rs33912345 — SIX6 Asn141His

SIX6 Asn141His — The Optic Nerve Development Variant

SIX6 (sine oculis homeobox homolog 6) is a transcription factor¹¹ transcription factor
A protein that binds to specific DNA sequences to control gene expression critical for eye development, particularly the formation of the retina²² retina
The light-sensitive layer at the back of the eye, optic nerve, and pituitary gland during embryonic development. While most people think of developmental genes as only mattering before birth, SIX6 continues to be expressed in the adult retina, where it plays a surprising role in retinal ganglion cell³³ retinal ganglion cell
Neurons that transmit visual information from the eye to the brain health and survival throughout life.

The rs33912345 variant, which changes a single amino acid at position 141 from asparagine (Asn, encoded by A) to histidine (His, encoded by C), is one of the most robustly replicated genetic risk factors⁴⁴ robustly replicated genetic risk factors
Confirmed across multiple independent studies in different populations for primary open-angle glaucoma (POAG), the most common form of glaucoma worldwide and a leading cause of irreversible blindness. About 15% of people of European descent carry two copies of the risk variant (CC), while this climbs to higher frequencies in East Asian populations where POAG is also more prevalent.

The Mechanism

The Asn141His substitution occurs within the homeodomain⁵⁵ homeodomain
A highly conserved DNA-binding region found in many developmental transcription factors, specifically in the alpha helix structure⁶⁶ alpha helix structure
A common protein structural motif that binds to the DNA major groove that makes direct contact with DNA. Remarkably, the protective Asn141 variant appears to be unique to humans—all other species studied carry the His141 version, suggesting the Asn variant may have been selected for during human evolution, possibly as protection against glaucoma.

Zebrafish complementation assays⁷⁷ Zebrafish complementation assays
A laboratory technique where human gene variants are tested in fish embryos to assess their function have demonstrated that the His141 (risk) variant has reduced function compared to Asn141, affecting both eye size and optic nerve volume during development. In adult humans, the mechanism becomes even more intriguing: the His141 variant drives increased expression of P16/INK4A⁸⁸ P16/INK4A
A cell cycle inhibitor protein that prevents cells from dividing, triggering cellular senescence⁹⁹ cellular senescence
A state where cells stop dividing and begin to dysfunction, similar to aging specifically in retinal ganglion cells (RGCs). This premature aging of the neurons that carry visual signals from your eye to your brain makes them more vulnerable to elevated intraocular pressure¹⁰¹⁰ intraocular pressure
The fluid pressure inside the eye, measured in mmHg and other glaucoma-related stressors.

The Evidence

The association between rs33912345 and glaucoma is exceptionally well-documented. A 2019 meta-analysis¹¹¹¹ 2019 meta-analysis
A statistical method that combines results from multiple studies to increase power pooled data from 22 studies involving over 10,500 POAG cases and 16,700 controls, confirming significant associations in both East Asian and Caucasian populations but not in South Asian or African cohorts, highlighting important ancestry-specific effects¹²¹² ancestry-specific effects
Genetic variants that have different impacts in different population groups.

In the EPIC-Norfolk Eye Study¹³¹³ EPIC-Norfolk Eye Study
A large population-based cohort study in the United Kingdom of over 5,400 Europeans, each C (risk) allele was associated with a 0.030 mm² smaller optic disc rim area (P=5.4×10⁻⁹), a 0.025 larger vertical cup-disc ratio¹⁴¹⁴ vertical cup-disc ratio
The ratio of the optic cup (central depression) to the disc; larger ratios indicate nerve damage (P=3.3×10⁻¹⁰), and a 0.39 μm thinner RNFL¹⁵¹⁵ RNFL
Retinal nerve fiber layer, the innermost layer of the retina containing ganglion cell axons (P=0.001). The Singapore Chinese Eye Study¹⁶¹⁶ Singapore Chinese Eye Study
Population study of over 1,200 Chinese individuals, where the C allele frequency reaches 80%, found even more pronounced effects: each C allele reduced RNFL thickness by 1.44 μm (P=0.001), with the strongest impact in the superior and inferior sectors where glaucomatous damage typically begins.

For disease risk, a Chinese population study¹⁷¹⁷ Chinese population study
Case-control study of 866 POAG patients and 266 controls found an odds ratio of 1.49 for POAG overall (P=3.84×10⁻⁴), climbing to 2.27 for normal-tension glaucoma¹⁸¹⁸ normal-tension glaucoma
A form of glaucoma that occurs despite normal eye pressure (P=2.72×10⁻⁶). The age-stratified analysis revealed that the genetic effect was strongest in individuals aged 40 and above, consistent with the adult-onset nature of most glaucoma.

Critically, a 2014 study¹⁹¹⁹ a 2014 study
First to identify the Asn141His variant through targeted sequencing comparing POAG patients who were homozygous for different genotypes found that CC individuals had significantly thinner global RNFL (58.3 ± 8.2 μm) compared to AA individuals (67.9 ± 12.4 μm, P=0.03), suggesting that the variant's structural effects on the optic nerve precede and may predispose to glaucomatous degeneration.

Practical Implications

This variant matters most for glaucoma screening and prevention. If you carry one or two copies of the C allele, you have measurably thinner retinal nerve fiber layers and altered optic disc structure even before any disease develops. This means you're starting with less "neural reserve" in your optic nerve, making you more susceptible to damage from elevated eye pressure, vascular insufficiency, or normal aging.

The good news: glaucoma is detectable and treatable²⁰²⁰ glaucoma is detectable and treatable
Early detection and pressure-lowering treatment can prevent vision loss when caught early. Baseline comprehensive eye exams²¹²¹ comprehensive eye exams
Include tonometry for pressure, ophthalmoscopy for optic nerve, and perimetry for visual fields by age 40 are recommended for everyone, but if you carry C alleles at rs33912345—especially if you have other risk factors like family history²²²² family history
First-degree relatives with glaucoma increase risk 4-9 fold, high myopia, or African ancestry—consider starting screening in your 30s and maintaining more frequent monitoring (annually rather than every 2-3 years).

Intraocular pressure²³²³ Intraocular pressure
Normal range is 10-21 mmHg; elevated pressure is the primary modifiable risk factor is the main modifiable risk factor. If your eye pressure trends toward the higher end of normal (>18 mmHg) and you carry C alleles, discussing preventive strategies with your ophthalmologist is warranted. Beyond pressure, cardiovascular health appears linked²⁴²⁴ cardiovascular health appears linked
Glaucoma shares risk factors with vascular disease including hypertension and atherosclerosis to glaucoma risk through effects on optic nerve blood flow, so maintaining healthy blood pressure, avoiding smoking, and regular aerobic exercise may provide additional protection.

For those already diagnosed with glaucoma, knowing your SIX6 genotype may influence treatment aggressiveness. CC individuals might benefit from tighter target intraocular pressure²⁵²⁵ target intraocular pressure
The pressure level aimed for to prevent progression, typically <15 mmHg in advanced cases goals given their compromised baseline optic nerve structure.

Interactions

The SIX6 locus contains several variants in strong linkage disequilibrium²⁶²⁶ linkage disequilibrium
Genetic variants inherited together more often than expected by chance, particularly rs10483727, which was the original GWAS discovery SNP (r²=0.95-0.98 with rs33912345). The two variants are so closely linked that they likely represent the same functional signal, with rs33912345 being the likely causal variant given its direct effect on protein function.

There is documented gene-gene interaction²⁷²⁷ gene-gene interaction
Combined effects of variants at different loci that exceed their individual impacts between SIX6 and the CDKN2B-AS1 locus²⁸²⁸ CDKN2B-AS1 locus
Another major POAG risk locus at chromosome 9p21 at 9p21, one of the most replicated glaucoma risk loci. The interaction involves trans-regulation²⁹²⁹ trans-regulation
When a transcription factor at one genomic location controls gene expression at a distant location, with the SIX6 His141 variant affecting expression of CDKN2A and CDKN2B genes, both of which are cell cycle regulators. Individuals carrying risk alleles at both loci may experience synergistic increases in glaucoma susceptibility, though specific compound recommendations await validation in larger interaction studies.

The SIX6-P16/INK4A pathway also shows interaction with TP53³⁰³⁰ TP53
The tumor suppressor gene that regulates cell cycle and apoptosis, with mouse studies demonstrating that absence of either Six6 or P16 protects against retinal ganglion cell death under elevated intraocular pressure conditions, suggesting potential therapeutic targets for future neuroprotective treatments.