Publications by authors named "Gitte Andersen"

47 Publications

Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis.

Biol Psychiatry 2021 02 10;89(3):278-287. Epub 2020 Jul 10.

Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, University of Copenhagen, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Background: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naïve patients.

Methods: In total, 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed.

Results: The whole group of antipsychotic-naïve patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = -.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons.

Conclusions: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.027DOI Listing
February 2021

Diagnostic Two-Gene Classifier in Early-Stage Mycosis Fungoides: A Retrospective Multicenter Study.

J Invest Dermatol 2021 Jan 23;141(1):213-217.e5. Epub 2020 May 23.

Department of Pathology, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.04.026DOI Listing
January 2021

Circulating miRNAs as Biomarker in Cancer.

Recent Results Cancer Res 2020 ;215:277-298

Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie Francois Jacob, Bâtiment G2, 2 rue Gaston Crémieux, 91000, Evry, France.

Deregulation of microRNA expression has been shown to play an important role in human malignancies. The identification of circulating-free miRNAs in biofluids a decade ago led to great enthusiasm and motivation to develop non-invasive tests based on the expression of these small non-coding RNAs. Herein, we review the progress within the field of research for identifying circulating miRNA cancer biomarkers and discuss the advantages and challenges associated with this. We also discuss the methodological and analytical variables, which may influence the final miRNA quantification and the importance of standardizing pre-analytical, analytical, and post-analytical processes in order to enable a successful translation of the results from basic research into the clinics.
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http://dx.doi.org/10.1007/978-3-030-26439-0_15DOI Listing
October 2019

A Summary of the Biological Processes, Disease-Associated Changes, and Clinical Applications of DNA Methylation.

Methods Mol Biol 2018 ;1708:3-30

Laboratory for Epigenetics & Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie Francois Jacob, Bâtiment G2, 2 rue Gaston Crémieux, 91000, Evry, France.

DNA methylation at cytosines followed by guanines, CpGs, forms one of the multiple layers of epigenetic mechanisms controlling and modulating gene expression through chromatin structure. It closely interacts with histone modifications and chromatin remodeling complexes to form the local genomic and higher-order chromatin landscape. DNA methylation is essential for proper mammalian development, crucial for imprinting and plays a role in maintaining genomic stability. DNA methylation patterns are susceptible to change in response to environmental stimuli such as diet or toxins, whereby the epigenome seems to be most vulnerable during early life. Changes of DNA methylation levels and patterns have been widely studied in several diseases, especially cancer, where interest has focused on biomarkers for early detection of cancer development, accurate diagnosis, and response to treatment, but have also been shown to occur in many other complex diseases. Recent advances in epigenome engineering technologies allow now for the large-scale assessment of the functional relevance of DNA methylation. As a stable nucleic acid-based modification that is technically easy to handle and which can be analyzed with great reproducibility and accuracy by different laboratories, DNA methylation is a promising biomarker for many applications.
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http://dx.doi.org/10.1007/978-1-4939-7481-8_1DOI Listing
July 2018

miRNA profiling identifies deregulated miRNAs associated with osteosarcoma development and time to metastasis in two large cohorts.

Mol Oncol 2018 01 1;12(1):114-131. Epub 2017 Dec 1.

Laboratory for Epigenetics and Environment, Centre National de la Recherche en Génomique Humaine, CEA - Institut de Biologie Francois Jaçob, Evry, France.

Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays. The identified miRNA expression changes were correlated with gene expression in the same samples. Furthermore, miRNA expression changes were validated in a second independent cohort consisting of 78 OS samples. Analysis of 752 miRNAs in the discovery cohort led to the identification of 33 deregulated miRNAs in OS. Twenty-nine miRNAs were validated with statistical significance in the second cohort comprising 78 OS samples. miRNA/mRNA targets were determined, and 361 genes with an inverse expression of the target miRNA were identified. Both the miRNAs and the identified target genes were associated with multiple pathways related to cancer as well as bone cell biology, thereby correlating the deregulated miRNAs with OS tumorigenesis. An analysis of the prognostic value of the 29 miRNAs identified miR-221/miR-222 to be significantly associated with time to metastasis in both cohorts. This study contributes to a more profound understanding of OS tumorigenesis, by substantiating the importance of miRNA deregulation. We have identified and validated 29 deregulated miRNAs in the - to our knowledge - largest discovery and validation cohorts used so far for miRNA analyses in OS. Two of the miRNAs showed a promising potential as prognostic biomarkers for the aggressiveness of OS.
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http://dx.doi.org/10.1002/1878-0261.12154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748490PMC
January 2018

Effects of milling on the extraction efficiency of incurred pesticides in cereals.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2017 Nov 3;34(11):1948-1958. Epub 2017 Jul 3.

a National Food Institute , Technical University of Denmark , Søborg , Denmark.

This study investigated the effects of particle size and milling temperature on the extraction efficiencies of pesticide residues from cereal flour. Samples of cereal grains (barley, oat, rye and wheat) were milled using a centrifugal mill with four different sieves (0.2, 1.0, 3.0 and 5.0 mm) or a knife mill both at room temperature and after freezing of the grain at -80°C overnight. The incurred pesticides in the test materials were extracted by the QuEChERS method and analysed by LC-MS/MS and GC-MS/MS. The particle size distribution for the milled samples was determined using a vibratory sieve shaker. Based on the pesticide levels recovered from each of the different millings and the corresponding particle size distributions, it was confirmed that smaller average particle sizes increase the extraction efficiency up to 31%, with all other factors equal. The cereals milled at room temperature produced lower pesticide extraction efficiencies compared with cereals milled when still frozen, especially for heat-sensitive pesticides. Furthermore, milling frozen grains was easier and resulted in more homogeneous samples with smaller relative particle sizes.
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http://dx.doi.org/10.1080/19440049.2017.1339915DOI Listing
November 2017

Stability study of methotrexate in 0.9% sodium chloride injection and 5% dextrose injection with limit tests for impurities.

Am J Health Syst Pharm 2017 May;74(9):e211-e223

Hospital Pharmacy Funen, Odense University Hospital, Odense, Denmark.

Purpose: Results of an evaluation of the stability of methotrexate in 0.9% sodium chloride injection and 5% dextrose injection are presented.

Methods: Methotrexate concentrated solution (100 mg/mL) was diluted to nominal concentrations of 0.2 and 20 mg/mL in infusion bags containing 0.9% sodium chloride injection or 5% dextrose injection. The filled bags were stored for 28 days at 25 °C and 60% relative humidity and protected from light. Samples were withdrawn for analysis on the day of preparation and after 3, 7, 14, 21, and 28 days. The test program included visual inspections, measurements of pH and infusion bag weight loss, and high-performance liquid chromatography assays to determine methotrexate content and characterize degradation products.

Results: At both evaluated concentrations, methotrexate in 0.9% sodium chloride injection was stable for 28 days; only minor (<0.05%) increases in amounts of known and unknown degradation products were detected. In 5% dextrose injection, methotrexate at the higher concentration was stable for 28 days, with minor formation of degradation products; in the 0.2-mg/mL solution, however, methotrexate was stable for only 3 days. At later time points, an unknown impurity present at a concentration higher than 0.1% was observed.

Conclusion: At concentrations of 0.2 and 20 mg/mL, methotrexate in 0.9% sodium chloride injection was found to be stable for 28 days when stored at 25 °C and protected from light. Under the same storage conditions, methotrexate in a 20-mg/mL solution prepared with 5% dextrose injection was stable for 28 days, whereas a 0.2-mg/mL solution in the same diluent was stable for only 3 days.
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http://dx.doi.org/10.2146/ajhp150818DOI Listing
May 2017

Tryptophan 2,3-dioxygenase (TDO)-reactive T cells differ in their functional characteristics in health and cancer.

Oncoimmunology 2015 Jan 30;4(1):e968480. Epub 2015 Jan 30.

Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.

Tryptophan-2,3-dioxygenase (TDO) physiologically regulates systemic tryptophan levels in the liver. However, numerous studies have linked cancer with activation of local and systemic tryptophan metabolism. Indeed, similar to other heme dioxygenases TDO is constitutively expressed in many cancers. In the present study, we detected the presence of both CD8 and CD4 T-cell reactivity toward TDO in peripheral blood of patients with malignant melanoma (MM) or breast cancer (BC) as well as healthy subjects. However, TDO-reactive CD4 T cells constituted distinct functional phenotypes in health and disease. In healthy subjects these cells predominately comprised interferon (IFN)γ and tumor necrosis factor (TNF)-α producing Th1 cells, while in cancer patients TDO-reactive CD4 T-cells were more differentiated with release of not only IFNγ and TNFα, but also interleukin (IL)-17 and IL-10 in response to TDO-derived MHC-class II restricted peptides. Hence, in healthy donors (HD) a Th1 helper response was predominant, whereas in cancer patients CD4 T-cell responses were skewed toward a regulatory T cell (Treg) response. Furthermore, MM patients hosting a TDO-specific IL-17 response showed a trend toward an improved overall survival (OS) compared to MM patients with IL-10 producing, TDO-reactive CD4 T cells. For further characterization, we isolated and expanded both CD8 and CD4 TDO-reactive T cells . TDO-reactive CD8 T cells were able to kill HLA-matched tumor cells of different origin. Interestingly, the processed and presented TDO-derived epitopes varied between different cancer cells. With respect to CD4 TDO-reactive T cells, expanded T-cell cultures comprised a Th1 and/or a Treg phenotype. In summary, our data demonstrate that the immune modulating enzyme TDO is a target for CD8 and CD4 T cell responses both in healthy subjects as well as patients with cancer; notably, however, the functional phenotype of these T-cell responses differ depending on the respective conditions of the host.
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http://dx.doi.org/10.4161/21624011.2014.968480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368150PMC
January 2015

Improved reproducibility in genome-wide DNA methylation analysis for PAXgene-fixed samples compared with restored formalin-fixed and paraffin-embedded DNA.

Anal Biochem 2015 01 30;468:50-8. Epub 2014 Sep 30.

Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institut de Génomique, 91000 Evry, France. Electronic address:

Formalin fixation has been the standard method for conservation of clinical specimens for decades. However, a major drawback is the high degradation of nucleic acids, which complicates its use in genome-wide analyses. Unbiased identification of biomarkers, however, requires genome-wide studies, precluding the use of the valuable archives of specimens with long-term follow-up data. Therefore, restoration protocols for DNA from formalin-fixed and paraffin-embedded (FFPE) samples have been developed, although they are cost-intensive and time-consuming. An alternative to FFPE and snap-freezing is the PAXgene Tissue System, developed for simultaneous preservation of morphology, proteins, and nucleic acids. In the current study, we compared the performance of DNA from either PAXgene or formalin-fixed tissues to snap-frozen material for genome-wide DNA methylation analysis using the Illumina 450K BeadChip. Quantitative DNA methylation analysis demonstrated that the methylation profile in PAXgene-fixed tissues showed, in comparison with restored FFPE samples, a higher concordance with the profile detected in frozen samples. We demonstrate, for the first time, that DNA from PAXgene conserved tissue performs better compared with restored FFPE DNA in genome-wide DNA methylation analysis. In addition, DNA from PAXgene tissue can be directly used on the array without prior restoration, rendering the analytical process significantly more time- and cost-effective.
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http://dx.doi.org/10.1016/j.ab.2014.09.012DOI Listing
January 2015

Effects of dopamine D2/D3 blockade on human sensory and sensorimotor gating in initially antipsychotic-naive, first-episode schizophrenia patients.

Neuropsychopharmacology 2014 Dec 23;39(13):3000-8. Epub 2014 Jul 23.

1] Center for Neuropsychiatric Schizophrenia Research (CNSR), Copenhagen University Hospital, Psychiatric Center Glostrup, Copenhagen, Denmark [2] Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Copenhagen University Hospital, Psychiatric Center Glostrup, Copenhagen, Denmark [3] Faculty of Health Sciences, Department of Neurology, Psychiatry, and Sensory Sciences, University of Copenhagen, Copenhagen, Denmark.

It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits.
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http://dx.doi.org/10.1038/npp.2014.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229570PMC
December 2014

The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4 T cells.

Oncoimmunology 2013 Apr;2(4):e23991

1Center for Cancer Immune Therapy (CCIT); Department of Hematology and Oncology; Copenhagen University Hospital; Herlev, Denmark.

Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8 T cells. In the present study, we develop these findings and report that CD4 helper T cells spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A*0201-restricted PD-L1-epitope for the presence of possible CD4 T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4 T cells among the peripheral blood lymphocytes of cancer patients and - to lesser extents - healthy donors, by means of ELISPOT assays. PD-L1-specific CD4 T cells appeared to be T17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4 T cells released interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-17 (IL-17) in response to a long PD-L1-derived peptide. Furthermore, we demonstrate that the specific recognition of PD-L1 by CD4 T cells is MHC class II-restricted. Natural T-cell responses against PD-L1 are noteworthy as they may play a prominent role in the regulation of the immune system. Thus, cytokine release from PD-L1-specific CD4 T cells may surmount the overall immunosuppressive actions of this immune checkpoint regulator. Moreover, PD-L1-specific T cells might be useful for anticancer immunotherapy, as they may counteract common mechanisms of immune escape mediated by the PD-L1/PD-1 pathway.
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http://dx.doi.org/10.4161/onci.23991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654604PMC
April 2013

HLA-restricted CTL that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients.

Cancer Res 2013 Mar 17;73(6):1764-76. Epub 2013 Jan 17.

Center for Cancer Immune Therapy, Department of Hematology and Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej, Herlev, Denmark.

PD-L1 (CD274) contributes to functional exhaustion of T cells and limits immune responses in patients with cancer. In this study, we report the identification of an human leukocyte antigen (HLA)-A2-restricted epitope from PD-L1, and we describe natural, cytolytic T-cell reactivity against PD-L1 in the peripheral blood of patients with cancer and healthy individuals. Notably, PD-L1-specific T cells were able not only to recognize and kill tumor cells but also PD-L1-expressing dendritic cells in a PD-L1-dependent manner, insofar as PD-L1 ablation rescued dendritic cells from killing. Furthermore, by incubating nonprofessional antigen-presenting cells with long peptides from PD-L1, we found that PD-L1 was rapidly internalized, processed, and cross-presented by HLA-A2 on the cell surface. Apparently, this cross-presentation was TAP-independent, as it was conducted not only by B cells but in addition by TAP-deficient T2-cells. This is intriguing, as soluble PD-L1 has been detected in the sera from patients with cancer. PD-L1-specific CTL may boost immunity by the killing of immunosuppressive tumor cells as well as regulatory cells. However, PD-L1-specific CTLs may as well suppress immunity by the elimination of normal immune cells especially PD-L1 expressing mature dendritic cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3507DOI Listing
March 2013

Competitive amplification of differentially melting amplicons (CADMA) enables sensitive and direct detection of all mutation types by high-resolution melting analysis.

Hum Mutat 2012 Jan 28;33(1):264-71. Epub 2011 Sep 28.

Department of Biomedicine, Aarhus University, Denmark.

Sensitive and specific mutation detection is of particular importance in cancer diagnostics, prognostics, and individualized patient treatment. However, the majority of molecular methodologies that have been developed with the aim of increasing the sensitivity of mutation testing have drawbacks in terms of specificity, convenience, or costs. Here, we have established a new method, Competitive Amplification of Differentially Melting Amplicons (CADMA), which allows very sensitive and specific detection of all mutation types. The principle of the method is to amplify wild-type and mutated sequences simultaneously using a three-primer system. A mutation-specific primer is designed to introduce melting temperature decreasing mutations in the resulting mutated amplicon, while a second overlapping primer is designed to amplify both wild-type and mutated sequences. When combined with a third common primer very sensitive mutation detection becomes possible, when using high-resolution melting (HRM) as detection platform. The introduction of melting temperature decreasing mutations in the mutated amplicon also allows for further mutation enrichment by fast coamplification at lower denaturation temperature PCR (COLD-PCR). For proof-of-concept, we have designed CADMA assays for clinically relevant BRAF, EGFR, KRAS, and PIK3CA mutations, which are sensitive to, between 0.025% and 0.25%, mutated alleles in a wild-type background. In conclusion, CADMA enables highly sensitive and specific mutation detection by HRM analysis.
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http://dx.doi.org/10.1002/humu.21598DOI Listing
January 2012

Estimation of allele frequency and association mapping using next-generation sequencing data.

BMC Bioinformatics 2011 Jun 11;12:231. Epub 2011 Jun 11.

Departments of Integrative Biology and Statistics, UC Berkeley, Berkeley, CA 94720, USA.

Background: Estimation of allele frequency is of fundamental importance in population genetic analyses and in association mapping. In most studies using next-generation sequencing, a cost effective approach is to use medium or low-coverage data (e.g., < 15X). However, SNP calling and allele frequency estimation in such studies is associated with substantial statistical uncertainty because of varying coverage and high error rates.

Results: We evaluate a new maximum likelihood method for estimating allele frequencies in low and medium coverage next-generation sequencing data. The method is based on integrating over uncertainty in the data for each individual rather than first calling genotypes. This method can be applied to directly test for associations in case/control studies. We use simulations to compare the likelihood method to methods based on genotype calling, and show that the likelihood method outperforms the genotype calling methods in terms of: (1) accuracy of allele frequency estimation, (2) accuracy of the estimation of the distribution of allele frequencies across neutrally evolving sites, and (3) statistical power in association mapping studies. Using real re-sequencing data from 200 individuals obtained from an exon-capture experiment, we show that the patterns observed in the simulations are also found in real data.

Conclusions: Overall, our results suggest that association mapping and estimation of allele frequencies should not be based on genotype calling in low to medium coverage data. Furthermore, if genotype calling methods are used, it is usually better not to filter genotypes based on the call confidence score.
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http://dx.doi.org/10.1186/1471-2105-12-231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212839PMC
June 2011

Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants.

Nat Genet 2010 Nov 3;42(11):969-72. Epub 2010 Oct 3.

BGI-Shenzhen, Shenzhen, China.

Targeted capture combined with massively parallel exome sequencing is a promising approach to identify genetic variants implicated in human traits. We report exome sequencing of 200 individuals from Denmark with targeted capture of 18,654 coding genes and sequence coverage of each individual exome at an average depth of 12-fold. On average, about 95% of the target regions were covered by at least one read. We identified 121,870 SNPs in the sample population, including 53,081 coding SNPs (cSNPs). Using a statistical method for SNP calling and an estimation of allelic frequencies based on our population data, we derived the allele frequency spectrum of cSNPs with a minor allele frequency greater than 0.02. We identified a 1.8-fold excess of deleterious, non-syonomyous cSNPs over synonymous cSNPs in the low-frequency range (minor allele frequencies between 2% and 5%). This excess was more pronounced for X-linked SNPs, suggesting that deleterious substitutions are primarily recessive.
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http://dx.doi.org/10.1038/ng.680DOI Listing
November 2010

A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B.

Nat Genet 2010 Oct 5;42(10):864-8. Epub 2010 Sep 5.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10⁻⁹; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10⁻⁹). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10⁻¹⁴, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.
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http://dx.doi.org/10.1038/ng.660DOI Listing
October 2010

Studies of association between LPIN1 variants and common metabolic phenotypes among 17,538 Danes.

Eur J Endocrinol 2010 Jul 31;163(1):81-7. Epub 2010 Mar 31.

Hagedorn Research Institute, Niels Steensens Vej 1, NLD 2.13, 2820 Gentofte, Copenhagen, Denmark.

Objective: Lipin-1, encoded by LPIN1, is expressed in the major metabolically active tissues. Decreased expression of lipin-1 in adipose tissue correlates with increased insulin resistance, and tagging of the LPIN1 locus has shown that rs33997857, rs6744682, and rs6708316 associate with metabolic phenotypes, specifically body mass index (BMI) and fasting serum lipid levels, both on the individual single-nucleotide polymorphism level and with a three-marker haplotype. Our aim was to validate the reported findings in the Danish population.

Design: In the present study, variants were analyzed in LPIN1 using case-control studies, haplotype analyses, and quantitative trait analyses in a population of 17,538 Danes.

Methods: The three LPIN1 variants were genotyped in 17,538 Danes from four study populations of middle-aged people. This provided us with a statistical power >99% to replicate previous findings. Variants were analyzed individually and in haplotype combinations in studies of quantitative metabolic traits and in case-control studies.

Results: None of the three variants were associated with the examined quantitative traits including BMI, waist circumference, blood pressure, fasting serum lipid concentrations, or plasma glucose or serum insulin concentrations in the fasting state and following an oral glucose tolerance test. Haplotypes were tested for association with quantitative traits; however, only nominal association with blood pressure (P=0.04) and waist circumference (P=0.04) was observed. In case-control studies, no association was found for individual variants or the three-marker haplotype.

Conclusion: LPIN1 rs33997857, rs6744682, and rs6708316 did not associate with type 2 diabetes, obesity, or related quantitative metabolic phenotypes in the Danish population examined.
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http://dx.doi.org/10.1530/EJE-10-0068DOI Listing
July 2010

Gene-environment interactions and obesity--further aspects of genomewide association studies.

Nutrition 2009 Oct 12;25(10):998-1003. Epub 2009 Jul 12.

Hagedorn Research Institute, Gentofte, Denmark.

Advances in genotyping technologies have facilitated the advent of the genomewide association studies in large study populations and thereby led to the identification of an impressive-and still increasing-number of genetic variants with significant impact on the risk of widespread lifestyle health problems such as obesity, diabetes, and cardiovascular disease. Yet, the scientific community is a long way from reaching a comprehensive picture of the heritable components of these diseases and advancing from plain statistical significance into a biological understanding where the true contribution to a trait is recognized. Increasingly large study populations, denser single-nucleotide polymorphism mapping, deep sequencing, and raised awareness of the importance of structural variants may add to the known genetic variance underlying common complex disorders; however, genetic variance alone probably cannot account for disease susceptibility without the addition of pre- and postnatal environmental and/or behavioral factors. Moreover, an interaction between genetic and environmental factors may hinder the detection of genetic effects if not accounted for, e.g., in genomewide association studies, and prospective cohort studies have hence been proposed to surpass the classic case-control design. With a focus on obesity we describe some of the recently reported gene-environment interactions for polymorphisms identified in the FTO and INSIG2 genes. Ultimately, a thorough understanding of the gene-environment interactions underlying a common complex condition such as obesity may suggest novel treatment or intervention strategies to complement the harmful effect of detrimental genetic variation and thus may assist in improving the quality of life for affected individuals.
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http://dx.doi.org/10.1016/j.nut.2009.06.001DOI Listing
October 2009

The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load.

PLoS One 2009 Jun 11;4(6):e5872. Epub 2009 Jun 11.

Hagedorn Research Institute, Gentofte, Denmark.

Background: Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897) on estimates of glucose stimulated insulin release.

Methodology/principal Findings: Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT) in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228.

Conclusion: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005872PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689931PMC
June 2009

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.

Genes Dev 2009 May;23(10):1171-6

Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, DK-2200 Copenhagen, Denmark.

The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A-ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS-RAF signaling pathway. JMJD3 is recruited to the INK4A-ARF locus and contributes to the transcriptional activation of p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.
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http://dx.doi.org/10.1101/gad.510809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685535PMC
May 2009

Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.

Nat Genet 2009 Jan 14;41(1):18-24. Epub 2008 Dec 14.

deCODE Genetics, Reykjavik, Iceland.

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
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http://dx.doi.org/10.1038/ng.274DOI Listing
January 2009

The KCNMB1 Glu65Lys polymorphism associates with reduced systolic and diastolic blood pressure in the Inter99 study of 5729 Danes.

J Hypertens 2008 Nov;26(11):2142-6

Steno Diabetes Center, Gentofte, Denmark.

Objective: The large Ca2+ and voltage-dependent potassium channel is important in regulating vascular tone in smooth muscle tissue. The rs11739136 KCNMB1 Glu65Lys polymorphism in the beta1 subunit of the Ca2+ and voltage-dependent potassium channel has, in some studies, been reported to associate with a protective effect on diastolic hypertension. The previous studies have, however, been conflicting, and the aim of the present study was to clarify the impact of the Glu65Lys polymorphism on hypertension at the population level of middle-aged people.

Design: Large-scale sex-stratified case-control studies and analyses of quantitative blood pressure.

Methods: The KCNMB1 Glu65Lys (rs11739136) polymorphism was genotyped in 5729 Danes using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of PCR-generated primer extension products.

Results: In the population-based Inter99 cohort, the Glu65Lys polymorphism was associated with a 1.3% decrease in systolic blood pressure (P=0.01) and a 1.1% decrease in diastolic blood pressure (P=0.04) per Lys-allele among 2668 men. Among women, we observed no association between systolic or diastolic blood pressure and the Glu65Lys polymorphism.

Conclusion: If replicated, our findings suggest that the KCNMB1 Glu65Lys polymorphism associates with reduced systolic and diastolic blood pressure in middle-aged men.
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http://dx.doi.org/10.1097/HJH.0b013e32830b894aDOI Listing
November 2008

SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations.

Nat Genet 2008 Sep;40(9):1098-102

Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Yokohama, Kanagawa 230-0045, Japan.

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 x 10(-12); OR = 1.26, 95% CI = 1.18-1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 x 10(-9); OR = 1.32, 95% CI = 1.20-1.45, rs2237897, P = 6.8 x 10(-13); OR = 1.41, 95% CI = 1.29-1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 x 10(-3); OR = 1.14, rs2237897, P = 2.4 x 10(-4); OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 x 10(-11); OR = 1.24, rs2237897, P = 1.2 x 10(-4); OR = 1.36).
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http://dx.doi.org/10.1038/ng.208DOI Listing
September 2008

Common nonsynonymous variants in PCSK1 confer risk of obesity.

Nat Genet 2008 Aug 6;40(8):943-5. Epub 2008 Jul 6.

Genomic Medicine, Imperial College London, Hammersmith Hospital, London W120NN, UK.

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
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http://dx.doi.org/10.1038/ng.177DOI Listing
August 2008

Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes.

Diabetes 2008 Sep 20;57(9):2534-40. Epub 2008 Jun 20.

Steno Diabetes Center, Copenhagen, Denmark.

Objective: We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes-associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data.

Research Design And Methods: We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT).

Results: Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10-27%; P = 4 x 10(-5)), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P = 4 x 10(-4)), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8-20%; P = 4 x 10(-4)). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9-4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5-8.4]; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2-6.7]; P = 0.005), and of the insulinogenic index (5.2% [1.9-8.6]; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9, or NOTCH2 variants.

Conclusions: If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic beta-cell function in the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.2337/db08-0436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518507PMC
September 2008

Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.

J Clin Invest 2008 Jul;118(7):2620-8

Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
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http://dx.doi.org/10.1172/JCI34566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398737PMC
July 2008

The Gly482Ser genotype at the PPARGC1A gene and elevated blood pressure: a meta-analysis involving 13,949 individuals.

J Appl Physiol (1985) 2008 Oct 8;105(4):1352-8. Epub 2008 May 8.

Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.

The protein encoded by the PPARGC1A gene is expressed at high levels in metabolically active tissues and is involved in the control of oxidative stress via reactive oxygen species detoxification. Several recent reports suggest that the PPARGC1A Gly482Ser (rs8192678) missense polymorphism may relate inversely with blood pressure. We used conventional meta-analysis methods to assess the association between Gly482Ser and systolic (SBP) or diastolic blood pressures (DBP) or hypertension in 13,949 individuals from 17 studies, of which 6,042 were previously unpublished observations. The studies comprised cohorts of white European, Asian, and American Indian adults, and adolescents from South America. Stratified analyses were conducted to control for population stratification. Pooled genotype frequencies were 0.47 (Gly482Gly), 0.42 (Gly482Ser), and 0.11 (Ser482Ser). We found no evidence of association between Gly482Ser and SBP [Gly482Gly: mean = 131.0 mmHg, 95% confidence interval (CI) = 130.5-131.5 mmHg; Gly482Ser mean = 133.1 mmHg, 95% CI = 132.6-133.6 mmHg; Ser482Ser: mean = 133.5 mmHg, 95% CI = 132.5-134.5 mmHg; P = 0.409] or DBP (Gly482Gly: mean = 80.3 mmHg, 95% CI = 80.0-80.6 mmHg; Gly482Ser mean = 81.5 mmHg, 95% CI = 81.2-81.8 mmHg; Ser482Ser: mean = 82.1 mmHg, 95% CI = 81.5-82.7 mmHg; P = 0.651). Contrary to previous reports, we did not observe significant effect modification by sex (SBP, P = 0.966; DBP, P = 0.715). We were also unable to confirm the previously reported association between the Ser482 allele and hypertension [odds ratio: 0.97, 95% CI = 0.87-1.08, P = 0.585]. These results were materially unchanged when analyses were focused on whites only. However, statistical evidence of gene-age interaction was apparent for DBP [Gly482Gly: 73.5 (72.8, 74.2), Gly482Ser: 77.0 (76.2, 77.8), Ser482Ser: 79.1 (77.4, 80.9), P = 4.20 x 10(-12)] and SBP [Gly482Gly: 121.4 (120.4, 122.5), Gly482Ser: 125.9 (124.6, 127.1), Ser482Ser: 129.2 (126.5, 131.9), P = 7.20 x 10(-12)] in individuals <50 yr (n = 2,511); these genetic effects were absent in those older than 50 yr (n = 5,088) (SBP, P = 0.41; DBP, P = 0.51). Our findings suggest that the PPARGC1A Ser482 allele may be associated with higher blood pressure, but this is only apparent in younger adults.
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http://dx.doi.org/10.1152/japplphysiol.90423.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2576025PMC
October 2008

Many sequence variants affecting diversity of adult human height.

Nat Genet 2008 May 6;40(5):609-15. Epub 2008 Apr 6.

deCODE Genetics, 101 Reykjavik, Iceland.

Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
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http://dx.doi.org/10.1038/ng.122DOI Listing
May 2008

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.

Nat Genet 2008 May 30;40(5):638-45. Epub 2008 Mar 30.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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http://dx.doi.org/10.1038/ng.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672416PMC
May 2008

AHSG tag single nucleotide polymorphisms associate with type 2 diabetes and dyslipidemia: studies of metabolic traits in 7,683 white Danish subjects.

Diabetes 2008 May 3;57(5):1427-32. Epub 2008 Mar 3.

Steno Diabetes Center, Niels Steensens Vej 1, NLC2.12, DK-2820 Gentofte, Denmark.

Objective: The gene encoding the alpha2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia.

Research Design And Methods: The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of >99% to replicate previous findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and beta-2-adrenergic receptor polymorphisms were investigated.

Results: The -469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes (P = 0.007 and P = 0.006, respectively, or P(corr) = 0.04 and P(corr) = 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study -469T>G remained significant (odds ratio 0.90 [95% CI 0.84-0.97]; P = 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia (P = 0.003 and P(corr) = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post-oral glucose tolerance test serum insulin release (P = 0.02, P(corr) = 0.1 for fasting and P = 0.04, P(corr) = 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of insulin resistance (9.0 vs. 8.6 mmol x l(-1) x pmol(-1) x l(-1); P = 0.01, P(corr) = 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations.

Conclusions: Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.
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http://dx.doi.org/10.2337/db07-0558DOI Listing
May 2008