Author + information
- Michael V. Holmes, MBBS, MSc∗∗ (, )
- Tabassome Simon, MD, PhD∗,
- Holly J. Exeter, PhD∗,
- Aroon D. Hingorani, MBBS, PhD∗,
- Marc S. Sabatine, MD, PhD∗,
- Ziad Mallat, MD, PhD∗,
- Juan P. Casas, MD, PhD∗ and
- Philippa J. Talmud, DSc∗
- ↵∗Faculty of Population Health Sciences, Department of Epidemiology and Public Health, University College London, Torington Place, London WC1E 6BT, England
We appreciate the remarks of Drs. Rosenson and Hurt-Camejo regarding our work (1). We agree that the association of levels of secretory phospholipase A2-IIA (sPLA2-IIA) mass and sPLA2 enzyme activity may differ in subjects with and without coronary heart disease (CHD). For this reason, all analyses were conducted separately for the general population and for those with acute coronary syndrome.
As expressed in multiple places throughout the report, sPLA2 activity was not used as a proxy of sPLA2-IIA activity but as a composite of several sPLA2 isoenzymes.
The single nucleotide polymorphism showing the strongest association with PLA2G2A messenger RNA expression (rs10732279) was in very strong linkage disequilibrium (R2 = 0.91) with the PLA2G2A rs11573156 variant used for our Mendelian randomization analysis.
The correlation between sPLA2-IIA mass and sPLA2 enzyme activity was moderate at best and does not imply a similar magnitude of association of the PLA2G2A rs11573156 variant with both of these measures. Because the mass assay is specific for sPLA2-IIA, but the activity assay is not, it is not surprising that rs11573156 showed a stronger association with mass than with activity.
sPLA2-IIA mass and sPLA2 enzyme activity were non-normally distributed, and therefore, these variables were log transformed for analysis. The difference in log values equates to the proportional difference in sPLA2-IIA mass and activity between the 2 groups.
The correspondents failed to read Online Table 11 carefully, in which values are differences in sPLA2-IIA mass on the absolute scale from treatment with 500 mg/day varespladib versus placebo pooled across the randomized controlled trials. The value (−13.13 pmol/l) for sPLA2-IIA mass corresponds to a 78% reduction in sPLA2-IIA mass (reported in the Results section), which is comparable to the 80% value to which the correspondents refer.
We did not specify a cut point of 500 participants for the inclusion of trial data; however, we reported information on the pooled effects of varespladib on biomarkers available in more than 500 subjects in total across all trials of varespladib.
We did not find evidence of a differential effect of varespladib on sPLA2-IIA mass or low-density lipoprotein cholesterol level when stratified by trials of patients with acute coronary syndrome or stable CHD (p = 0.48 and p = 0.42 for heterogeneity, respectively).
The review cited by the correspondents refers to 2 identical studies that we discussed (Online Fig. 1) and cited, providing evidence that the median inhibitory concentration values for varespladib are lower for IIA (9 to 14 nmol/l) than for V or X (77 and 15 nmol/l, respectively).
We agree that varespladib is a nonspecific sPLA2 inhibitor, and the genetic variant we studied was specific for sPLA2-IIA mass. This is why we stated repeatedly that our analysis informs on sPLA2-IIA as a therapeutic target, but not other sPLA2 isoforms.
We stand by the validity of our study and maintain our conclusion that sPLA2-IIA is unlikely to play a causal role in CHD.
↵∗ on behalf of all coauthors
Please note: Drs. Mallat and Simon are listed as coinventors on patents related to the use of sPLA2 activity and/or PLA2G2A rs11573156 single nucleotide polymorphism as a cardiovascular biomarker. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.
- American College of Cardiology Foundation