Martina Müller-Nurasyid

Publications (49) View all

• Article: Common variants in KCNN3 are associated with lone atrial fibrillation.

  Patrick T Ellinor, Kathryn L Lunetta, Nicole L Glazer, Arne Pfeufer, Alvaro Alonso, Mina K Chung, Moritz F Sinner, Paul I W de Bakker, Martina Mueller, Steven A Lubitz, [......], Bruce M Psaty, Dan M Roden, Thomas Meitinger, H-Erich Wichmann, Jacqueline C M Witteman, John Barnard, Dan E Arking, Emelia J Benjamin, Susan R Heckbert, Stefan Kääb
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  ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
  Nature Genetics 02/2010; 42(3):240-4. · 35.53 Impact Factor
• Source

  Available from: Esther E Creemers

  Article: Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.

  Ahmad S Amin, John R Giudicessi, Anke J Tijsen, Anne M Spanjaart, Yolan J Reckman, Christine A Klemens, Michael W Tanck, Jamie D Kapplinger, Nynke Hofman, Moritz F Sinner, Martina Müller, Wino J Wijnen, Hanno L Tan, Connie R Bezzina, Esther E Creemers, Arthur A M Wilde, Michael J Ackerman, Yigal M Pinto
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  ABSTRACT: Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3' untranslated region (3'UTR). This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3'UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3'UTR with the derived SNP variants was lower than the expression of the 3'UTR with the ancestral SNP variants. Our data indicate that 3'UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.
  European Heart Journal 12/2011; 33(6):714-23. · 10.48 Impact Factor
• Article: Acute air pollution effects on heart rate variability are modified by SNPs involved in cardiac rhythm in individuals with diabetes or impaired glucose tolerance.

  Regina Hampel, Susanne Breitner, Alexandra Schneider, Wojciech Zareba, Ute Kraus, Josef Cyrys, Uta Geruschkat, Petra Belcredi, Martina Müller, H-Erich Wichmann, Annette Peters
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  ABSTRACT: Epidemiological studies have shown associations between particulate matter (PM) and heart rate variability (HRV). We investigated the effects of air pollution on the root mean square of successive differences (RMSSD) and the standard deviation of normal-to-normal intervals (SDNN) and effect modifications by single nucleotide polymorphisms (SNP). Between March 2007 and December 2008 207 ECG recordings comprising 1153 1 h-intervals were measured in 61 individuals with type 2 diabetes or impaired glucose tolerance (IGT) from Augsburg, Germany. Associations between 1 h-averages of air pollutants (PM, sulphate, black carbon, and ultrafine particles) and ECG parameters were analyzed using additive mixed models. Genotypes of 139 SNPs supposed to be involved in cardiac rhythm were identified in the literature. Using regression trees for longitudinal data, SNPs associated with ECG parameters were determined and included as potential air pollution effect modifiers. We observed concurrent and lagged decreases in SDNN by about 2-5% in association with all air pollutants, especially in participants with at least one minor allele of rs332229. Increases in PM<2.5 μm (PM(2.5)) were associated with 4 h-lagged decreases of -6.6% [95%-confidence interval:-10.6;-2.6%] and -13.0% [-20.7;-5.1%] in SDNN in individuals with one or two minor alleles. We observed a -7.2% [-12.2;-1.8%] reduction in RMSSD associated with concurrent increases in PM(2.5.) Individuals with at least one minor allele of rs2096767 or at most one minor allele of rs2745967 exhibited stronger PM(2.5) effects. We identified a genetic predisposition in persons with diabetes or IGT making them potentially more susceptible to air pollutants with regard to changes in HRV.
  Environmental Research 11/2011; 112:177-85. · 3.40 Impact Factor
• Article: Chromosome 7p11.2 (EGFR) variation influences glioma risk.

  Marc Sanson, Fay J Hosking, Sanjay Shete, Diana Zelenika, Sara E Dobbins, Yussanne Ma, Victor Enciso-Mora, Ahmed Idbaih, Jean-Yves Delattre, Khe Hoang-Xuan, [......], Stefan Schreiber, Andre Franke, Susanne Moebus, Lewin Eisele, Asta Försti, Kari Hemminki, Mark Lathrop, Melissa Bondy, Richard S Houlston, Matthias Simon
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  ABSTRACT: While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.
  Human Molecular Genetics 07/2011; 20(14):2897-904. · 7.64 Impact Factor
• Source

  Available from: László Czirják

  Article: Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.

  Yannick Allanore, Mohamad Saad, Philippe Dieudé, Jérôme Avouac, Jorg H W Distler, Philippe Amouyel, Marco Matucci-Cerinic, Gabriella Riemekasten, Paolo Airo, Inga Melchers, [......], Valeria Riccieri, Barbara Ruiz, Jean-Luc Cracowski, Luc Letenneur, Anne Marie Dupuy, Oliver Meyer, André Kahan, Arnold Munnich, Catherine Boileau, Maria Martinez
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  ABSTRACT: Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10(-8), OR = 0.69, 95% CI [0.60-0.79]; rs6457617, P = 1.14×10(-7) and rs9275245, P = 1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10(-5), OR = 1.36 [1.18-1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10(-10), OR:1.25), TNIP1 (P = 4.68×10(-9), OR:1.31), and RHOB loci (P = 3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.
  PLoS Genetics 07/2011; 7(7):e1002091. · 8.69 Impact Factor