| 11. |
- Ong, Ken K., et al.
(författare)
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Genetic variation in LIN28B is associated with the timing of puberty
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:6, s. 729-733
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Tidskriftsartikel (refereegranskat)abstract
- The timing of puberty is highly variable(1). We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing(2), as the first genetic determinant regulating the timing of human pubertal growth and development.
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| 12. |
- Saeed, M, et al.
(författare)
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Age and founder effect of SOD1 A4V mutation causing ALS.
- 2009
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Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878 .- 1526-632X. ; 72:19, s. 1634-1639
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The alanine to valine mutation at codon 4 (A4V) of SOD1 causes a rapidly progressive dominant form of amyotrophic lateral sclerosis (ALS) with exclusively lower motor neuron disease and is responsible for 50% of SOD1 mutations associated with familial ALS in North America. This mutation is rare in Europe. The authors investigated the origin (geographic and time) of the A4V mutation. METHODS: Several cohorts were genotyped: North American patients with confirmed A4V mutation (n = 54), Swedish (n = 3) and Italian (n = 6) A4V patients, patients with ALS with SOD1 non-A4V mutations (n = 66) and patients with sporadic ALS (n = 96), healthy white (n = 96), African American (n = 17), Chinese (n = 53), Amerindian (n = 11), and Hispanic (n = 12) subjects. High-throughput SNP genotyping was performed using Taqman assay in 384-well format. A novel biallelic CA repeat in exon 5 of SOD1, tightly linked to A4V, was genotyped on sequencing gels. Association statistics were estimated using Haploview. p Values less than 0.05 were considered significant. Age of A4V was estimated using a novel method based on r(2) degeneration with genetic distance and a Bayesian method incorporated in DMLE+. RESULTS: A single haplotype of 10 polymorphisms across a 5.86-cM region was associated with A4V (p = 3.0e-11) when white controls were used, suggesting a founder effect. The strength of association of this haplotype progressively decreased when African American, Chinese, Hispanic, and Amerindian subjects were used as controls. The associated European haplotype was different from the North American haplotype, indicating two founder effects for A4V (Amerindian and European). The estimated age of A4V with the r(2) degeneration method was 458 +/- 59 years (range 398-569) and in agreement with the Bayesian method (554-734 years with 80-90% posterior probability). CONCLUSIONS: North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400-500 years ago.
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| 13. |
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| 14. |
- Valdmanis, P N, et al.
(författare)
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Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden
- 2008
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 71:7, s. 514-520
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations. METHODS: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls). RESULTS: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients. CONCLUSIONS: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.
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| 15. |
- van Es, Michael A, et al.
(författare)
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Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
- 2008
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:1, s. 29-31
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Tidskriftsartikel (refereegranskat)abstract
- We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.
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| 16. |
- van Es, Michael A, et al.
(författare)
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ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis : a genome-wide association study.
- 2007
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 6:10, s. 869-77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
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| 17. |
- Agner, Tove, et al.
(författare)
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Contact sensitisation in hand eczema patients-relation to subdiagnosis, severity and quality of life: a multi-centre study
- 2009
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Ingår i: Contact Dermatitis. - 0105-1873. ; 61:5, s. 291-296
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Tidskriftsartikel (refereegranskat)abstract
- Background Contact sensitisation has been identified as a factor associated with poor prognosis for patients with hand eczema. Objectives To study implications of contact sensitisation with respect to severity, quality of life (QoL) and subdiagnosis of hand eczema. Methods The study was performed as a multi-centre, cross-sectional study from 10 European clinics. All patients were patch tested, and severity of hand eczema assessed by Hand Eczema Severity Index. A multi-variate analysis was performed to explore which factors influenced severity, QoL and sick leave. Results A total 416 patients were included, and 63% had contact sensitisation to one or more of the tested allergens. More women (66%) than men (51%) were sensitized. No significant association was found between sensitisation to specific allergens, disease severity, QoL or diagnostic subgroups. High age, male sex, atopic eczema and presence of contact sensitisation were independent risk factors for increased severity as measured by Hand Eczema Severity Index. Furthermore, the severity of hand eczema increased by the number of contact sensitisations detected (P = 0.023). High age and personal history of atopic eczema were independent risk factors for low QoL, as measured by Dermatology Life Quality Index, and atopic eczema as well as allergic contact dermatitis as subdiagnosis was associated with increased sick leave. Conclusion Diagnostic subgroups were not found to be related to specific allergens. Contact sensitisation was found to be a risk factor for increased severity of hand eczema, as did high age, male sex and atopic eczema.
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| 18. |
- Agner, Tove, et al.
(författare)
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Hand eczema severity and quality of life: a cross-sectional, multicentre study of hand eczema patients
- 2008
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 59:1, s. 43-47
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: Hand eczema is a chronic disease with negative impact on quality of life (QoL). In this study, QoL in hand eczema patients is assessed and related to age, sex, severity, and diagnostic subgroups. Methods: A total of 416 patients with hand eczema from 10 European patch test clinics participated in the study. Data on QoL were obtained from a self-administered questionnaire using the Dermatology Life Quality Index (DLQI). Severity was assessed by a scoring system (Hand Eczema Severity Index, HECSI) as well as frequency of eruptions and sick leave due to hand eczema. Results: No significant difference was found between males and females with respect to QoL [DLQI median values and 25/75 percentiles for males and females being 7.0 (3-14) and 8.0 (3-13), respectively], although males were more severely affected than females (P < 0.025). A significant positive correlation was found for hand eczema severity and age (P < 0.001), while no significant correlation was found for QoL and age. QoL was found increasingly reduced when sick leave was getting higher (P < 0.001). A statistically significant correlation between QoL (as measured by DLQI) and hand eczema severity as measured by HECSI was found (P < 0.001). No significant difference in QoL was found between diagnostic subgroups. Conclusions: QoL was found markedly negatively affected in hand eczema patients and was significantly correlated to disease severity. No significant difference in QoL was found between males and females, in spite of significantly more severe eczema in males, indicating that QoL in female patients is more easily affected.
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