Our study firstly investigated the causal effects between hypothyroidism and hearing loss by bidirectional two-sample MR analysis. The results of the study indicated that genetically predicted hypothyroidism causally associated with an increased risk of hearing loss. Furthermore, no evidence was found to support causal relationship of hearing loss on hypothyroidism. our findings provided a better understanding of the role of hypothyroidism in hearing loss, indicating that regular hearing assessments for hypothyroidism patients are required, in order to prevent them from severe hearing loss.
Hearing loss is reported frequently associated with hypothyroidism, ranging from mild disturbances to severe disability. A case-control study conducted by Tsai et al. (18) in Taiwan demonstrated that after adjusting for confounders, associations were identified between a history of hypothyroidism and an elevated risk of SSNHL (adjusted odds ratio [AOR], 1.54; 95% CI, 1.02–2.32; p = 0.042). Similar results were obtained in a retrospective cohort study including 8658 SSNHL patients and 34,632 controls conducted by Kim et al. (17) in Korean. Meanwhile, A prospective observational study conducted by Almagor et al. (28) in Israel indicated a high prevalence of hearing impairment among patients with congenital hypothyroidism, predominantly of the conductive type. Unlike the above study, however, more observed that sensorineural hearing loss was most common in congenital hypothyroidism, higher frequencies in particular(29–32), and this phenomenon was not associated with THS and free T4 levels(33–35). There was also a contradictory conclusion, François et al. (36) found no significant difference for the auditory thresholds at high frequencies between congenital hypothyroidism treated with L-thyroxine and control group, regardless of the cause of the thyroid failure or hormone level and the age at the start of treatment.
These contradiction between observational studies could be due to confounding bias or reverse causality. For instance, some genetic or chromosomal disorders can also present with hypothyroidism and hearing loss at the same time, including Pendred syndrome variants in the SLC26A4 gene (37–39), Woodhouse-Sakati Syndrome variants in the DCAF17 gene(40), Down syndrome(41), and TBL1X mutations(42). In animal experiments, Oliveira et al. (43) observed that perinatal hypothyroidism leads to irreversible damage to cochlear function in offspring rats. Others found that the congenital hypothyroid mouse displayed consistent morphologic abnormalities of the stereocilia on both inner and outer hair cell systems. The surrounding and supporting cells showed no significant histologic abnormalities in hypothyroid mouse and control animals (44).
Despite an abundance of evidence from observational studies support the association between hypothyroidism and hearing loss, there still remain a question about their causative relationships. The present Mendelian randomization study employs IVs to eliminate confounders and offers a new perspective on the causality between hypothyroidism and hearing loss. We provided more statistically significant results through bidirectional two-sample MR analysis. It is possible be that the presence of hypothyroidism leads to the increasing risk of hearing loss, as opposed to hearing loss promoting the occurrence of hypothyroidism.
The current study has several strengths. First, the data we used containing 323,978 and 462,993 individuals of European ancestry, allowing us to gain more precise estimates and detect slight statistical differences, meanwhile preventing the simple error in previous cohort studies. Second, bidirectional two-sample MR methods were firstly applied to explore the causal associations with hypothyroidism and hearing loss, and these methods tend to be less biased than conventional observational studies. Third, the MR method took advantage of GWAS summary data on hypothyroidism and hearing loss that were derived from two different populations, which reduced the interference of sample overlap.
Nevertheless, there are still several limitations in our study. First, our conclusions were based on data from GWASs that were solely conducted in people with European ancestry, with relatively little variety in ethnicity or culture. Thus, the results may not be fully representative of the entire population and might not be generalizable. However, the participants' consistency assures that there is little chance of population admixture confounding the results. Second, as our study used summarized data for MR analysis, stratification based on gender, age or subtypes was not applicable. Third, we found that the two samples were somewhat heterogeneous. However, because the MRE-IVW that used as the primary analysis in this work can balance the pooled heterogeneity, the presence of heterogeneity did not render the MR estimates invalid.