A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults

China Kadoorie Biobank (CKB) collaborative group

doi:10.1093/ije/dyw087

A phenome-wide association study of a lipoprotein-associated phospholipase A₂ loss-of-function variant in 90 000 Chinese adults

China Kadoorie Biobank (CKB) collaborative group

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Abstract

Background: Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA₂ inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA₂.

Methods: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories.

Results: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) 1/4 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Conclusions: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.

Original language	English
Pages (from-to)	1588-1599
Number of pages	12
Journal	International Journal of Epidemiology
Volume	45
Issue number	5
DOIs	https://doi.org/10.1093/ije/dyw087
Publication status	Published - Oct 2016
Externally published	Yes

Bibliographical note

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Funder

Funding Information:
This work was supported by: the Kadoorie Charitable Foundation Hong Kong; UK Wellcome Trust (grant numbers 088158/Z/09/Z, 104085/Z/14/Z); Chinese Ministry of Science and Technology (grant number 2011BAI09B01); Chinese National Natural Science Foundation (grant numbers 81390541, 81390544); GlaxoSmithKline; and Merck Sharp & Dohme Corp. The British Heart Foundation, UK Medical Research Council and Cancer Research UK provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at the University of Oxford. Role of the funding source: the study was part-funded by GlaxoSmithKline, who collaborated in developing the study design, analysis plan, results interpretation and reporting. All data were analysed independently at CTSU. The corresponding authors had access to all the data in the study and had final responsibility for the decision to submit for publication.

Funding

This work was supported by: the Kadoorie Charitable Foundation Hong Kong; UK Wellcome Trust (grant numbers 088158/Z/09/Z, 104085/Z/14/Z); Chinese Ministry of Science and Technology (grant number 2011BAI09B01); Chinese National Natural Science Foundation (grant numbers 81390541, 81390544); GlaxoSmithKline; and Merck Sharp & Dohme Corp. The British Heart Foundation, UK Medical Research Council and Cancer Research UK provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at the University of Oxford. Role of the funding source: the study was part-funded by GlaxoSmithKline, who collaborated in developing the study design, analysis plan, results interpretation and reporting. All data were analysed independently at CTSU. The corresponding authors had access to all the data in the study and had final responsibility for the decision to submit for publication.

Keywords

China
Genetic association
Lp-PLA2
Phenome-wide
Vascular disease

ASJC Scopus subject areas

Epidemiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/ije/dyw087Licence: CC BY

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Cite this

@article{59b99d76d24547429df506965d35a157,

title = "A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults",

abstract = "Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2. Methods: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. Results: PLA2G7 V279F frequency was 5\% overall (range 3-7\% by region), and 9691 (11\%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) 1/4 0.98 per F variant, 95\% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Conclusions: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.",

keywords = "China, Genetic association, Lp-PLA2, Phenome-wide, Vascular disease",

author = "\{China Kadoorie Biobank (CKB) collaborative group\} and Millwood, \{Iona Y.\} and Bennett, \{Derrick A.\} and Walters, \{Robin G.\} and Robert Clarke and Dawn Waterworth and Toby Johnson and Yiping Chen and Ling Yang and Yu Guo and Zheng Bian and Alex Hacker and Astrid Yeo and Sarah Parish and Hill, \{Michael R.\} and Stephanie Chissoe and Richard Peto and Lon Cardon and Rory Collins and Liming Li and Zhengming Chen and Junshi Chen and Daniel Avery and Yumei Chang and Huaidong Du and Xuejuan Fan and Simon Gilbert and Michael Holmes and Andri Iona and Rene Kerosi and Ling Kong and Om Kurmi and Garry Lancaster and Sarah Lewington and John McDonnell and Winnie Mei and Qunhua Nie and Jayakrishnan Radhakrishnan and Paul Ryder and Sam Sansome and Dan Schmidt and Paul Sherliker and Rajani Sohoni and Luanlaun Sun and Jenny Wang and Lin Wang and Xiaoming Yang and Ge Chen and Lei Guo and Bingyang Han and Can Hou",

note = "This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.",

year = "2016",

month = oct,

doi = "10.1093/ije/dyw087",

language = "English",

volume = "45",

pages = "1588--1599",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults

AU - China Kadoorie Biobank (CKB) collaborative group

AU - Millwood, Iona Y.

AU - Bennett, Derrick A.

AU - Walters, Robin G.

AU - Clarke, Robert

AU - Waterworth, Dawn

AU - Johnson, Toby

AU - Chen, Yiping

AU - Yang, Ling

AU - Guo, Yu

AU - Bian, Zheng

AU - Hacker, Alex

AU - Yeo, Astrid

AU - Parish, Sarah

AU - Hill, Michael R.

AU - Chissoe, Stephanie

AU - Peto, Richard

AU - Cardon, Lon

AU - Collins, Rory

AU - Li, Liming

AU - Chen, Zhengming

AU - Chen, Junshi

AU - Avery, Daniel

AU - Chang, Yumei

AU - Du, Huaidong

AU - Fan, Xuejuan

AU - Gilbert, Simon

AU - Holmes, Michael

AU - Iona, Andri

AU - Kerosi, Rene

AU - Kong, Ling

AU - Kurmi, Om

AU - Lancaster, Garry

AU - Lewington, Sarah

AU - McDonnell, John

AU - Mei, Winnie

AU - Nie, Qunhua

AU - Radhakrishnan, Jayakrishnan

AU - Ryder, Paul

AU - Sansome, Sam

AU - Schmidt, Dan

AU - Sherliker, Paul

AU - Sohoni, Rajani

AU - Sun, Luanlaun

AU - Wang, Jenny

AU - Wang, Lin

AU - Yang, Xiaoming

AU - Chen, Ge

AU - Guo, Lei

AU - Han, Bingyang

AU - Hou, Can

N1 - This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

PY - 2016/10

Y1 - 2016/10

N2 - Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2. Methods: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. Results: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) 1/4 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Conclusions: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.

AB - Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2. Methods: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. Results: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) 1/4 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Conclusions: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.

KW - China

KW - Genetic association

KW - Lp-PLA2

KW - Phenome-wide

KW - Vascular disease

UR - https://www.scopus.com/pages/publications/85020565329

U2 - 10.1093/ije/dyw087

DO - 10.1093/ije/dyw087

M3 - Article

C2 - 27301456

AN - SCOPUS:85020565329

SN - 0300-5771

VL - 45

SP - 1588

EP - 1599

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 5

ER -