LOXL1 rs1048665: Understanding Your Genetic Risk
The rs1048665 variant (historically referenced in literature as rs1048661) is a common missense variation in the LOXL1 gene that results in an arginine-to-leucine amino acid change at position 141 (Arg141Leu). It has been widely investigated in association with exfoliation syndrome (pseudoexfoliation syndrome) and secondary open-angle glaucoma. While common in populations worldwide, its association is complex, with varying effects across ancestries and limited evidence for acting as an isolated diagnostic marker.
What each genotype means
Elevated exfoliation glaucoma risk
You carry two copies of the G allele, which encodes arginine at residue 141 (Arg141) of LOXL1. In genome-wide association studies, this genotype has been significantly correlated with an increased statistical risk of developing pseudoexfoliation syndrome and secondary open-angle glaucoma, particularly in European cohorts. However, the G allele is extremely prevalent among healthy older adults and displays inverted or non-significant risk patterns in some non-European ancestral populations, indicating that it is not sufficient on its own to cause disease.
Carried by approximately 55% to 70% of individuals across European and East Asian populations, making it the most frequent genotype globally.
Intermediate exfoliation glaucoma risk
You carry one G allele and one T allele at this locus, resulting in a heterozygous coding profile (Arg141Leu). Population research suggests an intermediate statistical association with exfoliation syndrome relative to homozygous genotypes, though exact risk varies considerably by broader genetic background and haplotype context. Because exfoliation syndrome is multifactorial, carrying this genotype alone does not mean you will develop eye complications.
Carried by approximately 25% to 35% of individuals across diverse continental populations.
Reduced exfoliation glaucoma risk
You carry two copies of the T allele, which corresponds to leucine at residue 141 (Leu141) of the LOXL1 enzyme. In Western European and several other investigated populations, this genotype is generally associated with a lower baseline risk of pseudoexfoliation syndrome and secondary glaucoma compared to the common G allele. Nevertheless, risk effects show notable variation across different ethnic backgrounds and are modulated by neighboring LOXL1 variants.
Found in roughly 2% to 10% of individuals worldwide, occurring least frequently in East Asian ancestries.
Genetic Location and Nature of rs1048665
The single nucleotide polymorphism rs1048665 is located on chromosome 15 within the first exon of the LOXL1 gene. In genomic reference literature and foundational genome-wide association studies, this specific Arg141Leu coding variation is frequently cataloged as rs1048661. The variant involves a nucleotide exchange between guanine (G) and thymine (T), which alters codon 141 of the encoded protein, substituting an arginine residue with a leucine residue. Because this alteration occurs in exon 1, which encodes the N-terminal region responsible for enzyme activation, substrate interaction, and proper cellular localization, researchers have intensely investigated whether this amino acid swap directly destabilizes or alters the physiological function of the LOXL1 enzyme.
Biological Role of the LOXL1 Gene
The LOXL1 gene provides instructions for making lysyl oxidase-like 1, an extracellular copper-dependent amine oxidase essential for elastic fiber biogenesis and connective tissue maintenance. LOXL1 facilitates the cross-linking of tropoelastin into mature, functional elastin fibers, which supply elasticity and tensile strength to ocular structures, skin, blood vessels, and other elastic tissues. When elastogenesis or connective tissue homeostasis is disrupted, abnormal fibrillar matrix aggregates can accumulate. In the eye, these microfibrillar aggregates collect on the anterior lens capsule, iris, ciliary body, and trabecular meshwork, causing mechanical blockage of aqueous humor outflow, elevated intraocular pressure, and secondary open-angle glaucoma.
Evidence Strength and Clinical Associations
Large genome-wide association studies initially highlighted rs1048665 as a principal susceptibility locus for exfoliation syndrome (XFS) and exfoliative glaucoma (XFG). However, the catalog evidence strength remains limited due to complex biological caveats. Functional assays demonstrate that the Arg141Leu change alone does not markedly impair LOXL1 enzymatic activity in vitro. Furthermore, epidemiological evaluations across diverse global populations revealed an 'allele reversal' phenomenon: while the G allele correlates with higher risk in individuals of European ancestry, it exhibits opposite or neutral associations in certain African and Asian cohorts. Consequently, geneticists regard this marker not as an independent causative mutation, but rather as a marker acting in concert with broader haplotypes, secondary genetic modifiers, and environmental triggers.
Distribution Across Ancestral Populations
The alleles of rs1048665 are widely distributed across global populations, exhibiting minor allele frequencies typically between 0.15 and 0.30 depending on continental ancestry. In European populations, the G allele is predominant, occurring at frequencies exceeding 70% to 85% among unaffected control subjects as well as cases. In specific East Asian and South African groups, the frequency of the T allele rises considerably, shifting the baseline distribution. Because the putative 'risk' allele is remarkably prevalent among millions of healthy individuals who never develop ocular fibrillopathy, the presence of the allele alone possesses weak predictive value for clinical disease.
Practical Implications and Medical Context
Carrying one or two copies of a statistically associated allele at rs1048665 is neither a medical diagnosis nor a guarantee that an individual will develop exfoliation syndrome or glaucoma. Direct-to-consumer genetic findings cannot replace comprehensive ophthalmic care. Exfoliation syndrome is primarily an age-related condition that typically presents in individuals over age 50 or 60, detected through standard slit-lamp examinations and eye pressure monitoring. Anyone with concerns about elevated intraocular pressure, personal vision changes, or a family history of glaucoma should maintain routine comprehensive eye examinations with an optometrist or ophthalmologist rather than making medical decisions based on single-variant genetic test results.
How common is this variant?
The rs1048665 variant is common globally, with minor allele frequencies generally ranging between 0.15 and 0.30 across continental ancestries. In many European populations, the G allele is present in over 80% of individuals, while the alternative T allele occurs at higher frequencies in certain African and Asian cohorts.
Frequently asked questions
What is exfoliation syndrome?
Exfoliation syndrome, also called pseudoexfoliation syndrome, is an age-related systemic condition characterized by the abnormal buildup of microscopic, dandruff-like protein fibers in tissues throughout the body. In the eye, these deposits can clog the drainage canals, leading to elevated eye pressure and a severe form of open-angle glaucoma.
Does having the GG genotype mean I will get glaucoma?
No. The G allele is very common in the general population, and the vast majority of people with the GG genotype never develop exfoliation syndrome or glaucoma. It represents an elevated relative statistical risk rather than a deterministic clinical diagnosis.
Why is rs1048665 often called rs1048661 in research papers?
In genetic research and older published literature, this exact missense change (LOXL1 Arg141Leu) was historically identified and cataloged under the identifier rs1048661. Subsequent dbSNP updates and reference genome assemblies mapped or cross-referenced the locus under rs1048665, but both labels refer to the same biological polymorphism in exon 1.
What steps should I take if I carry a risk-associated genotype?
You should continue with standard preventive healthcare, particularly routine comprehensive eye examinations that include pupil dilation and intraocular pressure checks, especially if you are over 50. Inform your eye care professional of any family history of glaucoma, but do not alter treatments or assume disease solely based on this genetic variant.
Sources & further reading
Educational information only, last refreshed 9/14/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This LOXL1 variant is associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG), though recent evidence suggests it may act as a proxy for other functional variants in the locus rather than being directly causative.
Common missense variant (Arg141Leu) in LOXL1 historically associated with pseudoexfoliation syndrome; recent evidence suggests these variants may be proxies for other causative regulatory variants.
Missense variant in LOXL1 associated with pseudoexfoliation syndrome and glaucoma.
Exonic missense variant (p.Gly153Asp) in LOXL1 conferring major risk for pseudoexfoliation syndrome and secondary glaucoma.
Missense variant in LOXL1 strongly associated with pseudoexfoliation syndrome and secondary glaucoma.
A missense variant (p.Gly153Asp) in LOXL1 strongly associated with pseudoexfoliation syndrome and secondary open-angle glaucoma.