rs4236601 — CAV1

Caveolin-1 and the Silent Vision Thief

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide, affecting over 70 million people¹¹ affecting over 70 million people
Glaucoma is a chronic degenerative optic neuropathy with progressive loss of retinal ganglion cells resulting in characteristic optic nerve cupping and visual field defects. The disease typically progresses silently for years before vision loss becomes noticeable. The rs4236601 variant sits in the regulatory region between the CAV1 and CAV2 genes on chromosome 7q31, and was the first common genetic risk factor identified for POAG through genome-wide association studies²² was the first common genetic risk factor identified for POAG through genome-wide association studies.

The Mechanism

This intergenic variant affects the expression and function of caveolin-1 and caveolin-2, structural proteins that form caveolae — specialized flask-shaped invaginations of the plasma membrane that are abundant in the trabecular meshwork and Schlemm's canal³³ caveolae — specialized flask-shaped invaginations of the plasma membrane that are abundant in the trabecular meshwork and Schlemm's canal
These structures regulate aqueous humor outflow, the drainage system that controls intraocular pressure. The trabecular meshwork is the primary site of resistance to aqueous humor outflow, and dysfunction in this tissue is the hallmark of POAG pathophysiology.

Studies in caveolin-1 knockout mice reveal the functional importance of this protein: Cav-1-deficient mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor⁴⁴ Cav-1-deficient mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. The loss of caveolae in the trabecular meshwork and Schlemm's canal renders these tissues unable to properly respond to mechanical stress from IOP fluctuations⁵⁵ renders these tissues unable to properly respond to mechanical stress from IOP fluctuations, suggesting that caveolae provide both mechanical buffering and mechanotransduction signaling platforms.

The rs4236601 risk variant may reduce CAV1 expression in relevant ocular tissues. While no correlation was found between rs4236601 and CAV1 expression in blood or adipose tissue⁶⁶ no correlation was found between rs4236601 and CAV1 expression in blood or adipose tissue, gene regulation is highly tissue-specific, and the variant likely affects expression specifically in the trabecular meshwork where it matters most. Some glaucoma-associated CAV1/CAV2 polymorphisms have been shown to reduce caveolin-1 expression in various tissues⁷⁷ reduce caveolin-1 expression in various tissues, supporting the hypothesis that reduced caveolae formation compromises aqueous outflow regulation.

The Evidence

The initial genome-wide association study in 1,263 Icelandic POAG cases and 34,877 controls identified rs4236601[A] with an odds ratio of 1.36 (P = 5.0 × 10⁻¹⁰)⁸⁸ genome-wide association study in 1,263 Icelandic POAG cases and 34,877 controls identified rs4236601[A] with an odds ratio of 1.36 (P = 5.0 × 10⁻¹⁰). The association was replicated in 2,175 European cases (combined OR = 1.18) and 299 Chinese cases (combined OR = 5.42)⁹⁹ replicated in 2,175 European cases (combined OR = 1.18) and 299 Chinese cases (combined OR = 5.42), demonstrating both reproducibility and striking ancestry-specific effect sizes.

The variant shows dramatic frequency differences across populations. In European populations, the A risk allele occurs at 27-29% frequency¹⁰¹⁰ 27-29% frequency, while in Chinese populations it is rare at 0.43-1.3% frequency¹¹¹¹ 0.43-1.3% frequency but carries a much larger effect size (OR = 5.26). This pattern suggests the A allele may be tagging different causal variants in different ancestral backgrounds, or that genetic background modifies penetrance.

Importantly, rs4236601 is also associated with elevated intraocular pressure (IOP) independent of glaucoma diagnosis. The minor allele A is associated with a 0.42 mm Hg increase in mean IOP¹²¹² The minor allele A is associated with a 0.42 mm Hg increase in mean IOP in European populations, and meta-analysis across multiple IOP GWAS studies achieved genome-wide significance (P = 4.0 × 10⁻¹¹)¹³¹³ meta-analysis across multiple IOP GWAS studies achieved genome-wide significance (P = 4.0 × 10⁻¹¹).

Replication studies have yielded mixed results across populations. While US Caucasian studies confirmed the association¹⁴¹⁴ US Caucasian studies confirmed the association, particularly in women, studies in Saudi Arabian¹⁵¹⁵ Saudi Arabian and Brazilian¹⁶¹⁶ Brazilian populations failed to replicate the finding. This heterogeneity may reflect differences in genetic background, linkage disequilibrium patterns, environmental factors, or POAG subtype distributions.

Practical Implications

Elevated IOP is the most important modifiable risk factor for glaucoma progression, and the only treatment target for which we have effective interventions. While rs4236601 genotype is not currently used in clinical decision-making, understanding your genetic risk can inform screening strategies and motivate adherence to regular comprehensive eye examinations.

The American Academy of Ophthalmology recommends comprehensive eye examinations for all adults over age 40¹⁷¹⁷ comprehensive eye examinations for all adults over age 40 to screen for glaucoma. Individuals with the AA genotype, particularly those with additional risk factors (family history, African ancestry, myopia, thin central corneal thickness), may benefit from more frequent screening and earlier initiation of monitoring protocols.

IOP exhibits substantial diurnal variation, with many glaucoma patients experiencing peak pressures in the early morning hours outside of office visit times¹⁸¹⁸ peak pressures in the early morning hours outside of office visit times. Home tonometry devices now enable continuous monitoring that may detect pressure spikes missed by clinic measurements, potentially enabling more personalized treatment approaches.

Interactions

The CAV1/CAV2 locus interacts functionally with the nitric oxide signaling pathway, as caveolin-1 regulates endothelial nitric oxide synthase (eNOS) activity in caveolae. This connection may explain the association between CAV1/CAV2 variants and POAG subtypes characterized by vascular dysregulation¹⁹¹⁹ association between CAV1/CAV2 variants and POAG subtypes characterized by vascular dysregulation, particularly normal-tension glaucoma and cases with paracentral visual field defects. The interaction between ET-1 (endothelin-1), NO, and CAV1 is suspected to underlie aberrant retinal hemodynamic responses to postural changes observed in POAG patients.

Other POAG risk loci include CDKN2B-AS1 (rs2157719), TMCO1 (rs7518099), and SIX1/SIX6 (rs10483727). While no specific gene-gene interactions between rs4236601 and these loci have been definitively established, polygenic risk scores incorporating multiple POAG variants show additive effects on disease risk.