| 1. |
- Fransen, Erik, et al.
(författare)
-
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
-
Ingår i: Journal of the Association for Research in Otolaryngology. - : Springer. - 1525-3961 .- 1438-7573. ; 9:3, s. 264-276
-
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
|
|
| 2. |
- Hendrickx, Jan-Jaap, et al.
(författare)
-
Familial aggregation of pure tone hearing thresholds in an aging European population
- 2013
-
Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 34:5, s. 838-844
-
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.
|
|
| 3. |
- Hendrickx, Jan-Jaap, et al.
(författare)
-
Familial aggregation of tinnitus : a European multicentre study
- 2007
-
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
-
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.
|
|
| 4. |
- Huyghe, Jeroen R., et al.
(författare)
-
Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait
- 2008
-
Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 83:3, s. 401-407
-
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.
|
|
| 5. |
- Roels, Juliette, et al.
(författare)
-
Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia
- 2020
-
Ingår i: Blood cancer discovery. - : American Association for Cancer Research. - 2643-3249. ; 1:3, s. 274-289
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.
|
|
| 6. |
- Van Eyken, Els, et al.
(författare)
-
Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment
- 2007
-
Ingår i: Journal of Medical Genetics. - : B M J Group. - 0022-2593 .- 1468-6244. ; 44:9, s. 570-578
-
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.
|
|
| 7. |
- Van Eyken, Els, et al.
(författare)
-
The Contribution of GJB2 (Connexin 26) 35delG to Age-Related Hearing Impairment and Noise-Induced Hearing Loss
- 2007
-
Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 28:7, s. 970-975
-
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.
|
|
| 8. |
- Van Laer, Lut, et al.
(författare)
-
The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment
- 2008
-
Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 17:2, s. 159-169
-
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.
|
|
| 9. |
- Huyghe, Jeroen R, et al.
(författare)
-
A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies
- 2011
-
Ingår i: EUROPEAN JOURNAL OF HUMAN GENETICS. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 19:3, s. 347-352
-
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.
|
|
| 10. |
- Huyghe, Jeroen R., et al.
(författare)
-
Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami
- 2010
-
Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 18:5, s. 569-574
-
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.
|
|
