It was suggested that hypertension may play a significant role on the onset of POAG in previous observational studies, however the association is still elusive. A genetical exploration was conducted in our research to clarify the causality between hypertension and POAG. Our results demonstrated that hypertension increased the POAG risk by 5.372 times, which was supported by supplementary analysis, and the reliability and stability were verified by sensitivity analysis.
Systemic arterial hypertension is the primary modifiable hazard factor for all-cause incidence rate and mortality worldwide[23]. Hypertension is also a major risk factor for many eye diseases, such as retinal vascular diseases, hypertension retinopathy and age-related macular degenerations[24]. Retinal ganglion cells are vulnerable to ischemic damage when exposed to reduced blood supply or hypoperfusion to the optic nerve head (ONH)[25]. Clinically, OPP is often calculated as the difference between BP and IOP, which determines the ocular blood flow to the ONH. Many recent studies have revealed that vascular factors played critical roles in the development of glaucoma[26, 27]. Beaver Dam Eye Research and Egna-Neumarkt research reported that IOP would increase by 0.21 mmHg and 0.24 mmHg respectively for every 10mmHg increased in systolic BP[28, 29]. However, up to 50% of POAG patients develop glaucomatous neuropathy without any evidence of increased IOP, that is, normal-tension glaucoma (NTG)[30]. Moreover, many studies reported that individuals with high BP were associated with higher prevalence of POAG, independent of IOP[26, 31]. Therefore, it is of significance to illustrate the relationship between hypertension and POAG, which might help to improve clinical management of POAG.
In the current two-sample MR study, we found that hypertension increased the risk of POAG, which was consistent with some previous findings. Hypertension increases the capillary pressure in the ciliary body, which in turn leads to increased IOP[32–34]. Hypertension also induces atherosclerosis and impairs vascular autoregulation, thereby reducing blood flow in the eyes, which causes nerve fiber damage and RGC loss in the long-term[35]. Besides, some systemic antihypertension medications such as angiotensin-converting enzyme inhibitors (ACEIs) or diuretics, are strongly associated with the progression of glaucoma[7, 36–38]. ACEIs not only cause nocturnal hypotension to reduce ocular perfusion, but also induce abnormal accumulation of amyloid-β protein, which exerts toxic effects on neuronal health[6, 7, 36, 37, 39].
However, there was also a previous case-control study reporting a much lower incidence of glaucoma increased by 0.31-fold in patients with hypertension [5]. The reasons for the inconsistency may lie in: 1) MR studies analyze the impacts of lifelong exposure factors on specific diseases, while the clinical studies usually reflect the cumulative effect of one particular risk factor over a certain period of time; 2) patients with hypertension usually requires antihypertensive drugs to control BP, which is an important confounding factor to cause the underestimation of the impact of hypertension on glaucoma in clinical studies. Thus, MR studies are able to provide more reliable and accurate results than the traditional observational studies. And in the current study, the results are credible because it was conducted based on three principal IVs assumptions and referred to the checklists for performing the MR analysis. Also, population stratification bias was avoided for the two GWASs were both from the European ancestries. Besides, multiple MR analysis methods and sensitivity analysis were performed to evaluate the causality consistency. However, the original articles of hypertension and POAG GWAS were not available, which may cause bias to the results for the detail information of the two cohort is missing. Nevertheless, the MR analysis was designed to avoid traditional confounders such as diabetes, family history of glaucoma and other glaucoma risk factors by introducing instrumental variables, and to monitor their interfere by sensitivity analysis. Therefore, the influences of the currently known common risk factors for glaucoma can be balanced and would hardly affect the conclusion.
There are also limitations for the MR study. Confining participants to European population limited the generalizability of our findings to other populations. And it was not able to acquire the individual BP information of patients with hypertension, which made it hard to judge whether high systolic pressure or diastolic pressure was the main cause for POAG. Thus, further MR study should focus on the causal association between the systolic/diastolic hypertension and POAG. Another interesting point is whether increasing BP in hypertension patients raised POAG risk.
Taken together, hypertension was found to have a genetic role on POAG occurrence by significant increase in risk. Long-term cohort studies are expected to verify the impact of hypertension on POAG.