angiotensinogen and Otosclerosis

Otosclerosis is a frequent cause of hearing impairment characterized by abnormal resorption and deposition of bone in the human otic capsule. It is a disease of complex etiopathogenesis that is caused by both environmental and genetic factors. The goal of this study is to replicate association for genes that were previously reported to be associated with otosclerosis. However, in this study, patients were used in which the presence of otosclerotic foci was confirmed by histologic investigation, in contrast to previous studies, that did not use histologic confirmation.. Case-control association study using 153 cases and 300 controls. Thirteen single nucleotide polymorphisms (SNPs) in 6 genes (COL1A1, TGFB1, BMP2, BMP4, AGT, and RELN) were genotyped.. An association between TGFB1 (rs1800472) and otosclerosis was detected, confirming several previous reports. It is surprising that no association was found between RELN and otosclerosis because the current analysis had very reasonable power and the RELN association has been published before in different articles using several independent populations.. Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis. The fact that other genes did not replicate could be due to different reasons like lack of power (BMP2 and BMP4) and possible false-positive initial association (COL1A1 and AGT). A plausible explanation for the lack of association for RELN is that RELN could be associated with a specific otosclerosis-like phenotype that is different from the histologically confirmed phenotype of the patients in this study, and that is clinically not distinguishable.

Topics: Adult; Angiotensinogen; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Case-Control Studies; Cell Adhesion Molecules, Neuronal; Collagen Type I; Collagen Type I, alpha 1 Chain; Extracellular Matrix Proteins; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Nerve Tissue Proteins; Otosclerosis; Phenotype; Polymorphism, Single Nucleotide; Reelin Protein; Serine Endopeptidases; Transforming Growth Factor beta1; Young Adult

Otosclerosis is a frequent cause of hearing impairment in the Caucasian population and is characterized by abnormal bone remodeling of the otic capsule. Associations with several genes have been reported, and recently, an association between the renin-angiotensin-aldosterone system and otosclerosis has been suggested. Polymorphisms in 3 genes were investigated: angiotensinogen (AGT), angiotensin I-converting enzyme (ACE), and angiotensin II receptor, type 1. The polymorphisms in AGT and ACE were associated with disease, and both were reported to interact with each other. In the current study, a replication study was done in a large Belgian-Dutch population to investigate whether this association could be replicated.. The same 3 polymorphisms in AGT, ACE, and angiotensin II receptor, type 1 as analyzed in the original study were investigated in 692 otosclerosis patients and 692 controls of Belgian-Dutch origin.. None of the polymorphisms were significantly associated with disease. Interaction between AGT and ACE polymorphisms was not significant either.. We could not confirm the association between AGT and ACE, nor could we find evidence for interaction between both genes in otosclerosis. Because the current patient set is much larger than the one from the original study, this study holds sufficient power to detect the previously reported associations. Nonreplication in this case probably indicates that the initial results were false positive, although a role for these genes in otosclerosis cannot be definitively ruled out.

Topics: Angiotensinogen; Belgium; Data Interpretation, Statistical; DNA; Genotype; Netherlands; Otosclerosis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction

Angiotensin II (Ang II) may be implicated in the regulation of bone remodeling, and its activity is related to several gene polymorphisms including AGT M235T for plasmatic and tissular concentrations of angiotensinogen (AGT), ACE I/D for the angiotensin-converting enzyme activity, and AT(1)R A/C(1166) for the Ang II receptor function. The objective of this study was to investigate the implication of this hormone in otosclerosis.. Prospective case-control study.. The above-mentionedpolymorphisms were investigated in 186 patients with otosclerosis and 526 healthy controls, both groups originated from the French Caucasian population. Primary cell cultures of stapedial bone from patients with otosclerosis (n = 6) and control subjects (n = 5) were investigated for the messenger ribonucleic acid expressions of Ang II receptors (Types 1 and 2) and cellular AGT and the effect of Ang II (10(-7) mol/L, 24 h) on the alkaline phosphatase activity and the interleukin-6 secretion in the culture media.. A significant association was found between otosclerosis and the AGT M235T and the ACE I/D polymorphisms. Higher proportions of TT (29% versus 16%; p < 0.01) and DD (50% versus 38%; p < 0.05) genotypes were observed in cases versus controls. No association was found between the AT(1)R A/C(1166) polymorphism and otosclerosis. Ang II receptor Types 1 and 2 and AGT were detected in the cultures. Ang II increased the in vitro secretion of interleukin-6 and decreased the alkaline phosphatase activity only in otosclerotic cells.. These observations suggest a relation between the local renin angiotensin system activity and otosclerosis, opening new therapeutic insights.

Topics: Adult; Alkaline Phosphatase; Angiotensin II; Angiotensinogen; Case-Control Studies; Cells, Cultured; Genotype; Humans; In Vitro Techniques; Interleukin-6; Middle Aged; Otosclerosis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; RNA, Messenger; Stapes