|(G;G)||1||possibly higher glaucoma risk?|
|(G;T)||0.5||possibly higher glaucoma risk?|
rs1048661, also known as R141L, a SNP causing an amino acid change in the lysyl oxidase 1 LOXL1 gene, has been linked to exfoliation glaucoma. This form of glaucoma causes up to 10% of the cases of blindness in many countries, including the US. [Science DOI: 10.1126/science.1146554] From the abstract of this study: "Approximately 25% of the general population is homozygous for the highest risk haplotype and their risk of suffering XFG (exfoliation glaucoma) is over 100 times that of those only carrying low-risk haplotypes."
The risk allele for this SNP is rs1048661(G), and it confers a estimated relative risk (by itself) of 3.04. The odds ratio is 2.46 (CI 1.91-3.16). [Note that the (G) allele is actually quite common in most European populations.]
However, a meta-analysis published in 2010 concluded that it's likely that SNPs rs1048661 and rs2165241 are not directly implicated in the pathogenesis of glaucoma; only the nearby rs3825942 seemed to be the disease-associated SNP.[PMID 20142848]
In the original publications, the haplotypes identified as being of highest risk consisted of the combination of two SNPs together, rs1048661(G) and rs3825942(C), oriented with respect to the dbSNP entry. In the two populations studied combined (from Iceland and Sweden), the (G;C) haplotype has an odds ratio of 27.05, and the (T;C) haplotype has an OR of 8.90, relative to the (G;T) haplotype. The (T;T) haplotype is presumed to be at even lower risk than the (G;T) haplotype, but due at least in part to the high frequency of the rs1048661(G) allele, no individuals in this study carried it. In the populations studied, ~25% of all individuals in the population carry two copies of the (G;C), highest risk haplotype.
If the risk of carrying two such haplotypes is multiplicative (which isn't known actually), the authors estimate that individuals carrying two copies of the (G;C) high risk haplotype would have 700 times the risk of developing this type of glaucoma compared to individuals carrying two copies of the (G;T) haplotype. Overall, (G;C) individuals are at ~2.5 fold higher risk than the average person in the populations studied.
With so many people at high risk, shouldn't the number of cases be much higher? Not necessarily, since glaucoma risk only becomes high in older individuals. [To put it another way: plenty of folks don't live long enough to find out if they would have gotten glaucoma.] The estimate for glaucoma incidence worldwide is 10-20% only for individuals over 60 years of age; in Iceland, where glaucoma incidence is high, 40% of individuals 80 or older show signs of exfoliation syndrome, which has been seen to convert to exfolation glaucoma at a rate of 60% - over a 15 year period. [PMID 12928689, PMID 10463402, PMID 17224761]
Discussed in this blog post
[PMID 18385063] Confirmed as risk for pseudoexfoliation (PEX) and pseudoexfoliation glaucoma (PEXG) in populations of German and Italian descent.
[PMID 18385788] rs1048661 (G), rs3825942 (G), and rs2165241 (T) are highly associated with XFS and XFG in American and European populations. The GGT haplotype constitutes a major risk haplotype for exfoliation.
[PMID 19503743] Association of LOXL1 polymorphisms with pseudoexfoliation in the Chinese
[PMID 19936304] Evaluation of LOXL1 polymorphisms in exfoliation syndrome in a Chinese population
[PMID 20431720] Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population
[PMID 21320968] An Investigation Into LOXL1 Variants in Black South African Individuals With Exfoliation Syndrome
[PMID 21510775] Lack of association between LOXL1 gene polymorphisms and primary open angle glaucoma in the Saudi Arabian population
[PMID 21970694] Prevalence of high-risk alleles in the LOXL1 gene and its association with pseudoexfoliation syndrome and exfoliation glaucoma in a Latin American population
[PMID 22194657] Analysis of LOXL1 gene variants in Japanese patients with branch retinal vein occlusion
[PMID 22065931] Decreased total antioxidants status in the plasma of patients with pseudoexfoliation glaucoma.
[PMID 22765198] TT polymorphism in rs2165241 and rs1048661 region in lysyl oxidase like-1 gene may have a role in stress urinary incontinence physiopathology
|CLNDBN||Exfoliation syndrome, susceptibility to|
|CLNSRC||OMIM Allelic Variant UniProtKB (protein)|
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[PMID 18223248] The LOXL1 gene variations are not associated with primary open-angle and primary angle-closure glaucomas.
[PMID 18224312] Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment.
[PMID 18254956] DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a U.S. clinic-based population with broad ethnic diversity.
[PMID 18334928] Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma.
[PMID 18334947] Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India.
[PMID 18421074] Lack of association between LOXL1 variants and primary open-angle glaucoma in three different populations.
[PMID 18450598] Association of LOXL1 gene polymorphisms with pseudoexfoliation in the Japanese.
[PMID 18483563] Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population.
[PMID 18552979] LOXL1 genetic polymorphisms are associated with exfoliation glaucoma in the Japanese population.
[PMID 18618003] Exfoliation syndrome and exfoliation glaucoma-associated LOXL1 variations are not involved in pigment dispersion syndrome and pigmentary glaucoma.
[PMID 18636115] Lysyl oxidase-like 1 gene polymorphisms in Japanese patients with primary open angle glaucoma and exfoliation syndrome.
[PMID 18648524] Evaluation of LOXL1 polymorphisms in eyes with exfoliation glaucoma in Japanese.
[PMID 18958304] LOXL1 variants in elderly Japanese patients with exfoliation syndrome/glaucoma, primary open-angle glaucoma, normal tension glaucoma, and cataract.
[PMID 18974306] Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients.
[PMID 19098994] Evaluation of LOXL1 polymorphisms in primary open-angle glaucoma in southern and northern Chinese.
[PMID 19112534] Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma.
[PMID 19279689] TNF-alpha -308 G>A and -238 G>A polymorphisms are not major risk factors in Caucasian patients with exfoliation glaucoma.
[PMID 19343041] Association of LOXL1 gene with Finnish exfoliation syndrome patients.
[PMID 19373106] Lysyl oxidase-like 1 gene polymorphisms in German patients with normal tension glaucoma, pigmentary glaucoma and exfoliation glaucoma.
[PMID 19779542] A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1.
[PMID 21150032] Complex genetic mechanisms in glaucoma: an overview.
[PMID 21272281] Analysis of LOXL1 single nucleotide polymorphisms in Polish population with pseudoexfoliation syndrome.
[PMID 21364909] Eurasian and Sub-Saharan African mitochondrial DNA haplogroup influences pseudoexfoliation glaucoma development in Saudi patients.
[PMID 21559813] No association of LOXL1 gene polymorphisms with Alzheimer's disease.
[PMID 22605916] Role of Lysyl oxidase-like 1 gene polymorphisms in Pakistani patients with pseudoexfoliative glaucoma
[PMID 23441117] Evaluation of lysyl oxidase-like 1 gene polymorphisms in pseudoexfoliation syndrome in a Korean population
[PMID 23869164] Association of lysyl oxidase-like 1 gene common sequence variants in Greek patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma
[PMID 24603551] Association between Polymorphisms in Lysyl Oxidase-Like 1 and Susceptibility to Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma
[PMID 24892565] Association of lysyl oxidase-like 1 gene polymorphisms in pseudoexfoliation syndrome and pseudoexfoliation glaucoma in a Spanish population
[PMID 24967207] Lack of association between lysyl oxidase-like 1 polymorphisms and primary open angle glaucoma: a meta-analysis
[PMID 25304275] LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma: A Meta-Analysis
[PMID 25709925] The association of LOXL1 polymorphisms with exfoliation syndrome/glaucoma: Meta-analysis
[PMID 26319397] LOXL1 gene variants and their association with pseudoexfoliation glaucoma (XFG) in Spanish patients
[PMID 27116380] Correlation of Aqueous Humor Lysyl Oxidase Activity with TGF-ß Levels and LOXL1 Genotype in Pseudoexfoliation.
[PMID 30405941] Three Single Nucleotide Polymorphisms of LOXL1' in a Turkish Population with Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma.
[PMID 31850260] Association of LOXL1 Gene Polymorphisms with Exfoliation Glaucoma Patients.
[PMID 32253563] Associations of polymorphisms in LOXL1 and copper chaperone genes with pseudoexfoliation-syndrome-related cataract in a Chinese Uygur population.