Identification of Genetic Risk Factors in Pigmentary Glaucoma

We focus on the identification of genetic risk factors of a type of glaucoma, termed pigmentary glaucoma by using two screening strategies that complement each other in an ideal way. Candidate genes were selected based on identification of related genes in different mouse models exhibiting pigment dispersion and based on pathway and protein-protein interaction annotations. These candidate genes will be subjected to a technique called direct mutation scanning AND will be analyzed by means of a case control study.

Pigmentary glaucoma is caused by pigment deposited from the iris that clogs the drainage systems of the eye, preventing the liquid aqueous humor from leaving the eye. Over time, the inflammatory response to the blockage damages the drainage system. In one study, 2% of patients had this form of glaucoma. Pigmentary glaucoma tends to run in families, indicating a strong genetic background. Researchers hope that identification of genes will help improve screening of high-risk patients. So far, no causative genes have been identified for this condition. We will focus on the identification of genes responsible for pigmentary glaucoma. Our approach is to combine two screening methods.

1. A regional cohort of 200 German pigmentary glaucoma patients will be analyzed by means of a direct mutation scanning. Changes in DNA caused by a mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. We aim to identify such mutations in genes that were selected due to their role in several mouse strains that exhibit features which resemble the features in human pigmentary glaucoma. The direct mutation scanning enables to detect mutations in a single patient, however, due to methodological limitations, mutations can be missed sometimes.
2. The direct mutation scanning will therefore be complemented with the analyses of SNPs. A single nucleotide polymorphism (SNP, pronounced snip) is a DNA sequence variation occurring when a single nucleotide – A, T, C, or G – in the genome differs between members of a species. The analysis of SNPs can overcome the limitation of the direct mutation scanning technology when used in a case control study. Case-control is a type of epidemiological study design and is used to identify factors that may contribute to a disease by comparing subjects who have that condition (the ‘cases’) with patients who do not have the condition but are otherwise similar (the ‘controls’). We will therefore compare our 200 patients with 280 healthy controls by analyzing many SNPs surrounding the abovementioned genes. Differences in the frequency of these SNPs between the two groups may indicate that the genetic marker increases the risk of developing pigmentary glaucoma.

Progress Updates

We performed a comprehensive screening for mutations in two prime candidate genes in one hundred patients with pigmentary glaucoma. We were able to identify novel variants in three cases. The pathogenic relevance of these variants still needs to be evaluated. Our data indicate that DNA coding sequence (or “spelling) variants in the two candidate genes do not seem to have a major impact on the pathogenesis of human pigmentary glaucoma. Therefore, we will continue to investigate our patients by means of a case control study.

While the direct mutation screening approach favors the individual, a case control study is a type of epidemiological study (i.e. the study of factors affecting the health and illness of populations) designed to define a relative risk of a group. We will use well-characterized groups of people with and without pigmentary glaucoma, and compare common variation(s) in a range of candidate genes in both groups. If the majority of cases with pigmentary glaucoma are due to the combined effects of multiple genetic variants, this will be a more powerful approach to identify genetic risk factors that affect the likelihood of developing glaucoma.