Genetic Association and Gene-gene interaction ofHAS2,HABP1andHYAL3Implicate Hyaluronan Metabolic Genes in Glaucomatous Neurodegeneration

Abstract

Hyaluronan (HA) plays a significant role in maintaining aqueous humor outflow in trabecular meshwork, the primary ocular tissue involved in glaucoma. We examined potential association of the single nucleotide polymorphisms (SNPs) of the HA synthesizing gene – hyaluronan synthase 2 (HAS2), hyaluronan binding protein 1 (HABP1) and HA catabolic gene hyaluronidase 3 (HYAL3) in the primary open angle glaucoma (POAG) patients in the Indian population. Thirteen tagged SNPs (6 forHAS2, 3 forHABP1and 4 forHYAL3) were genotyped in 116 high tension (HTG), 321 non-high tension glaucoma (NHTG) samples and 96 unrelated, age-matched, glaucoma-negative, control samples. Allelic and genotypic association were analyzed by PLINK v1.04; haplotypes were identified using PHASE v2.1 and gene-gene interaction was analyzed using multifactor dimensionality reduction (MDR) v2.0. An allelic association (rs6651224;p= 0.03; OR: 0.49; 95% CI: 0.25–0.94) was observed at the second intron (C>G) ofHAS2both for NHTG and HTG. rs1057308 revealed a genotypic association (p= 0.03) at the 5’ UTR ofHAS2with only HTG. TCT haplotype (rs1805429 – rs2472614 – rs8072363) inHABP1and TTAG and TTGA (rs2285044 – rs3774753 – rs1310073 – rs1076872) inHYAL3were found to be significantly high (p< 0.05) both for HTG and NHTG compared to controls. Gene-gene interaction revealedHABP1predominantly interacts withHAS2in HTG while it associates with bothHYAL3andHAS2in NHTG. This is the first genetic evidence, albeit from a smaller study, that the natural polymorphisms in the genes involved in hyaluronan metabolism are potentially involved in glaucomatous neurodegeneration.