, Amand F.
AU - Holmes, Michael V.
AU - Preiss, David
AU - Swerdlow, Daniel I.
AU - Denaxas, Spiros
AU - Fatemifar, Ghazaleh
AU - Faraway, Rupert
AU - Finan, Chris
AU - Valentine, Dennis
AU - Fairhurst-Hunter, Zammy
AU - Hartwig, Fernando Pires
AU - Horta, Bernardo Lessa
AU - Hypponen, Elina
AU - Power, Christine
AU - Moldovan, Max
AU - Van Iperen, Erik
AU - Hovingh, Kees
AU - Demuth, Ilja
AU - Norman, Kristina
AU - Steinhagen-Thiessen, Elisabeth
AU - Demuth, Juri
AU - Bertram, Lars
AU - Lill, Christina M.
AU - Coassin, Stefan
AU - Willeit, Johann
AU - Kiechl, Stefan
AU - Willeit, Karin
AU - Mason, Dan
AU - Wright, John
AU - Morris, Richard
AU - Wanamethee, Goya
AU - Whincup, Peter
AU - Ben-Shlomo, Yoav
AU - McLachlan, Stela
AU - Price, Jackie F.
AU - Kivimaki, Mika
AU - Welch, Catherine
AU - Sanchez-Galvez, Adelaida
AU - Marques-Vidal, Pedro
AU - Nicolaides, Andrew
AU - Panayiotou, Andrie G.
AU - Onland-Moret, N. Charlotte
AU - Van Der Schouw, Yvonne T.
AU - Matullo, Giuseppe
AU - Fiorito, Giovanni
AU - Guarrera, Simonetta
AU - Sacerdote, Carlotta
AU - Wareham, Nicholas J.
AU - Langenberg, Claudia
AU - Scott, Robert A.
AU - Luan, Jian'An
AU - Bobak, Martin
AU - Malyutina, Sofia
AU - Pajak, Andrzej
AU - Kubinova, Ruzena
AU - Tamosiunas, Abdonas
AU - Pikhart, Hynek
AU - Grarup, Niels
AU - Pedersen, Oluf
AU - Hansen, Torben
AU - Linneberg, Allan
AU - Jess, Tine
AU - Cooper, Jackie
AU - Humphries, Steve E.
AU - Brilliant, Murray
AU - Kitchner, Terrie
AU - Hakonarson, Hakon
AU - Carrell, David S.
AU - McCarty, Catherine A.
AU - Lester, Kirchner H.
AU - Larson, Eric B.
AU - Crosslin, David R.
AU - De Andrade, Mariza
AU - Roden, Dan M.
AU - Denny, Joshua C.
AU - Carty, Cara
AU - Hancock, Stephen
AU - Attia, John
AU - Holliday, Elizabeth
AU - Scott, Rodney
AU - Schofield, Peter
AU - O'Donnell, Martin
AU - Yusuf, Salim
AU - Chong, Michael
AU - Pare, Guillaume
AU - Van Der Harst, Pim
AU - Said, M. Abdullah
AU - Eppinga, Ruben N.
AU - Verweij, Niek
AU - Snieder, Harold
AU - Christen, Tim
AU - Mook-Kanamori, D. O.
AU - Gustafsson, Stefan
AU - Lind, Lars
AU - Ingelsson, Erik
AU - Pazoki, Raha
AU - Franco, Oscar
AU - Hofman, Albert
AU - Uitterlinden, Andre
AU - Dehghan, Abbas
AU - Teumer, Alexander
AU - Baumeister, Sebastian
AU - Dörr, Marcus
AU - Lerch, Markus M.
AU - Völker, Uwe
AU - Völzke, Henry
AU - Ward, Joey
AU - Pell, Jill P.
AU - Meade, Tom
AU - Christophersen, Ingrid E.
AU - Maitland-Van Der Zee, Anke H.
AU - Baranova, Ekaterina V.
AU - Young, Robin
AU - Ford, Ian
AU - Campbell, Archie
AU - Padmanabhan, Sandosh
AU - Bots, Michiel L.
AU - Grobbee, Diederick E.
AU - Froguel, Philippe
AU - Thuillier, Dorothée
AU - Roussel, Ronan
AU - Bonnefond, Amélie
AU - Cariou, Bertrand
AU - Smart, Melissa
AU - Bao, Yanchun
AU - Kumari, Meena
AU - Mahajan, Anubha
AU - Hopewell, Jemma C.
AU - Seshadri, Sudha
AU - Dale, Caroline
AU - Costa, Rui Providencia E.
AU - Ridker, Paul M.
AU - Chasman, Daniel I.
AU - Reiner, Alex P.
AU - Ritchie, Marylyn D.
AU - Lange, Leslie A.
AU - Cornish, Alex J.
AU - Dobbins, Sara E.
AU - Hemminki, Kari
AU - Kinnersley, Ben
AU - Sanson, Marc
AU - Labreche, Karim
AU - Simon, Matthias
AU - Bondy, Melissa
AU - Law, Philip
AU - Speedy, Helen
AU - Allan, James
AU - Li, Ni
AU - Went, Molly
AU - Weinhold, Niels
AU - Morgan, Gareth
AU - Sonneveld, Pieter
AU - Nilsson, Björn
AU - Goldschmidt, Hartmut
AU - Sud, Amit
AU - Engert, Andreas
AU - Hansson, Markus
AU - Hemingway, Harry
AU - Asselbergs, Folkert W.
AU - Patel, Riyaz S.
AU - Keating, Brendan J.
AU - Sattar, Naveed
AU - Houlston, Richard
AU - Casas, Juan P.
AU - Hingorani, Aroon D.
PY - 2019/10/29
Y1 - 2019/10/29
N2 - Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
AB - Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
KW - Genetic association studies
KW - LDL-cholesterol
KW - Mendelian randomisation
KW - Phenome-wide association scan
UR - http://www.scopus.com/inward/record.url?scp=85074350493&partnerID=8YFLogxK
U2 - 10.1186/s12872-019-1187-z
DO - 10.1186/s12872-019-1187-z
M3 - Article
C2 - 31664920
AN - SCOPUS:85074350493
VL - 19
JO - BMC Cardiovascular Disorders
JF - BMC Cardiovascular Disorders
SN - 1471-2261
IS - 1
M1 - 240
ER -