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  • 1.
    Akimoto, Chizuru
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Volk, Alexander E.
    van Blitterswijk, Marka
    Van den Broeck, Marleen
    Leblond, Claire S.
    Lumbroso, Serge
    Camu, William
    Neitzel, Birgit
    Onodera, Osamu
    van Rheenen, Wouter
    Pinto, Susana
    Weber, Markus
    Smith, Bradley
    Proven, Melanie
    Talbot, Kevin
    Keagle, Pamela
    Chesi, Alessandra
    Ratti, Antonia
    van der Zee, Julie
    Alstermark, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Calini, Daniela
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Tradowsky, Daniela C.
    Just, Walter
    Daoud, Hussein
    Angerbauer, Sabrina
    DeJesus-Hernandez, Mariely
    Konno, Takuya
    Lloyd-Jani, Anjali
    de Carvalho, Mamede
    Mouzat, Kevin
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Gitler, Aaron D.
    Shaw, Christopher E.
    Rouleau, Guy A.
    van den Berg, Leonard H.
    Van Broeckhoven, Christine
    Rademakers, Rosa
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Kubisch, Christian
    A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories2014Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, nr 6, s. 419-424Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

  • 2.
    Albagha, O M E
    et al.
    University of Aberdeen.
    Pettersson, Ulrika
    University of Aberdeen .
    Stewart, A
    University of Aberdeen.
    McGuigan, F E A
    University of Aberdeen.
    MacDonald, H M
    University of Aberdeen.
    Reid, D M
    University of Aberdeen.
    Ralston, S H
    University of Aberdeen.
    Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.2005Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 42, nr 3, s. 240-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.

    OBJECTIVE: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.

    RESULTS: There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.

    CONCLUSIONS: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

  • 3. Dahgam, Santosh
    et al.
    Modig, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Naluai, Asa Torinsson
    Olin, Anna-Carin
    Nyberg, Fredrik
    Haplotypes of the inducible nitric oxide synthase gene are strongly associated with exhaled nitric oxide levels in adults: a population-based study2014Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, nr 7, s. 449-454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Previous genetic association studies have reported evidence for association of single-nucleotide polymorphisms (SNPs) in the NOS2 gene, encoding inducible nitric oxide synthase (iNOS), to variation in levels of fractional exhaled nitric oxide (FENO) in children and adults. In this study, we evaluated 10 SNPs in the region of chromosome 17 from 26.07Mb to 26.13Mb to further understand the contribution of NOS2 to variation in levels of FENO. Methods In a cohort of 5912 adults 25-75years of age, we investigated the relationship between NOS2 haplotypes and FENO, and effect modification by asthma. Results Seven common (frequency 5%) haplotypes (H1-H7) were inferred from all possible haplotype combinations. One haplotype (H3) was significantly associated with lower levels of FENO: -5.8% (95% CI -9.8 to -1.7; p=0.006) compared with the most common baseline haplotype H1. Two haplotypes (H5 and H6) were significantly associated with higher levels of FENO: +10.7% (95% CI 5.0 to 16.7; p=0.0002) and +14.9% (95% CI 10.6 to 19.3; p=7.8x10(-13)), respectively. The effect of haplotype H3 was mainly seen in subjects with asthma (-21.6% (95% CI -33.5 to -5.9)) and was not significant in subjects without asthma (-4.2% (95% CI -8.4 to 0.2)). The p value for interaction between H3 and asthma status was 0.004. Conclusions Our findings suggest that several common haplotypes in the NOS2 gene contribute to variation in FENO in adults. We also saw some evidence of effect modification by asthma status on haplotype H3.

  • 4. Dahgam, Santosh
    et al.
    Nyberg, Fredrik
    Modig, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Naluai, Åsa Torinsson
    Olin, Anna-Carin
    Single nucleotide polymorphisms in the NOS2 and NOS3 genes are associated with exhaled nitric oxide2012Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, nr 3, s. 200-205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Polymorphisms in nitric oxide synthase genes (NOS1, NOS2, and NOS3) have been suggested to have a major impact on fraction of exhaled nitric oxide (FENO), a biomarker of airway inflammation. However, the genetic contribution of NOS polymorphisms to FENO is not fully understood. The aim of this study was to investigate comprehensively the association between single nucleotide polymorphisms (SNPs) in all three NOS genes and FENO in an adult population, and to assess whether such associations are modified by asthma or atopy.

    Method In 1737 adults from a Swedish general population sample, FENO was measured and genetic variation in the NOS genes was assessed using 49 SNPs. The genetic effect of NOS polymorphisms on FENO, asthma, and atopy was estimated using multiple regression methods.

    Results In a multi-SNP model based on stepwise regression analysis, two SNPs in NOS2 and one in NOS3 showed independent associations with levels of FENO. For NOS2 SNP rs9901734, subjects had 5.3% (95% CI 1.0% to 9.7%) higher levels of FENO per G allele, and for rs3729508, subjects with CC or CT genotypes had 9.4% (95% CI 3.1% to 15.2%) higher levels compared with TT. For NOS3 SNP rs7830, subjects with GT or TT had 5.6% (95% CI 0.4% to 11.1%) higher levels than GG; the genetic effect of this SNP was stronger in asthmatics (21.9%, 95% CI 4.6% to 42.0%).

    Conclusion These results suggest that NOS2 is the major NOS gene determining variability in exhaled nitric oxide in the healthy adult population, while NOS3 may play a more important role in asthmatic adults.

  • 5. Huesing, Anika
    et al.
    Canzian, Federico
    Beckmann, Lars
    Garcia-Closas, Montserrat
    Diver, W. Ryan
    Thun, Michael J.
    Berg, Christine D.
    Hoover, Robert N.
    Ziegler, Regina G.
    Figueroa, Jonine D.
    Isaacs, Claudine
    Olsen, Anja
    Viallon, Vivian
    Boeing, Heiner
    Masala, Giovanna
    Trichopoulos, Dimitrios
    Peeters, Petra H. M.
    Lund, Eiliv
    Ardanaz, Eva
    Khaw, Kay-Tee
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kolonel, Laurence N.
    Stram, Daniel O.
    Le Marchand, Loic
    McCarty, Catherine A.
    Buring, Julie E.
    Lee, I-Min
    Zhang, Shumin
    Lindstroem, Sara
    Hankinson, Susan E.
    Riboli, Elio
    Hunter, David J.
    Henderson, Brian E.
    Chanock, Stephen J.
    Haiman, Christopher A.
    Kraft, Peter
    Kaaks, Rudolf
    Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status2012Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, nr 9, s. 601-608Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumours with different hormone receptor status. Material and methods Within the Breast and Prostate Cancer Cohort Consortium, we analysed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age adjusted and cohort-adjusted concordance statistic (AUROC(a)). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement was used to measure improvements in risk prediction. Results We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROC(a) going from 2.7% to 4%). Discriminatory ability for all models varied strongly by hormone receptor status. Discussion and conclusions Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor-positive cases, but the gain in discriminatory quality is not sufficient for clinical application.

  • 6. Lambrechts, Diether
    et al.
    Poesen, Koen
    Fernández-Santiago, Rubén
    Al-Chalabi, Ammar
    Del Bo, Roberto
    Van Vught, Paul Wj
    Khan, Saeed
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brockington, Alice
    Van Marion, Ingrid
    Anneser, Johanna
    Shaw, Christopher
    Ludolph, Albert
    Leigh, Nigel
    Comi, Giacomo
    Gasser, Thomas
    Shaw, Pamela J
    Morrison, Karen
    Andersen, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Van den Berg, Leonard H
    Thijs, Vincent
    Siddique, Teepu
    Robberecht, Wim
    Carmeliet, Peter
    Meta-analysis of VEGF variations in ALS: increased susceptibility in male carriers of the -2578AA genotype2008Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 46, nr 12, s. 840-846Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding.

    Methods and findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (−2578C/A, −1154G/A and −634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the −2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing.

    Conclusions: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF −2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

  • 7. Nylander, P O
    et al.
    Engström, C
    Chotai, Jayanti
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Wahlström, J
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Anticipation in Swedish families with bipolar affective disorder.1994Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 31, nr 9, s. 686-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.

  • 8. Oei, Ling
    et al.
    Hsu, Yi-Hsiang
    Styrkarsdottir, Unnur
    Eussen, Bert H
    de Klein, Annelies
    Peters, Marjolein J
    Halldorsson, Bjarni
    Liu, Ching-Ti
    Alonso, Nerea
    Kaptoge, Stephen K
    Thorleifsson, Gudmar
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Hocking, Lynne J
    Husted, Lise Bjerre
    Jameson, Karen A
    Kruk, Marcin
    Lewis, Joshua R
    Patel, Millan S
    Scollen, Serena
    Svensson, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Trompet, Stella
    van Schoor, Natasja M
    Zhu, Kun
    Buckley, Brendan M
    Cooper, Cyrus
    Ford, Ian
    Goltzman, David
    González-Macías, Jesús
    Langdahl, Bente Lomholt
    Leslie, William D
    Lips, Paul
    Lorenc, Roman S
    Olmos, José M
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Reid, David M
    Riancho, José A
    Slagboom, P Eline
    Garcia-Ibarbia, Carmen
    Ingvarsson, Thorvaldur
    Johannsdottir, Hrefna
    Luben, Robert
    Medina-Gómez, Carolina
    Arp, Pascal
    Nandakumar, Kannabiran
    Palsson, Stefan Th
    Sigurdsson, Gunnar
    van Meurs, Joyce B J
    Zhou, Yanhua
    Hofman, Albert
    Jukema, J Wouter
    Pols, Huibert A P
    Prince, Richard L
    Cupples, L Adrienne
    Marshall, Christian R
    Pinto, Dalila
    Sato, Daisuke
    Scherer, Stephen W
    Reeve, Jonathan
    Thorsteinsdottir, Unnur
    Karasik, David
    Richards, J Brent
    Stefansson, Kari
    Uitterlinden, André G
    Ralston, Stuart H
    Ioannidis, John P A
    Kiel, Douglas P
    Rivadeneira, Fernando
    Estrada, Karol
    A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus2014Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, nr 2, s. 122-131Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

    AIM: To identify CNVs associated with osteoporotic bone fracture risk.

    METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.

    RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.

    CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

  • 9. Zheng, Hou-Feng
    et al.
    Duncan, Emma L.
    Yerges-Armstrong, Laura M.
    Eriksson, Joel
    Bergström, Ulrica
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Leo, Paul J.
    Leslie, William D.
    Goltzman, David
    Blangero, John
    Hanley, David A.
    Carless, Melanie A.
    Streeten, Elizabeth A.
    Lorentzon, Mattias
    Brown, Matthew A.
    Spector, Tim D.
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Ohlsson, Claes
    Mitchell, Braxton D.
    Richards, J. Brent
    Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm2013Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, nr 7, s. 473-478Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5x10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01x10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

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