| 1. |
- Fransen, Erik, et al.
(författare)
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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
- 2008
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Ingår i: Journal of the Association for Research in Otolaryngology. - : Springer. - 1525-3961 .- 1438-7573. ; 9:3, s. 264-276
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Tidskriftsartikel (refereegranskat)abstract
- 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
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| 2. |
- Hendrickx, Jan-Jaap, et al.
(författare)
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Familial aggregation of pure tone hearing thresholds in an aging European population
- 2013
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Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 34:5, s. 838-844
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated.STUDY DESIGN: Multicenter survey in 8 European centers.SUBJECTS: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study.RESULTS: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies.DISCUSSION: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.
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| 3. |
- Hendrickx, Jan-Jaap, et al.
(författare)
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Familial aggregation of tinnitus : a European multicentre study
- 2007
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Ingår i: B-ENT. - Louvain, Belgium : Societe Royale Belge d'Oto - Rhino - Laryngologie et de Chirurgie Cervico - Faciale. - 0001-6497. ; 3:Suppl 7, s. 51-60
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION AND AIM:Tinnitus is a common condition affecting approximately 20% of the older population. There is increasing evidence that changes in the central auditory system following cochlear malfunctioning are responsible for tinnitus. To date, few investigators have studied the influence of genetic factors on tinnitus. The present report investigates the presence of a familial effect in tinnitus subjects.METHODS:In a European multicentre study, 198 families were recruited in seven European countries. Each family had at least 3 siblings. Subjects were screened for causes of hearing loss other than presbyacusis by clinical examination and a questionnaire. The presence of tinnitus was evaluated with the question "Nowadays, do you ever get noises in your head or ear (tinnitus) which usually last longer than five minutes". Familial aggregation was tested using three methods: a mixed model approach, calculating familial correlations, and estimating the risk of a subject having tinnitus if the disorder is present in another family member.RESULTS:All methods demonstrated a significant familial effect for tinnitus. The effect persisted after correction for the effect of other risk factors such as hearing loss, gender and age. The size of the familial effect is smaller than that for age-related hearing impairment, with a familial correlation of 0.15.CONCLUSION:The presence of a familial effect for tinnitus opens the door to specific studies that can determine whether this effect is due to a shared familial environment or the involvement of genetic factors. Subsequent association studies may result in the identification of the factors responsible. In addition, more emphasis should be placed on the effect of role models in the treatment of tinnitus.
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| 4. |
- Huyghe, Jeroen R., et al.
(författare)
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Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait
- 2008
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 83:3, s. 401-407
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Van Eyken, Els, et al.
(författare)
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Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment
- 2007
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Ingår i: Journal of Medical Genetics. - : B M J Group. - 0022-2593 .- 1468-6244. ; 44:9, s. 570-578
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAge‐related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4.MethodsIn the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Zlow and Zhigh, representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and gene–environment and gene–gene interactions.ResultsWe found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data.ConclusionAs replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.
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| 6. |
- Van Eyken, Els, et al.
(författare)
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The Contribution of GJB2 (Connexin 26) 35delG to Age-Related Hearing Impairment and Noise-Induced Hearing Loss
- 2007
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Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 28:7, s. 970-975
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Tidskriftsartikel (refereegranskat)abstract
- Hypothesis: The common GJB2 (Connexin 26) 35delG mutation might contribute to the development of age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL).Background: GJB2, a gene encoding a gap junction protein expressed in the inner ear, has been suggested to be involved in the potassium recycling pathway in the cochlea. GJB2 mutations account for a large number of individuals with nonsyndromic recessive hearing loss, with 35delG being the most frequent mutation in populations of European origin. Other genes involved in potassium homeostasis have been suggested to be associated with ARHI and NIHL, and distortion product otoacoustic emission distortions indicative of hearing loss alterations have been found in 35delG carriers.Method: We genotyped 35delG in two distinct sample sets: an ARHI sample set, composed of 2,311 Caucasian samples from nine different centers originating from seven different countries with an age range between 53 and 67 years, and an NIHL sample set consisting of 702 samples from the two extremes of a noise-exposed Polish sample.Results: After statistical analysis, we were unable to detect an association between 35delG and ARHI, nor between 35delG and NIHL.Conclusion: Our findings indicate that there is no increased susceptibility in 35delG carriers for the development of ARHI or NIHL.
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| 7. |
- Van Laer, Lut, et al.
(författare)
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The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 17:2, s. 159-169
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Walsh, Roddy, et al.
(författare)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 9. |
- Huyghe, Jeroen R, et al.
(författare)
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A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies
- 2011
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Ingår i: EUROPEAN JOURNAL OF HUMAN GENETICS. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 19:3, s. 347-352
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Tidskriftsartikel (refereegranskat)abstract
- The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F-ST statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F-ST was smallest for the comparison with the Russians (F-ST=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.
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| 10. |
- Huyghe, Jeroen R., et al.
(författare)
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Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami
- 2010
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 18:5, s. 569-574
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Tidskriftsartikel (refereegranskat)abstract
- The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a 'hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami.
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| 11. |
- Van Laer, Lut, et al.
(författare)
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A genome-wide association study for age-related hearing impairment in the Saami
- 2010
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Ingår i: European Journal of Human Genetics. - : BMJ Publishing Group Ltd. - 1018-4813 .- 1476-5438. ; 18:6, s. 685-693
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 x 10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.
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| 12. |
- Carlsson, Per-Inge, et al.
(författare)
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The influence of genetic variation in oxidative stress genes on human noise susceptibility
- 2005
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Ingår i: Hearing Research. - 0378-5955 .- 1878-5891. ; 202:1-2, s. 87-96
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Tidskriftsartikel (refereegranskat)abstract
- Noise induced hearing loss (NIHL) is a complex disease caused by an interaction between genetic and environmental factors. Damage in the cochlea as a result of noise exposure appears to be mediated by reactive oxygen species (ROS). To investigate whether genetic variation in the human protective antioxidant system is associated with high or low susceptibility to NIHL, genetic polymorphisms derived from genes involved in the oxidative stress response were analysed in the 10% most susceptible and 10% most resistant extremes of 1200 Swedish noise-exposed workers. The genetic polymorphisms included 2 deletion polymorphisms for the GSTM1 and GSTT1 gene, and 14 SNPs derived from the CAT, SOD, GPX, GSR and GSTP1 genes. No significant differences were found between susceptible and resistant groups, providing no support for a major role of genetic variation of antioxidant enzymes in the susceptibility to NIHL.
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| 13. |
- Konings, Annelies, et al.
(författare)
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Association between variations in CAT and noise-induced hearing loss in two independent noise-exposed populations
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:15, s. 1872-1883
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is an important occupational hazard that results from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied quite extensively, little is known about the genetic factors. On the basis of multiple studies, it was proposed that oxidative stress plays an important role in the development of NIHL. Here, we investigated whether variations (single nucleotide polymorphisms; SNPs) in the catalase gene (CAT), one of the genes involved in oxidative stress, influence noise susceptibility. Audiometric data from 1261 Swedish and 4500 Polish noise-exposed labourers were analysed. DNA samples were collected from the 10% most susceptible and the 10% most resistant individuals. Twelve SNPs were selected and genotyped. Subsequently, the interaction between noise exposure and genotypes and their effect on NIHL were analysed using logistic regression. Significant interactions were observed between noise exposure levels and genotypes of two SNPs for the Swedish population and of five SNPs for the Polish population. Two of these SNPs were significant in both populations. The interaction between predictor haplotypes and tagSNP haplotypes and noise exposure levels and their effect on NIHL were also analysed, resulting in several significant associations. In conclusion, this study identified significant associations between catalase SNPs and haplotypes and susceptibility to development of NIHL. These results indicate that catalase is a NIHL susceptibility gene, but that the effect of CAT polymorphisms can only be detected when noise exposure levels are taken into account.
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| 14. |
- Konings, Annelies, et al.
(författare)
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Variations in HSP70 genes associated with noise-induced hearing loss in two independent populations
- 2009
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 17:3, s. 329-35
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is one of the most important occupational health hazards. Millions of people worldwide are exposed daily to harmful levels of noise. NIHL is a complex disease resulting from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied extensively, little is known about the genetic factors. Heat-shock proteins (HSPs) are induced after exposure to severe noise. When first induced by exposure to moderate sound levels, they can protect the ear from damage from excessive noise exposure. This protection is highly variable between individuals. An association of HSP70 genes with NIHL has been described by Yang et al (2006) in a Chinese sample set of noise-exposed workers. In this study, three polymorphisms (rs1043618, rs1061581 and rs2227956) in HSP70-1, HSP70-2 and HSP70-hom, respectively, were genotyped in 206 Swedish and 238 Polish DNA samples of noise-exposed subjects and analyzed. One SNP, rs2227956 in HSP70-hom, resulted in a significant association with NIHL in both sample sets. In addition, rs1043618 and rs1061581 were significant in the Swedish sample set. Analysis of the haplotypes composed of the three SNPs revealed significant associations between NIHL and haplotype GAC in both sample sets and with haplotype CGT in the Swedish sample set. In conclusion, this study replicated the association of HSP70 genes with NIHL in a second and third independent noise-exposed sample set, hereby adding to the evidence that HSP70 genes may be NIHL susceptibility genes.
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| 15. |
- Ostergaard, Pia, et al.
(författare)
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Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy.
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 90:2
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Tidskriftsartikel (refereegranskat)abstract
- We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.
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| 16. |
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| 17. |
- Van Laer, Lut, et al.
(författare)
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The contribution of genes involved in potassium-recyclingin the inner ear to noise-induced hearing loss
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:8, s. 786-795
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is one of the most important occupational diseases and, after presbyacusis, the most frequent cause of hearing loss. NIHL is a complex disease caused by an interaction between environmental and genetic factors. The various environmental factors involved in NIHL have been relatively extensively studied. On the other hand, little research has been performed on the genetic factors responsible for NIHL. To test whether the variation in genes involved in coupling of cells and potassium recycling in the inner ear might partly explain the variability in susceptibility to noise, we performed a case-control association study using 35 SNPs selected in 10 candidate genes on a total of 218 samples selected from a population of 1,261 Swedish male noise,exposed workers. We have obtained significant differences between susceptible and resistant individuals for the allele, genotype, and haplotype frequencies for three SNPs of the KCNEI gene, and for the allele frequencies for one SNP of KCNQ1 and one SNP of KCNQ4. Patch-clamp experiments in high K+-concentrations using a Chinese hamster ovary (CHO) cell model were performed to investigate the possibility that the KCNE1-p.85N variant (NT_011512.10:g.21483550G > A; NP_00210.2:p.Asp85Asn) was causative for high noise susceptibility. The normalized current density generated by KCNQ1/KCNE1-p.85N channels, thus containing the susceptibility variant, differed significantly from that from wild-type channels. Furthermore, the midpoint potential of KCNQ1/KCNE1-p.85N channels (i.e., the voltage at which 50% of the channels are open) differed from that of wild-type channels. Further genetic and physiological studies will be necessary to confirm these findings.
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