Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study

Michael V. Holmes; Tabassome Simon; Holly J. Exeter; Lasse Folkersen; Folkert W. Asselbergs; Montse Guardiola; Jackie A. Cooper; Jutta Palmen; Jaroslav A. Hubacek; Kathryn F. Carruthers; Benjamin D. Horne; Kimberly D. Brunisholz; Jessica L. Mega; Erik P. A. van Iperen; Mingyao Li; Maarten Leusink; Stella Trompet; Jeffrey J. W. Verschuren; G. Kees Hovingh; Abbas Dehghan; Christopher P. Nelson; Salma Kotti; Nicolas Danchin; Markus Scholz; Christiane L. Haase; Dietrich Rothenbacher; Daniel I. Swerdlow; Karoline B. Kuchenbaecker; Eleonora Staines-Urias; Anuj Goel; Ferdinand van 't Hooft; Karl Gertow; Ulf de Faire; Andrie G. Panayiotou; Elena Tremoli; Damiano Baldassarre; Fabrizio Veglia; Lesca M. Holdt; Frank Beutner; Ron T. Gansevoort; Gerjan J. Navis; Irene Mateo Leach; Lutz P. Breitling; Hermann Brenner; Joachim Thiery; Dhayana Dallmeier; Anders Franco-Cereceda; Jolanda M. A. Boer; Jeffrey W. Stephens; Marten H. Hofker; Alain Tedgui; Albert Hofman; André G. Uitterlinden; Vera Adamkova; Jan Pitha; N. Charlotte Onland-Moret; Maarten J. Cramer; Hendrik M. Nathoe; Wilko Spiering; Olaf H. Klungel; Meena Kumari; Peter H. Whincup; David A. Morrow; Peter S. Braund; Alistair S. Hall; Anders G. Olsson; Pieter A. Doevendans; Mieke D. Trip; Martin D. Tobin; Anders Hamsten; Hugh Watkins; Wolfgang Koenig; Andrew N. Nicolaides; Daniel Teupser; Ian N. M. Day; John F. Carlquist; Tom R. Gaunt; Ian Ford; Naveed Sattar; Sotirios Tsimikas; Gregory G. Schwartz; Debbie A. Lawlor; Richard W. Morris; Manjinder S. Sandhu; Rudolf Poledne; Anke H. Maitland-van der Zee; Kay-Tee Khaw; Brendan J. Keating; Pim van der Harst; Jackie F. Price; Shamir R. Mehta; Salim Yusuf; Jaqueline C. M. Witteman; Oscar H. Franco; J. Wouter Jukema; Peter de Knijff; Anne Tybjaerg-Hansen; Daniel J. Rader; Martin Farrall; Nilesh J. Samani; Mika Kivimaki; Keith A. A. Fox; Steve E. Humphries; Jeffrey L. Anderson; S. Matthijs Boekholdt; Tom M. Palmer; Per Eriksson; Guillaume Paré; Aroon D. Hingorani; Marc S. Sabatine; Ziad Mallat; Juan P. Casas; Philippa J. Talmud

doi:https://doi.org/10.1016/j.jacc.2013.06.044

Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study

Michael V. Holmes, Tabassome Simon, Holly J. Exeter, Lasse Folkersen, Folkert W. Asselbergs, Montse Guardiola, Jackie A. Cooper, Jutta Palmen, Jaroslav A. Hubacek, Kathryn F. Carruthers, Benjamin D. Horne, Kimberly D. Brunisholz, Jessica L. Mega, Erik P. A. van Iperen, Mingyao Li, Maarten Leusink, Stella Trompet, Jeffrey J. W. Verschuren, G. Kees Hovingh, Abbas DehghanChristopher P. Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L. Haase, Dietrich Rothenbacher, Daniel I. Swerdlow, Karoline B. Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van 't Hooft, Karl Gertow, Ulf de Faire, Andrie G. Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca M. Holdt, Frank Beutner, Ron T. Gansevoort, Gerjan J. Navis, Irene Mateo Leach, Lutz P. Breitling, Hermann Brenner, Joachim Thiery, Dhayana Dallmeier, Anders Franco-Cereceda, Jolanda M. A. Boer, Jeffrey W. Stephens, Marten H. Hofker, Alain Tedgui, Albert Hofman, André G. Uitterlinden, Vera Adamkova, Jan Pitha, N. Charlotte Onland-Moret, Maarten J. Cramer, Hendrik M. Nathoe, Wilko Spiering, Olaf H. Klungel, Meena Kumari, Peter H. Whincup, David A. Morrow, Peter S. Braund, Alistair S. Hall, Anders G. Olsson, Pieter A. Doevendans, Mieke D. Trip, Martin D. Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Koenig, Andrew N. Nicolaides, Daniel Teupser, Ian N. M. Day, John F. Carlquist, Tom R. Gaunt, Ian Ford, Naveed Sattar, Sotirios Tsimikas, Gregory G. Schwartz, Debbie A. Lawlor, Richard W. Morris, Manjinder S. Sandhu, Rudolf Poledne, Anke H. Maitland-van der Zee, Kay-Tee Khaw, Brendan J. Keating, Pim van der Harst, Jackie F. Price, Shamir R. Mehta, Salim Yusuf, Jaqueline C. M. Witteman, Oscar H. Franco, J. Wouter Jukema, Peter de Knijff, Anne Tybjaerg-Hansen, Daniel J. Rader, Martin Farrall, Nilesh J. Samani, Mika Kivimaki, Keith A. A. Fox, Steve E. Humphries, Jeffrey L. Anderson, S. Matthijs Boekholdt, Tom M. Palmer, Per Eriksson, Guillaume Paré, Aroon D. Hingorani, Marc S. Sabatine, Ziad Mallat, Juan P. Casas, Philippa J. Talmud

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

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Abstract

This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events

Original language	English
Pages (from-to)	1966-1976
Journal	Journal of the American College of Cardiology
Volume	62
Issue number	21
DOIs	https://doi.org/10.1016/j.jacc.2013.06.044
Publication status	Published - 2013

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Cite this

Holmes, M. V., Simon, T., Exeter, H. J., Folkersen, L., Asselbergs, F. W., Guardiola, M., Cooper, J. A., Palmen, J., Hubacek, J. A., Carruthers, K. F., Horne, B. D., Brunisholz, K. D., Mega, J. L., van Iperen, E. P. A., Li, M., Leusink, M., Trompet, S., Verschuren, J. J. W., Hovingh, G. K., ... Talmud, P. J. (2013). Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study. Journal of the American College of Cardiology, 62(21), 1966-1976. https://doi.org/10.1016/j.jacc.2013.06.044

@article{aa0abe472510438899c41a77d2a380ed,

title = "Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study",

abstract = "This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events",

author = "Holmes, {Michael V.} and Tabassome Simon and Exeter, {Holly J.} and Lasse Folkersen and Asselbergs, {Folkert W.} and Montse Guardiola and Cooper, {Jackie A.} and Jutta Palmen and Hubacek, {Jaroslav A.} and Carruthers, {Kathryn F.} and Horne, {Benjamin D.} and Brunisholz, {Kimberly D.} and Mega, {Jessica L.} and {van Iperen}, {Erik P. A.} and Mingyao Li and Maarten Leusink and Stella Trompet and Verschuren, {Jeffrey J. W.} and Hovingh, {G. Kees} and Abbas Dehghan and Nelson, {Christopher P.} and Salma Kotti and Nicolas Danchin and Markus Scholz and Haase, {Christiane L.} and Dietrich Rothenbacher and Swerdlow, {Daniel I.} and Kuchenbaecker, {Karoline B.} and Eleonora Staines-Urias and Anuj Goel and {van 't Hooft}, Ferdinand and Karl Gertow and {de Faire}, Ulf and Panayiotou, {Andrie G.} and Elena Tremoli and Damiano Baldassarre and Fabrizio Veglia and Holdt, {Lesca M.} and Frank Beutner and Gansevoort, {Ron T.} and Navis, {Gerjan J.} and {Mateo Leach}, Irene and Breitling, {Lutz P.} and Hermann Brenner and Joachim Thiery and Dhayana Dallmeier and Anders Franco-Cereceda and Boer, {Jolanda M. A.} and Stephens, {Jeffrey W.} and Hofker, {Marten H.} and Alain Tedgui and Albert Hofman and Uitterlinden, {Andr{\'e} G.} and Vera Adamkova and Jan Pitha and Onland-Moret, {N. Charlotte} and Cramer, {Maarten J.} and Nathoe, {Hendrik M.} and Wilko Spiering and Klungel, {Olaf H.} and Meena Kumari and Whincup, {Peter H.} and Morrow, {David A.} and Braund, {Peter S.} and Hall, {Alistair S.} and Olsson, {Anders G.} and Doevendans, {Pieter A.} and Trip, {Mieke D.} and Tobin, {Martin D.} and Anders Hamsten and Hugh Watkins and Wolfgang Koenig and Nicolaides, {Andrew N.} and Daniel Teupser and Day, {Ian N. M.} and Carlquist, {John F.} and Gaunt, {Tom R.} and Ian Ford and Naveed Sattar and Sotirios Tsimikas and Schwartz, {Gregory G.} and Lawlor, {Debbie A.} and Morris, {Richard W.} and Sandhu, {Manjinder S.} and Rudolf Poledne and {Maitland-van der Zee}, {Anke H.} and Kay-Tee Khaw and Keating, {Brendan J.} and {van der Harst}, Pim and Price, {Jackie F.} and Mehta, {Shamir R.} and Salim Yusuf and Witteman, {Jaqueline C. M.} and Franco, {Oscar H.} and Jukema, {J. Wouter} and {de Knijff}, Peter and Anne Tybjaerg-Hansen and Rader, {Daniel J.} and Martin Farrall and Samani, {Nilesh J.} and Mika Kivimaki and Fox, {Keith A. A.} and Humphries, {Steve E.} and Anderson, {Jeffrey L.} and Boekholdt, {S. Matthijs} and Palmer, {Tom M.} and Per Eriksson and Guillaume Par{\'e} and Hingorani, {Aroon D.} and Sabatine, {Marc S.} and Ziad Mallat and Casas, {Juan P.} and Talmud, {Philippa J.}",

year = "2013",

doi = "https://doi.org/10.1016/j.jacc.2013.06.044",

language = "English",

volume = "62",

pages = "1966--1976",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "21",

}

Holmes, MV, Simon, T, Exeter, HJ, Folkersen, L, Asselbergs, FW, Guardiola, M, Cooper, JA, Palmen, J, Hubacek, JA, Carruthers, KF, Horne, BD, Brunisholz, KD, Mega, JL, van Iperen, EPA, Li, M, Leusink, M, Trompet, S, Verschuren, JJW, Hovingh, GK, Dehghan, A, Nelson, CP, Kotti, S, Danchin, N, Scholz, M, Haase, CL, Rothenbacher, D, Swerdlow, DI, Kuchenbaecker, KB, Staines-Urias, E, Goel, A, van 't Hooft, F, Gertow, K, de Faire, U, Panayiotou, AG, Tremoli, E, Baldassarre, D, Veglia, F, Holdt, LM, Beutner, F, Gansevoort, RT, Navis, GJ, Mateo Leach, I, Breitling, LP, Brenner, H, Thiery, J, Dallmeier, D, Franco-Cereceda, A, Boer, JMA, Stephens, JW, Hofker, MH, Tedgui, A, Hofman, A, Uitterlinden, AG, Adamkova, V, Pitha, J, Onland-Moret, NC, Cramer, MJ, Nathoe, HM, Spiering, W, Klungel, OH, Kumari, M, Whincup, PH, Morrow, DA, Braund, PS, Hall, AS, Olsson, AG, Doevendans, PA, Trip, MD, Tobin, MD, Hamsten, A, Watkins, H, Koenig, W, Nicolaides, AN, Teupser, D, Day, INM, Carlquist, JF, Gaunt, TR, Ford, I, Sattar, N, Tsimikas, S, Schwartz, GG, Lawlor, DA, Morris, RW, Sandhu, MS, Poledne, R, Maitland-van der Zee, AH, Khaw, K-T, Keating, BJ, van der Harst, P, Price, JF, Mehta, SR, Yusuf, S, Witteman, JCM, Franco, OH, Jukema, JW, de Knijff, P, Tybjaerg-Hansen, A, Rader, DJ, Farrall, M, Samani, NJ, Kivimaki, M, Fox, KAA, Humphries, SE, Anderson, JL, Boekholdt, SM, Palmer, TM, Eriksson, P, Paré, G, Hingorani, AD, Sabatine, MS, Mallat, Z, Casas, JP & Talmud, PJ 2013, 'Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study', Journal of the American College of Cardiology, vol. 62, no. 21, pp. 1966-1976. https://doi.org/10.1016/j.jacc.2013.06.044

TY - JOUR

T1 - Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study

AU - Holmes, Michael V.

AU - Simon, Tabassome

AU - Exeter, Holly J.

AU - Folkersen, Lasse

AU - Asselbergs, Folkert W.

AU - Guardiola, Montse

AU - Cooper, Jackie A.

AU - Palmen, Jutta

AU - Hubacek, Jaroslav A.

AU - Carruthers, Kathryn F.

AU - Horne, Benjamin D.

AU - Brunisholz, Kimberly D.

AU - Mega, Jessica L.

AU - van Iperen, Erik P. A.

AU - Li, Mingyao

AU - Leusink, Maarten

AU - Trompet, Stella

AU - Verschuren, Jeffrey J. W.

AU - Hovingh, G. Kees

AU - Dehghan, Abbas

AU - Nelson, Christopher P.

AU - Kotti, Salma

AU - Danchin, Nicolas

AU - Scholz, Markus

AU - Haase, Christiane L.

AU - Rothenbacher, Dietrich

AU - Swerdlow, Daniel I.

AU - Kuchenbaecker, Karoline B.

AU - Staines-Urias, Eleonora

AU - Goel, Anuj

AU - van 't Hooft, Ferdinand

AU - Gertow, Karl

AU - de Faire, Ulf

AU - Panayiotou, Andrie G.

AU - Tremoli, Elena

AU - Baldassarre, Damiano

AU - Veglia, Fabrizio

AU - Holdt, Lesca M.

AU - Beutner, Frank

AU - Gansevoort, Ron T.

AU - Navis, Gerjan J.

AU - Mateo Leach, Irene

AU - Breitling, Lutz P.

AU - Brenner, Hermann

AU - Thiery, Joachim

AU - Dallmeier, Dhayana

AU - Franco-Cereceda, Anders

AU - Boer, Jolanda M. A.

AU - Stephens, Jeffrey W.

AU - Hofker, Marten H.

AU - Tedgui, Alain

AU - Hofman, Albert

AU - Uitterlinden, André G.

AU - Adamkova, Vera

AU - Pitha, Jan

AU - Onland-Moret, N. Charlotte

AU - Cramer, Maarten J.

AU - Nathoe, Hendrik M.

AU - Spiering, Wilko

AU - Klungel, Olaf H.

AU - Kumari, Meena

AU - Whincup, Peter H.

AU - Morrow, David A.

AU - Braund, Peter S.

AU - Hall, Alistair S.

AU - Olsson, Anders G.

AU - Doevendans, Pieter A.

AU - Trip, Mieke D.

AU - Tobin, Martin D.

AU - Hamsten, Anders

AU - Watkins, Hugh

AU - Koenig, Wolfgang

AU - Nicolaides, Andrew N.

AU - Teupser, Daniel

AU - Day, Ian N. M.

AU - Carlquist, John F.

AU - Gaunt, Tom R.

AU - Ford, Ian

AU - Sattar, Naveed

AU - Tsimikas, Sotirios

AU - Schwartz, Gregory G.

AU - Lawlor, Debbie A.

AU - Morris, Richard W.

AU - Sandhu, Manjinder S.

AU - Poledne, Rudolf

AU - Maitland-van der Zee, Anke H.

AU - Khaw, Kay-Tee

AU - Keating, Brendan J.

AU - van der Harst, Pim

AU - Price, Jackie F.

AU - Mehta, Shamir R.

AU - Yusuf, Salim

AU - Witteman, Jaqueline C. M.

AU - Franco, Oscar H.

AU - Jukema, J. Wouter

AU - de Knijff, Peter

AU - Tybjaerg-Hansen, Anne

AU - Rader, Daniel J.

AU - Farrall, Martin

AU - Samani, Nilesh J.

AU - Kivimaki, Mika

AU - Fox, Keith A. A.

AU - Humphries, Steve E.

AU - Anderson, Jeffrey L.

AU - Boekholdt, S. Matthijs

AU - Palmer, Tom M.

AU - Eriksson, Per

AU - Paré, Guillaume

AU - Hingorani, Aroon D.

AU - Sabatine, Marc S.

AU - Mallat, Ziad

AU - Casas, Juan P.

AU - Talmud, Philippa J.

PY - 2013

Y1 - 2013

N2 - This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events

AB - This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events

U2 - https://doi.org/10.1016/j.jacc.2013.06.044

DO - https://doi.org/10.1016/j.jacc.2013.06.044

M3 - Article

C2 - 23916927

SN - 0735-1097

VL - 62

SP - 1966

EP - 1976

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 21

ER -