Rs1048661

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.

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

Confirmed as risk for pseudoexfoliation (PEX) and pseudoexfoliation glaucoma (PEXG) in populations of German and Italian descent.

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.