Re: “Polymorphisms of three genes (ACE, AGT and CYP11B2) in the renin–angiotensin–aldosterone system are not associated with blood pressure salt sensitivity: a systematic meta-analysis”

We read with interest the article recently published in Blood Pressure by J. Sun and colleagues.[1] The authors conducted a meta-analysis of the literature investigating genetic variations in ACE (I/D), AGT (M235T) and CYP11B2 (C344T) with salt-sensitive hypertension. According to the title and conclusions of the paper, the authors conclude that these genetic variants are not associated with salt-sensitive hypertension. However, notable limitations in the design of their study preclude making this conclusion. The main limitation is that the authors did not consider other studies that examined genetic variants that are in strong linkage disequilibrium (LD) with the 3 markers of interest and they did not identify this as a limitation in their discussion. For example, ACE I/D is in complete LD with ACE rs4343 and studies that report either of these two variants are examining essentially the same variant.[2–4] Other examples include AGT (M235T) which is in strong LD with AGT A(-6)G [5] and CYP11B2 (C344T), which is in complete LD with CYP11B2 at rs28491316 [6]. Because of this oversight, the authors failed to identify several studies. One study that was omitted was completed by Iwai et al., which found an association between the C344T variant in CYP11B2, which is in complete LD with CYP11B2 rs28491316 and salt-sensitive hypertension.[6,7] To ensure that all biologically relevant studies are included in the meta-analysis, the search terms should have included SNPs that are in complete or strong (>80%) LD with the three variants of interest in order to assess all relevant literature to appropriately and adequately address the research question. Furthermore, there was no discussion detailing the reason for excluding randomized controlled trials (RCTs), or how the exclusion of such studies may have impacted the conclusion. As RCTs did not meet the inclusion criteria, several robust studies were disregarded including a randomized, double-blinded, placebocontrolled Latin-square trial, which found a significant link between salt-sensitive hypertension and the AGT gene at M235T.[8] An additional limitation is that only one study that did not meet the inclusion criteria was cited and discussed. That study also found no significant association between the three variants of interest and blood pressure salt sensitivity.[2] However, the authors failed to discuss other opposing studies, which did find that the variants of interest affected blood pressure salt sensitivity.[8] Given the main limitation of omitting highly relevant studies, which could alter the conclusions drawn, the authors should consider updating their methods and analysis to include all relevant studies.