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Unraveling causal pathways in retinal vein occlusion: a systematic review of
Mendelian randomization studies
#MMPMID41339966
Alamoudi A
; Alnabihi A
; Al-Qahtani S
; Aljiayyd AAS
; Alsarhani WK
; Alharbi SY
; Mihalache A
; Popovic M
; Muni RH
; Alakeely AG
Int J Retina Vitreous
2025[Dec]; 11
(1
): 133
PMID41339966
show ga
BACKGROUND: Retinal vein occlusion (RVO) is a leading cause of vision loss, yet
there are inconsistent risk estimates related to risk factors. Mendelian
randomization (MR) uses genetic variants as proxies for lifelong exposure and can
clarify causal pathways for RVO. We aimed to systematically review MR studies to
identify causally supported systemic and ocular risk factors for RVO. METHODS:
Four databases (PubMed, Embase, Scopus, and Web of Science) were searched from
inception to June 2025 for peer-reviewed MR studies evaluating modifiable
systemic or ocular risk factors in relation to any form of RVO utilizing GWAS
data. Narrative synthesis was undertaken as methodological heterogeneity
precluded meta-analysis. All effect estimates (ORs) were extracted directly from
individual studies and robustness of evidence for each exposure across studies
was assessed as robust, probable, suggestive, insufficient, and non-evaluable
based on significance and direction of evidence. RESULTS: Twelve two-sample MR
studies, all conducted in European cohorts, met inclusion criteria. Ocular traits
showed the most consistent signals: higher intraocular pressure (RVO (OR?=?1.53,
95% CI: 1.0402.26) and glaucoma liability (OR?=?1.31, 95% CI: 1.18-1.45) were
robustly associated with greater risk of RVO. Among cardiovascular factors,
elevated blood pressure/hypertension liability demonstrated probable evidence of
increased RVO risk (OR?=?1.58, 95% CI: 1.34-1.85), whereas lipid profiles yielded
mixed signals, with some support for higher LDL (OR?=?1.23, 95% CI: 1.05-1.44)
and total cholesterol (OR?=?1.44, 95% CI: 1.08-1.92) effects. For metabolic
factors, glycemic traits showed probable to robust evidence with fasting glucose
(OR?=?5.01, 95% CI: 2.00-12.55) and two-hour glucose (OR?=?3.17, 95% CI:
1.63-6.18) associated with higher RVO risk. Similarly, type 2 diabetes liability
showed probable evidence (OR?=?2.82, 95% CI: 2.07-3.85); anthropometric measures
offered probable to robust support with body mass index (OR?=?1.94, 95% CI:
1.23-3.08) and waist circumference (OR?=?2.40, 95% CI: 1.36-4.24) associated with
RVO. In other domains, selected coagulation and platelet traits showed
probable-robust signals, vitamin D evidence was insufficient, and gut microbiota
instruments provided preliminary robust evidence for Bacilli and Family XIII
AD3011 association with RVO. CONCLUSION: Genetic evidence supports a
multifactorial vascular-metabolic model for RVO in which elevated IOP, glaucoma,
hypertension, adiposity, and acute hyperglycemia are genetically supported risk
factors. These findings highlight blood-pressure control, weight management, and
glycemic regulation as important prevention targets and underscore the need for
ancestry-diverse MR studies with refined phenotyping.
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