The impact of cardiovascular diseases on hearing deterioration: a 13-year follow-up study.

OBJECTIVE: To study the impact of cardiovascular diseases (CVDs) on hearing deterioration among ageing adults in a longitudinal setting. Furthermore, to describe the pure tone threshold changes at the 0.125-8 kHz frequency range over 13 years. DESIGN: A population-based follow-up study. STUDY SAMPLE: A random sample of 850 adults, of whom 559 participated in the follow-up study. Otological examination, a structured interview, and pure tone audiometry were conducted. Multivariate regression models were used to estimate the effect of CVD (participants had at least one cardiovascular condition) on hearing deterioration of the better ear hearing level (BEHL), defined as a change in the pure-tone average (PTA) of the frequencies 0.5, 1, 2, and 4 kHz and separately at the lower (0.125, 0.25, and 0.5 kHz) and higher (4, 6, and 8 kHz) frequencies. RESULTS: In the multivariable-adjusted analysis, the BEHL change at 13 years was 0.7 dB greater among participants with CVD (p = 0.3). The mean BEHL change during the 13-year follow-up was 12.0 dB (95% CI 11.4-12.6) among all participants. CONCLUSIONS: No significant association between CVD and hearing threshold changes was found.

Prevalence and incidence of hearing impairment among adults: a 13-year follow-up study.

OBJECTIVE: The aim of this study was to investigate the prevalence and incidence of hearing impairment (HI) in a longitudinal setting among adults. DESIGN: An unscreened, population-based epidemiological 13-year follow-up study. Study sample: 850 randomly sampled 54 to 66-year-old baseline participants, of whom 559 participated in the follow-up study at the age of 68 to 79 years. A questionnaire-based interview, an otological examination and pure-tone audiometry were performed. RESULTS: The overall prevalence of HI was 70.3%, defined by better ear hearing level (BEHL) ≥ 20 dB in the 0.5-4 kHz frequency range. The prevalence was higher among men (78.6%) than among women (63.7%). The overall incidence rate for HI was 45.8 per 1000 person years and the 13-year cumulative incidence was 60.9%. The incidence was higher among men and older participants. CONCLUSION: HI is highly prevalent and incident among older adults in Northern Finland.

Whole-exome sequencing suggests multiallelic inheritance for childhood-onset Ménière's disease.

The genetic background of Ménière's disease (MD) was studied in one patient with childhood-onset MD and his grandfather affected with middle age-onset MD. Whole-exome sequencing was performed and the data were compared to 76 exomes from unrelated subjects without MD. Thirteen rare inner ear expressed variants with pathogenic estimations were observed in the case of childhood-onset MD. These variants were in genes involved in the formation of cell membranes or the cytoskeleton and in genes participating in cell death or gene-regulation pathways. His grandfather shared two of the variants: p.Y273N in HMX2 and p.L229F in TMEM55B. HMX2 p.Y273N was considered the more likely candidate for MD, as the gene is known to affect both hearing and vestibular function. The variant in the HMX2 gene may affect inner ear development and structural integrity and thus might predispose to the onset of MD. As there was a significant difference in onset between the patients, an accumulation of defects in several pathways is probably responsible for the exceptionally early onset of the disease, and the genetic etiology of childhood-onset MD is most likely multifactorial. This is the first molecular genetic study of childhood-onset MD.

Mutations in the two ribosomal RNA genes in mitochondrial DNA among Finnish children with hearing impairment.

BACKGROUND: Mutations in the two MT-RNR genes in mitochondrial DNA can cause hearing impairment that presents with variable severity and age of onset. In order to study the prevalence of mutations in MT-RNR1 and MT-RNR2 genes among Finnish children, we studied a ten-year cohort of hearing impaired children born in Northern Finland. METHODS: We studied children, who had been born in Northern Finland in 1993-2002 and who had been ascertained to have hearing impairment by 31 December 2007. Samples from 103 children were sequenced in order to find mutations in the MT-RNR1 and MT-RNR2 genes. RESULTS: One child harboured the pathogenic m.1555A > G mutation in MT-RNR1 suggesting a frequency of 4.4/100,000 in the Finnish paediatric population. In addition, eight rare variants and 13 polymorphisms were found in MT-RNR1 and MT-RNR2 genes. Five of the rare variants were deemed to be haplogroup-specific polymorphisms rather than putative pathogenic mutations, while the remaining three variants have been reported in various haplogroups. Among them m.990 T > C occurs at a conserved site. CONCLUSIONS: The presence of m.990 T > C variant in various haplogroups and the rather high degree of conservation at this site suggest that this transition is a pathogenic rather than homoplasic neutral variant. Identification of further patients with m.990 T > C and segregation analysis in their families should help in determining the pathogenic potential of this variant.

Hearing impairment among adults: the impact of cardiovascular diseases and cardiovascular risk factors.

OBJECTIVE: To investigate the influence of cardiovascular diseases on hearing impairment (HI) among adults. Furthermore, to seek other potential risk factors for HI, such as smoking, obesity, and socioeconomic class. DESIGN: A cross-sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Cardiovascular diseases did not increase the risk for HI in a propensity-score adjusted logistic regression model: OR 1.24, 95% CI 0.79 to 1.96 for HI defined by better ear hearing level (BEHL), and OR 1.48, 95% CI 0.96 to 2.28 for HI defined by worse ear hearing level (WEHL), in the 0.5-4 kHz frequency range. Heavy smoking is a risk factor for HI among men (BEHL: OR 1.96, WEHL: OR 1.88) and women (WEHL: OR 2.4). Among men, obesity (BEHL, OR 1.85) and lower socioeconomic class (BEHL: OR 2.79, WEHL: OR 2.28) are also risk factors for HI. CONCLUSION: No significant association between cardiovascular disease and HI was found.

WFS1 mutations in hearing-impaired children.

OBJECTIVE: Mutations in the WFS1 gene can cause Wolfram syndrome or nonsyndromic hearing impairment (HI). The objective of this study was to ascertain the presence of mutations in WFS1 among children with HI from unknown causes. DESIGN: We screened 105 Finnish children with HI for mutations in exon 8 in WFS1. STUDY SAMPLE: Children were born in a defined area in Northern Finland and they had sensorineural, mild to profound, syndromic, or nonsyndromic HI. They were negative for GJB2 mutations and for the m.1555A> G and m.3243A> G mutations in mitochondrial DNA. RESULTS: We found three rare variants and the novel p.Gly831Ser variant in WFS1. Segregation analysis suggested that the novel variant had arisen de novo. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI, while the pathogenicity of the rare variant p.Gly674Arg remained unclear. The other two rare variants, p.Glu385Lys and p.Glu776Val, did not segregate with HI in the families. CONCLUSIONS: WFS1 gene mutations are a rare cause of HI among Finnish children with HI.

Audiological follow-up of children with the m.1555A>G mutation in mitochondrial DNA.

The age at onset and the severity of hearing impairment (HI) varies widely among subjects and within families with the m.1555A>G mutation in mitochondrial DNA. We examined prospectively the hearing of 19 children in three nuclear families of a pedigree with m.1555A>G during a period of 7.8 years. The children underwent an audiological examination annually. At the end of the follow-up, the children were 2-13 years old. The parents were asked about the exposure of the children to risk factors of HI. We found that the 19 children with m.1555A>G were born with normal hearing and that 10 of them had developed HI by the end of the follow-up. High frequencies were affected first. The median age at the onset of HI was 3.7 years. Both the severity of HI and the age of onset varied within and between families. Most commonly, audiograms revealed a sensorineural, progressive HI sloping towards high frequencies. We could not identify environmental factors which could modify the development of HI. In conclusion, we were able to pinpoint the time of onset of HI and to follow the progression of HI in childhood. Our results show that there are distinct phenotypes, but at present there are no means to predict which phenotype will develop. It is important to follow up the hearing of children in families with the m.1555A>G mutation, because these children generally pass the newborn hearing screening, and the age at onset or the phenotype of HI cannot be predicted.

Ear diseases and other risk factors for hearing impairment among adults: an epidemiological study.

OBJECTIVE: To investigate the prevalence of ear diseases, other otological risk factors potentially affecting hearing, and noise exposure among adults. Furthermore, subject-related factors possibly associated with hearing impairment (HI), i.e. handedness, eye color, and susceptibility to sunburn, were studied. DESIGN: A cross-sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Chronic middle-ear disease (both active and inactive) was the most common ear disease with a prevalence of 5.3%, while the prevalence of otosclerosis was 1.3%, and that of Ménière's disease, 0.7%. Noise exposure was reported by 46% of the subjects, and it had no effect on hearing among those with no ear disease or other otological risk factors for HI. Dark eye color and non-susceptibility to sunburn were associated with HI among noise-exposed subjects. CONCLUSIONS: Common ear diseases and other otological risk factors constitute a major part of the etiologies of HI among adults. Contrary to previous studies, noise exposure turned out to have only marginal effect on hearing among those with no otological risk factors.

A replication study on proposed candidate genes in Ménière's disease, and a review of the current status of genetic studies.

OBJECTIVE: Multiple candidate genes have been presented for Ménière's disease (MD), but to date no positive replications have been reported. We review here all the previously proposed candidate genes for MD and report our results on the analysis of six such genes, AQP2, KCNE1, KCNE3, HCFC1, COCH, and ADD1. STUDY SAMPLE: A well-defined sample set of 38 sporadic and 21 familial Finnish MD patients. DESIGN: Mutation analysis, case-control study, and review of literature. RESULTS: A polymorphism rs1805127 in the potassium channel gene, KCNE1, was associated with MD in sporadic (p = 0.011), but not familial patients (p = 0.62). In addition, we identified four novel unique variations in the KCNE1 gene. PolyPhen and Mutation Taster analyses indicated that at least one of the variations c.259T > C; p.Trp87Arg is probably damaging to the coded protein. CONCLUSIONS: Our review of the reported candidate genes shows that the current understanding of the genetic factors contributing to the development of MD is limited, and that the study of its etiology would benefit greatly from more comprehensive genetic knowledge.

New Genetic Variants in CYP2B6 and SLC6A Support the Role of Oxidative Stress in Familial Ménière's Disease.

The objective was to study the genetic etiology of Ménière's disease (MD) using next-generation sequencing in three families with three cases of MD. Whole exome sequencing was used to identify rare genetic variants co-segregating with MD in Finnish families. In silico estimations and population databases were used to estimate the frequency and pathogenicity of the variants. Variants were validated and genotyped from additional family members using capillary sequencing. A geneMANIA analysis was conducted to investigate the functional pathways and protein interactions of candidate genes. Seven rare variants were identified to co-segregate with MD in the three families: one variant in the CYP2B6 gene in family I, one variant in GUSB and EPB42 in family II, and one variant in each of the SLC6A, ASPM, KNTC1, and OVCH1 genes in family III. Four of these genes were linked to the same co-expression network with previous familial MD candidate genes. Dysfunction of CYP2B6 and SLC6A could predispose to MD via the oxidative stress pathway. Identification of ASPM and KNTC1 as candidate genes for MD suggests dysregulation of mitotic spindle formation in familial MD. The genetic etiology of familial MD is heterogenic. Our findings suggest a role for genes acting on oxidative stress and mitotic spindle formation in MD but also highlight the genetic complexity of MD.

GRM7 variants confer susceptibility to age-related hearing impairment.

Age-related hearing impairment (ARHI), or presbycusis, is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. Here we describe the results of the first whole genome association study for ARHI. The study was performed using 846 cases and 846 controls selected from 3434 individuals collected by eight centers in six European countries. DNA pools for cases and controls were allelotyped on the Affymetrix 500K GeneChip for each center separately. The 252 top-ranked single nucleotide polymorphisms (SNPs) identified in a non-Finnish European sample group (1332 samples) and the 177 top-ranked SNPs from a Finnish sample group (360 samples) were confirmed using individual genotyping. Subsequently, the 23 most interesting SNPs were individually genotyped in an independent European replication group (138 samples). This resulted in the identification of a highly significant and replicated SNP located in GRM7, the gene encoding metabotropic glutamate receptor type 7. Also in the Finnish sample group, two GRM7 SNPs were significant, albeit in a different region of the gene. As the Finnish are genetically distinct from the rest of the European population, this may be due to allelic heterogeneity. We performed histochemical studies in human and mouse and showed that mGluR7 is expressed in hair cells and in spiral ganglion cells of the inner ear. Together these data indicate that common alleles of GRM7 contribute to an individual's risk of developing ARHI, possibly through a mechanism of altered susceptibility to glutamate excitotoxicity.

Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait.

Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.

Finnish familial Meniere disease is not linked to chromosome 12p12.3, and anticipation and cosegregation with migraine are not common findings.

PURPOSE: To study the inheritance and characteristics of familial Meniere disease in Finland and genetic linkage to the previously proposed locus on chromosome 12p12.3. METHODS: Sixteen Meniere families recruited from Kainuu Central Hospital and Helsinki and Oulu University Hospitals in the period 2001-2004 were reevaluated in 2009 using hospital records and mailed questionnaire forms. Ten highly polymorphic microsatellite markers were selected from the area of chromosome 12p12.3 and studied for linkage using the GENEHUNTER protocol. RESULTS: The families showed autosomal dominant inheritance without cosegregation with migraine. Anticipation was seen only in one family, and in the rest of the families, the age of onset varied randomly among generations and individuals. The severity of the disease was not related to descending generations. None of the maximum logarithm of odds (LOD)/heterogeneity LOD scores in the analysis of chromosome 12p12.3 in Finnish Meniere families reached a significant value of 3.0 (maximum cumulative LOD score: -7.29, heterogeneity LOD: -0.95, α = 0.4). CONCLUSIONS: Families affected by Meniere disease are highly heterogeneous. Migraine, age at onset, anticipation, or penetrance was not a shared feature. The findings support the multifactorial nature of the disease and indicate that genetic heterogeneity exists within familial Meniere disease.

Audiogram configurations among older adults: prevalence and relation to self-reported hearing problems.

OBJECTIVE: There are only a few population-based epidemiological studies on audiogram configurations among adults. The aim of this study was to investigate the prevalence of different audiogram configurations among older adults. In addition, audiogram configurations among subjects reporting hearing problems were examined. DESIGN: Cross-sectional, population-based, unscreened epidemiological study among older adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: The most prevalent audiogram configuration among men was high-frequency steeply sloping (65.3% left ear, 51.2% right ear) and among women, high-frequency gently sloping (33.0% left ear, 31.5% right ear). There were significantly more flat configurations among women than among men. Unclassified audiograms were common especially among women (17.5%). Subjects reporting hearing difficulties, difficulties in following conversation in noise, or tinnitus, more often had a high-frequency steeply sloping configuration than those not reporting. CONCLUSIONS: High-frequency sloping audiogram configurations were common among older adults, and a high-frequency steeply sloping configuration was common among those reporting hearing problems.

Self-reported hearing problems among older adults: prevalence and comparison to measured hearing impairment.

BACKGROUND: There are not many population-based epidemiological studies on the association between self-reported hearing problems and measured hearing thresholds in older adults. Previous studies have shown that the relationship between self-reported hearing difficulties and measured hearing thresholds is unclear and, according to our knowledge, there are no previous population-based studies reporting hearing thresholds among subjects with hyperacusis. PURPOSE: The aim was to investigate the prevalence of self-reported hearing problems, that is, hearing difficulties, difficulties in following a conversation in noise, tinnitus, and hyperacusis, and to compare the results with measured hearing thresholds in older adults. RESEARCH DESIGN: Cross-sectional, population-based, and unscreened. STUDY SAMPLE: Random sample of subjects (n=850) aged 54-66 yr living in the city of Oulu (Finland) and the surrounding areas. DATA COLLECTION AND ANALYSIS: Otological examination, pure tone audiometry, questionnaire survey RESULTS: The prevalence of self-reported hearing problems was 37.1% for hearing difficulties, 43.3% for difficulties in following a conversation in noise, 29.2% for tinnitus, and 17.2% for hyperacusis. More than half of the subjects had no hearing impairment, or HI (BEHL[better ear hearing level]0.5-4 kHz<20 dB HL) even though they reported hearing problems. Subjects with self-reported hearing problems, including tinnitus and hyperacusis, had significantly poorer hearing thresholds than those who did not report hearing problems. Self-reported hearing difficulties predicted hearing impairment in the pure-tone average at 4, 6, and 8 kHz, and at the single frequency of 4 kHz. CONCLUSIONS: The results indicate that self-reported hearing difficulties are more frequent than hearing impairment defined by audiometric measurement. Furthermore, self-reported hearing difficulties seem to predict hearing impairment at high frequencies (4-8 kHz) rather than at the frequencies of 0.5-4 kHz, which are commonly used to define the degree of hearing impairment in medical and legal issues.

Vowel confusion patterns in adults during initial 4 years of implant use.

This study investigated adult cochlear implant users' (n = 39) vowel recognition and confusions by an open-set syllable test during 4 years of implant use, in a prospective repeated-measures design. Subjects' responses were coded for phoneme errors and estimated by the generalized mixed model. Improvement in overall vowel recognition was highest during the first 6 months, showing statistically significant change until 4 years, especially for the mediocre performers. The best performers improved statistically significantly until 18 months. The poorest performers improved until 12 months and exhibited more vowel confusions. No differences were found in overall vowel recognition between Nucleus24M/24R and Med-ElC40+ device users (matched comparison), but certain vowels showed statistically significant differences. Vowel confusions between adjacent vowels were evident, probably due to the implant users' inability to discriminate formant frequencies. Vowel confusions were also dominated by vowels whose average F1 and/or F2 frequencies were higher than the target vowel, indicating a basalward shift in the confusions.

The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment.

Age-related hearing impairment (ARHI) is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. The contribution of various environmental factors has been relatively extensively studied. In contrast, investigations to identify the genetic risk factors have only recently been initiated. In this paper we describe the results of an association study performed on 2418 ARHI samples derived from nine centers from seven European countries. In 70 candidate genes, a total of 768 tag single nucleotide polymorphisms (SNPs) were selected based on HAPMAP data. These genes were chosen among the monogenic hearing loss genes identified in mice and men in addition to several strong functional candidates. After genotyping and data polishing, statistical analysis of all samples combined resulted in a P-value that survived correction for multiple testing for one SNP in the GRHL2 gene. Other SNPs in this gene were also associated, albeit to a lesser degree. Subsequently, an analysis of the most significant GRHL2 SNP was performed separately for each center. The direction of the association was identical in all nine centers. Two centers showed significant associations and a third center showed a trend towards significance. Subsequent fine mapping of this locus demonstrated that the majority of the associated SNPs reside in intron 1. We hypothesize that the causative variant may change the expression levels of a GRHL2 isoform.

Hearing in a 54- to 66-year-old population in northern Finland.

There are only a few large, population-based epidemiological studies on hearing impairment (HI) in adults. The objective of this study was to investigate the prevalence of HI and possible differences between ears in older adults. The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. Another questionnaire was mailed to collect information on non-participants. The prevalence of HI averaged over the frequencies of 0.5, 1, 2, and 4 kHz for the better ear ≥20 dB HL was 26.7% (men: 36.8%, women: 18.4%). There was no difference between left and right ear pure-tone averages over the frequencies 0.5, 1, 2, and 4 kHz (PTA(0.5-4 kHz)), but a significant difference of -0.8 dB HL was found for the low frequencies 0.125, 0.25, and 0.5 kHz (PTA(0.125-0.5 kHz)), and 4.4 dB HL for the high frequencies over 4, 6, and 8 kHz (PTA(4-8 kHz)). In conclusion, HI was a highly prevalent finding in this age group.

Radio speech communication problems reported in a survey of military pilots.

INTRODUCTION: Despite technological advances in conveying information, speech communication is still a key safety factor in aviation. Effective radio communication is necessary, for example, in building and maintaining good team situation awareness. However, little has been reported concerning the prevalence and nature of radio communication problems in everyday working environments in military aviation. METHODS: We surveyed Finnish Defense Forces pilots regarding the prevalence of radio speech communication problems. RESULTS: Of the 225 pilots contacted, 75% replied to our survey. Altogether 138 of the respondents were fixed-wing pilots and 31 were helicopter pilots. Problems in radio communication occurred, on average, during 14% of flight time. The most prevalent problems were multiple speakers on the same radio frequency band causing overlapping speech, missing acknowledgments, high background noise especially during helicopter operations, and technical problems. Of the respondents, 18% (31 pilots) reported having encountered at least one potentially dangerous event caused by problems in radio communication during their military aviation career. If the employer were to offer extra hearing protection, such as custom-made ear plugs, 93% of the pilots indicated that they would use it. DISCUSSION: Communication can be a flight safety factor especially during intense air combat exercises and other information-loaded flights. During these situations, communication should be clear and focused on the most essential information. So, training and technical improvements are necessary for better communication. High quality radio speech communication also improves operational effectiveness in military aviation.

Occupational noise, smoking, and a high body mass index are risk factors for age-related hearing impairment and moderate alcohol consumption is protective: a European population-based multicenter study.

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.