Functional Variants inNOS1andNOS2AAre Not Associated with Progressive Hearing Loss in Ménière's Disease in a European Caucasian Population

Abstract

Hearing loss in Ménière's disease (MD) is associated with loss of spiral ganglion neurons and hair cells. In a guinea pig model of endolymphatic hydrops, nitric oxide synthases (NOS) and oxidative stress mediate loss of spiral ganglion neurons. To test the hypothesis that functional variants of NOS1 and NOS2A are associated with MD, we genotyped three functional variants of NOS1 (rs41279104, rs2682826, and a cytosine-adenosine microsatellite repeat in exon 1f) and the CCTTT repeat in the promoter of NOS2A gene (rs3833912) in two independent MD sets (273 patients in total) and 550 controls. A third cohort of American patients was genotyped as replication cohort for the CCTTT repeat. Neither allele nor genotype frequencies of rs41279104 and rs2682826 were associated with MD, although longer alleles of the cytosine-adenosine microsatellite repeat were marginally significant (corrected p = 0.05) in the Mediterranean cohort but not in a second Galicia cohort. Shorter numbers of the CCTTT repeat in NOS2A were significantly more frequent in Galicia controls (OR = 0.37 [CI, 0.18-0.76], corrected p = 0.04), but this finding could not be replicated in Mediterranean or American case-control populations. Meta-analysis did not support an association between CCTTT repeats and risk for MD. Severe hearing loss (>75 dB) was also not associated with any functional variants studied. Functional variants of NOS1 and NOS2A do not confer susceptibility for MD.

A Drosophila model for Meniere’s disease: Dystrobrevin is required for support cell function in hearing and proprioception

“…These studies have suggested the link with NOS dysregulation. However, genetic studies in large MD patient cohorts showed that functional variants in NOS1 and NOS2A are not associated with progressive hearing loss in MD (Gazquez et al, 2011;Teranishi et al, 2013). Our results suggest that the link between the NOS pathway, hydrops and MD could be the DGC complex and alterations in the homeostatic stability of the system.…”

Pathogenesis and pathophysiology of Meniere’s disease: An update

“…Surprisingly, not only NOS1, but also NOS2A are upregulated in SGNs in a model of endolymphatic hydrops, suggesting that alternatives of these genes may be related to the neurotoxicity and programmed cell death of SGNs in MD. [41] Incremented NO-synthesis is related to the development of ROS-like lipid peroxides, hydroxyl radicals or peroxynitrite (ONOO -). As it is well-known, oxidative stress by ROS may damage mitochondria complexes, deoxyribonucleic acid, lipid membranes, and proteins.…”

Genetics of Recurrent Vertigo and Vestibular Disorders

“…A candidate gene approach, either by case-control studies or by the sequencing of selected genes, has been used to search genetic markers associated with MD (Table 3 ). These genes include antiquitin [ 60 ], aquaporin 2 [ 61 ], COCH ( coagulation factor C homology ) [ 62 ], potassium channels genes (KCNE1 and KCNE3) [ 63 ], MHC class II genes [ 64 , 65 ], alpha-adducin [ 66 ], heat-shock protein 70 [ 67 ], PARP-1 [ 68 ], PTPN22 [ 69 ], Fc gamma receptors CD32 and CD16a [ 70 ] and nitric oxide synthases type 1 and 2 [ 71 ]. However, none of these genes could be replicated in an independent set of MD patients [ 72 - 74 ].…”