Do ß2–Adrenergic Receptor Single Nucleotide Polymorphisms and Haplotypes Contribute to Aqueous Humor Flow Variations in Humans?

Abstract

Purpose: : Intraocular pressure (IOP) fluctuation contributes to glaucoma progression. Since aqueous humor flow is a determinant of IOP, our objectives were to determine the following: 1) whether ß₂–adrenergic receptor (AR) single nucleotide polymorphisms (SNPs) and haplotypes contribute to flow variation, and 2) whether the ß₂–AR gene is a glaucoma susceptibility locus.

Methods: : Flow was measured by fluorophotometry in the morning and nighttime in normal human subjects. Differences in flow and concordance of individual morning and nighttime flows were analyzed. The ß₂–AR SNPs and haplotypes were determined by sequencing and allele–specific polymerase chain reaction (PCR) combined with restriction enzyme digestion.

Results: : Flow was similar between eyes within a subject (n = 28). Using one eye from each subject, the average morning flow was 3.12 + 1.09 µl/min, which decreased significantly to 1.59 + 0.58 µl/min at nighttime (p–value < 0.0001). For both time periods, the flow data were normally distributed. A new finding is concordance of individual flow in the morning and nighttime. When flow variation is largest the in morning, ß₂–AR haplotypes appear to contribute to this variation. In a case–control study stratified by race and disease (White control, n = 150; Black control, n = 158; vs. White primary open–angle glaucoma, n = 138; Black primary open–angle glaucoma, n = 143), there were no statistically significant differences in ß₂–AR alleles and haplotypes between controls and POAG cases whether analyzed together or by race. Previously described race–based differences in ß₂–AR allele frequencies and haplotypes were found.

Conclusions: : We have shown two new findings regarding flow variation. First, individuals show concordance of flow in morning and nighttime. Second, when the flow distribution is large in the morning, that ß₂–AR haplotypes seem to contribute to this variation. Since the ß₂–AR gene is not a glaucoma susceptibility locus, we can determine the role of ß₂–AR and other potential candidate genes on IOP variation, which is an important risk factor for glaucoma progression.

Keywords: aqueous • circadian rhythms • inflow/ciliary body