A common missense variant of LILRB5 is associated with statin intolerance and myalgia

Moneeza K. Siddiqui; Cyrielle Maroteau; Abirami Veluchamy; Aleksi Tornio; Roger Tavendale; Fiona Carr; Ngu-Uma Abelega; Dan Carr; Katyrzyna Bloch; Par Hallberg; Qun-Ying Yue; Ewan R. Pearson; Helen Colhoun; Andrew D. Morris; Eleanor Dow; Jacob George; Munir Pirmohamed; Paul M. Ridker; Alex S. F. Doney; Ana Alfirevic; Mia Wadelius; Anke Hilse Maitland-van der Zee; Daniel I. Chasman; Colin N. A. Palmer; PREDICTION-ADR Consortium

doi:10.1093/eurheartj/ehx467

A common missense variant of LILRB₅ is associated with statin intolerance and myalgia

Moneeza K. Siddiqui, Cyrielle Maroteau, Abirami Veluchamy, Aleksi Tornio, Roger Tavendale, Fiona Carr, Ngu-Uma Abelega, Dan Carr, Katyrzyna Bloch, Par Hallberg, Qun-Ying Yue, Ewan R. Pearson, Helen Colhoun, Andrew D. Morris, Eleanor Dow, Jacob George, Munir Pirmohamed, Paul M. Ridker, Alex S. F. Doney, Ana AlfirevicMia Wadelius, Anke Hilse Maitland-van der Zee, Daniel I. Chasman, Colin N. A. Palmer (Lead / Corresponding author), PREDICTION-ADR Consortium

Population Health and Genomics

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

39 Citations (Scopus)

228 Downloads (Pure)

Abstract

Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366:T>C:Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.

Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy (OR1.81;95%CI:1.34, 2.45) and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36;95%CI:1.07, 1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48;95%CI:1.05,2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35,95%CI:1.10,1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34;95%CI:1.16,1.54).

Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

Original language	English
Pages (from-to)	3569-3575
Number of pages	7
Journal	European Heart Journal
Volume	38
Issue number	48
Early online date	29 Aug 2017
DOIs	https://doi.org/10.1093/eurheartj/ehx467
Publication status	Published - 21 Dec 2017

Keywords

Statins
Pharmacogenetics
Immunogenetics
Precision medicine
Adverse Drug Reactions
Myalgia

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10.1093/eurheartj/ehx467Licence: CC BY

Final Published Version
© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology. 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.
Final published version, 156 KBLicence: CC BY

PREDICTION-ADR: Personalisation of tREatment In Cardiovascular Disease Through Next Generation Sequencing - Adverse Drug Reactions (Joint with University of Uppsala, University of Liverpool and University of Utrecht)
Palmer, C. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/09/13 → 28/02/17
Project: Research
The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)
Colhoun, H. (Investigator), Donnan, P. (Investigator), Guthrie, B. (Investigator), Jefferson, E. (Investigator), MacDonald, T. (Investigator), McCowan, C. (Investigator), Morris, A. (Investigator), Pearson, E. (Investigator), Sullivan, F. (Investigator) & Swedlow, J. (Investigator)
Medical Research Council
1/03/13 → 31/12/18
Project: Research

Doney, Alexander
- Cardiovascular Research - Clinical Reader (Teaching and Research)
Person: Academic
Palmer, Colin
- Population Health and Genomics - Professor (Teaching and Research) of Pharmacogenomics
Person: Academic

Health Informatics Centre
Health and Clinical Services
Facility/equipment: Facility

Cite this

Siddiqui, M. K., Maroteau, C., Veluchamy, A., Tornio, A., Tavendale, R., Carr, F., Abelega, N.-U., Carr, D., Bloch, K., Hallberg, P., Yue, Q.-Y., Pearson, E. R., Colhoun, H., Morris, A. D., Dow, E., George, J., Pirmohamed, M., Ridker, P. M., Doney, A. S. F., ... PREDICTION-ADR Consortium (2017). A common missense variant of LILRB₅ is associated with statin intolerance and myalgia. European Heart Journal, 38(48), 3569-3575. https://doi.org/10.1093/eurheartj/ehx467

@article{bd7cd5f054f04903ac0aaad904ef7e28,

title = "A common missense variant of LILRB5 is associated with statin intolerance and myalgia",

abstract = "Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366:T>C:Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy (OR1.81;95%CI:1.34, 2.45) and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36;95%CI:1.07, 1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48;95%CI:1.05,2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35,95%CI:1.10,1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34;95%CI:1.16,1.54).Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.",

keywords = "Statins, Pharmacogenetics, Immunogenetics, Precision medicine, Adverse Drug Reactions, Myalgia",

author = "Siddiqui, {Moneeza K.} and Cyrielle Maroteau and Abirami Veluchamy and Aleksi Tornio and Roger Tavendale and Fiona Carr and Ngu-Uma Abelega and Dan Carr and Katyrzyna Bloch and Par Hallberg and Qun-Ying Yue and Pearson, {Ewan R.} and Helen Colhoun and Morris, {Andrew D.} and Eleanor Dow and Jacob George and Munir Pirmohamed and Ridker, {Paul M.} and Doney, {Alex S. F.} and Ana Alfirevic and Mia Wadelius and {Maitland-van der Zee}, {Anke Hilse} and Chasman, {Daniel I.} and Palmer, {Colin N. A.} and {PREDICTION-ADR Consortium}",

note = "This work was supported by funded from the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) [Grant no. 602108] through the PREDICTION-ADR project to MKS, CM, DC, KB, MP, MW, AA, AHM, and CNAP. PREDICTION-ADR cohort used individuals from the SHARE Bioresource (GoSHARE) and SHARE has ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. The GoDARTS study was funded by The Wellcome Trust (Award 072960 and 084726) and the UK Medical Research Council (Award G0601261). Genetic analysis in the JUPITER trial was supported by a research grant from AstraZeneca jointly to DIC and PMR. Recruitment of Swedish patients was supported by the Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), Swedish Heart and Lung Foundation (20120557 and 20140291), the Medical Products Agency, Selander{\textquoteright}s Foundation, Thureus{\textquoteright} Foundation, and the Clinical Research Support {\textquoteleft}Avtal om Lӓkarutbildning och Forskning{\textquoteright} at Uppsala University, Sweden. CPRD-STAGE was funded by a grant from the e-Health Initiative funded jointly by the Medical Research Council (reference: MC_qA137929), the Wellcome Trust, the Engineering and Physical Sciences Research Council, and The Economic and Social Research Council. M.P. is a National Institute for Health Research senior investigator.",

year = "2017",

month = dec,

day = "21",

doi = "10.1093/eurheartj/ehx467",

language = "English",

volume = "38",

pages = "3569--3575",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "48",

}

Siddiqui, MK, Maroteau, C, Veluchamy, A, Tornio, A, Tavendale, R, Carr, F, Abelega, N-U, Carr, D, Bloch, K, Hallberg, P, Yue, Q-Y, Pearson, ER, Colhoun, H, Morris, AD, Dow, E, George, J, Pirmohamed, M, Ridker, PM, Doney, ASF, Alfirevic, A, Wadelius, M, Maitland-van der Zee, AH, Chasman, DI, Palmer, CNA & PREDICTION-ADR Consortium 2017, 'A common missense variant of LILRB₅ is associated with statin intolerance and myalgia', European Heart Journal, vol. 38, no. 48, pp. 3569-3575. https://doi.org/10.1093/eurheartj/ehx467

TY - JOUR

T1 - A common missense variant of LILRB5 is associated with statin intolerance and myalgia

AU - Siddiqui, Moneeza K.

AU - Maroteau, Cyrielle

AU - Veluchamy, Abirami

AU - Tornio, Aleksi

AU - Tavendale, Roger

AU - Carr, Fiona

AU - Abelega, Ngu-Uma

AU - Carr, Dan

AU - Bloch, Katyrzyna

AU - Hallberg, Par

AU - Yue, Qun-Ying

AU - Pearson, Ewan R.

AU - Colhoun, Helen

AU - Morris, Andrew D.

AU - Dow, Eleanor

AU - George, Jacob

AU - Pirmohamed, Munir

AU - Ridker, Paul M.

AU - Doney, Alex S. F.

AU - Alfirevic, Ana

AU - Wadelius, Mia

AU - Maitland-van der Zee, Anke Hilse

AU - Chasman, Daniel I.

AU - Palmer, Colin N. A.

AU - PREDICTION-ADR Consortium

N1 - This work was supported by funded from the European Community’s Seventh Framework Programme (FP7/2007-2013) [Grant no. 602108] through the PREDICTION-ADR project to MKS, CM, DC, KB, MP, MW, AA, AHM, and CNAP. PREDICTION-ADR cohort used individuals from the SHARE Bioresource (GoSHARE) and SHARE has ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. The GoDARTS study was funded by The Wellcome Trust (Award 072960 and 084726) and the UK Medical Research Council (Award G0601261). Genetic analysis in the JUPITER trial was supported by a research grant from AstraZeneca jointly to DIC and PMR. Recruitment of Swedish patients was supported by the Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), Swedish Heart and Lung Foundation (20120557 and 20140291), the Medical Products Agency, Selander’s Foundation, Thureus’ Foundation, and the Clinical Research Support ‘Avtal om Lӓkarutbildning och Forskning’ at Uppsala University, Sweden. CPRD-STAGE was funded by a grant from the e-Health Initiative funded jointly by the Medical Research Council (reference: MC_qA137929), the Wellcome Trust, the Engineering and Physical Sciences Research Council, and The Economic and Social Research Council. M.P. is a National Institute for Health Research senior investigator.

PY - 2017/12/21

Y1 - 2017/12/21

N2 - Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366:T>C:Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy (OR1.81;95%CI:1.34, 2.45) and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36;95%CI:1.07, 1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48;95%CI:1.05,2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35,95%CI:1.10,1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34;95%CI:1.16,1.54).Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

AB - Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366:T>C:Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy (OR1.81;95%CI:1.34, 2.45) and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36;95%CI:1.07, 1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48;95%CI:1.05,2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35,95%CI:1.10,1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34;95%CI:1.16,1.54).Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

KW - Statins

KW - Pharmacogenetics

KW - Immunogenetics

KW - Precision medicine

KW - Adverse Drug Reactions

KW - Myalgia

U2 - 10.1093/eurheartj/ehx467

DO - 10.1093/eurheartj/ehx467

M3 - Article

C2 - 29020356

SN - 0195-668X

VL - 38

SP - 3569

EP - 3575

JO - European Heart Journal

JF - European Heart Journal

IS - 48

ER -

A common missense variant of LILRB5 is associated with statin intolerance and myalgia

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PREDICTION-ADR: Personalisation of tREatment In Cardiovascular Disease Through Next Generation Sequencing - Adverse Drug Reactions (Joint with University of Uppsala, University of Liverpool and University of Utrecht)

The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)

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Doney, Alexander

Palmer, Colin

Equipment

Health Informatics Centre

Cite this

A common missense variant of LILRB₅ is associated with statin intolerance and myalgia