TY - JOUR
T1 - Mendelian randomization of blood lipids for coronary heart disease
AU - Holmes, Michael V
AU - Asselbergs, Folkert W
AU - Palmer, Tom M
AU - Drenos, Fotios
AU - Lanktree, Matthew B
AU - Nelson, Christopher P
AU - Dale, Caroline E
AU - Padmanabhan, Sandosh
AU - Finan, Chris
AU - Swerdlow, Daniel I
AU - Tragante, Vinicius
AU - van Iperen, Erik P A
AU - Sivapalaratnam, Suthesh
AU - Shah, Sonia
AU - Elbers, Clara C
AU - Shah, Tina
AU - Engmann, Jorgen
AU - Giambartolomei, Claudia
AU - White, Jon
AU - Zabaneh, Delilah
AU - Sofat, Reecha
AU - McLachlan, Stela
AU - Doevendans, Pieter A
AU - Balmforth, Anthony J
AU - Hall, Alistair S
AU - North, Kari E
AU - Almoguera, Berta
AU - Hoogeveen, Ron C
AU - Cushman, Mary
AU - Fornage, Myriam
AU - Patel, Sanjay R
AU - Redline, Susan
AU - Siscovick, David S
AU - Tsai, Michael Y
AU - Karczewski, Konrad J
AU - Hofker, Marten H
AU - Verschuren, W Monique
AU - Bots, Michiel L
AU - van der Schouw, Yvonne T
AU - Melander, Olle
AU - Dominiczak, Anna F
AU - Morris, Richard
AU - Ben-Shlomo, Yoav
AU - Price, Jackie
AU - Kumari, Meena
AU - Baumert, Jens
AU - Gaunt, Tom R
AU - Wilson, James G
AU - Davey Smith, George
AU - Lawlor, Debbie A
AU - UCLEB Consortium
PY - 2014/1/27
Y1 - 2014/1/27
N2 - AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
AB - AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
U2 - 10.1093/eurheartj/eht571
DO - 10.1093/eurheartj/eht571
M3 - Article (Academic Journal)
C2 - 24474739
VL - 36
SP - 539
EP - 550
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 9
ER -
