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Epicure Consortium,
Eminet Consortium,
Michael Steffens,
Costin Leu,
Ann-Kathrin Ruppert,
Federico Zara,
Pasquale Striano,
Angela Robbiano,
Giuseppe Capovilla,
Paolo Tinuper, [......],
Herbert Schulz,
Franz Rüschendorf,
Markus Leber,
Steffen M Pauck,
Holger Trucks,
Mohammad R Toliat,
Peter Nürnberg,
Giuliano Avanzini,
Bobby P C Koeleman,
Thomas Sander
[show abstract]
[hide abstract]
ABSTRACT: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
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Birgit Filipiak-Pittroff,
Christina Schnopp,
Dietrich Berdel,
Aline Naumann,
Simon Sedlmeier,
Anna Onken,
Elke Rodriguez,
Regina Fölster-Holst,
Hansjörg Baurecht,
Markus Ollert, [......],
Claudia Cramer,
Andrea von Berg,
Carl Peter Bauer,
Olf Herbarth,
Irina Lehmann,
Beate Schaaf,
Sibylle Koletzko, Heinz-Erich Wichmann,
Joachim Heinrich,
Stephan Weidinger
[show abstract]
[hide abstract]
ABSTRACT: It was reported that in infants with eczema and food sensitization, the presence of a filaggrin (FLG) null mutation predicts future asthma with a specificity and positive predictive value of 100%.
We sought to evaluate the predictive value of food sensitization and food allergy, FLG haploinsufficiency, and their combination in infants with early-onset eczema for persistent eczema and childhood asthma.
The German Infant Nutritional Intervention (GINI) and Influence of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood (LISA) birth cohorts, as well as a collection of 65 cases of early-onset eczema with and without food allergy were investigated.
The risk for asthma was significantly increased by food sensitization (positive diagnostic likelihood ratios [PLRs] of 1.9 [95% CI, 1.1-3.4] in the GINI cohort and 5.5 [95% CI, 2.8-10.8] in the LISA cohort) and the presence of an FLG mutation (PLRs of 2.9 [95% CI, 1.2-6.6] in the GINI cohort and 2.8 [95% CI, 1.0-7.9] in the LISA cohort) with a rather high specificity (79.1% and 92.9% in the GINI cohort and 89.0% and 91.7% in the LISA cohort, respectively) but low sensitivity (40.0% and 39.3% in the GINI cohort and 31.6% and 23.5% in the LISA cohort, respectively). Likewise, the risk for persistent eczema was increased. In the clinical cases neither food allergy nor FLG mutations had a significant effect. The combination of both parameters did not improve prediction and reached positive predictive values of 52.3% (GINI cohort), 66.9% (LISA cohort), and 30.6% (clinical cases), assuming an asthma prevalence in children with early eczema of 30%.
Early food sensitization and the presence of an FLG mutation in infants with early eczema increase the risk for later asthma, but the combination of the 2 factors does not represent a clinically useful approach to reliably identify children at risk.
The Journal of allergy and clinical immunology 12/2011; 128(6):1235-1241.e5. · 9.17 Impact Factor
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Kirstin Mittelstrass,
Janina S Ried,
Zhonghao Yu,
Jan Krumsiek,
Christian Gieger,
Cornelia Prehn,
Werner Roemisch-Margl,
Alexey Polonikov,
Annette Peters,
Fabian J Theis,
Thomas Meitinger,
Florian Kronenberg,
Stephan Weidinger, Heinz Erich Wichmann,
Karsten Suhre,
Rui Wang-Sattler,
Jerzy Adamski,
Thomas Illig
[show abstract]
[hide abstract]
ABSTRACT: Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
PLoS Genetics 08/2011; 7(8):e1002215. · 8.69 Impact Factor
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Philipp S Wild,
Tanja Zeller,
Arne Schillert,
Silke Szymczak,
Christoph R Sinning,
Arne Deiseroth,
Renate B Schnabel,
Edith Lubos,
Till Keller,
Medea S Eleftheriadis, [......],
Christopher J O'Donnell,
Nilesh J Samani,
Heribert Schunkert,
Francois Cambien,
Karl J Lackner,
Laurence Tiret,
Veikko Salomaa,
Thomas Munzel,
Andreas Ziegler,
Stefan Blankenberg
[show abstract]
[hide abstract]
ABSTRACT: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).
In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)).
The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
Circulation Cardiovascular Genetics 05/2011; 4(4):403-12. · 6.11 Impact Factor
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Ayşe Demirkan,
Najaf Amin,
Aaron Isaacs,
Marjo-Riitta Jarvelin,
John B Whitfield, Heinz-Erich Wichmann,
Kirsten O H M Kyvik,
Igor Rudan,
Christian Gieger,
Andrew A Hicks, [......],
Birgit Hoehne,
Nicholas G Martin,
Ben A Oostra,
Mark McCarthy,
Leena Peltonen-Palotie,
Yurii Aulchenko,
Peter M Visscher,
Samuli Ripatti,
A Cecile J W Janssens,
Cornelia M van Duijn
[show abstract]
[hide abstract]
ABSTRACT: Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
European journal of human genetics: EJHG 03/2011; 19(7):813-9. · 3.56 Impact Factor
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Dirk Sibbing,
Arne Pfeufer,
Tamara Perisic,
Alexander M Mannes,
Karin Fritz-Wolf,
Sarah Unwin,
Moritz F Sinner,
Christian Gieger,
Christian Johannes Gloeckner, Heinz-Erich Wichmann, [......],
Axel Walch,
Martin Hinterseer,
Michael Näbauer,
Stefan Kääb,
Adnan Kastrati,
Albert Schömig,
Thomas Meitinger,
Georg W Bornkamm,
Marcus Conrad,
Nicolas von Beckerath
[show abstract]
[hide abstract]
ABSTRACT: Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases.
Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism.
For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden.
European Heart Journal 01/2011; 32(9):1121-33. · 10.48 Impact Factor
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Maria Timofeeva,
Silke Kropp,
Wiebke Sauter,
Lars Beckmann,
Albert Rosenberger,
Thomas Illig,
Birgit Jäger,
Kirstin Mittelstrass,
Hendrik Dienemann,
Helmut Bartsch,
Heike Bickeböller,
Jenny Chang-Claude,
Angela Risch, Heinz-Erich Wichmann
[show abstract]
[hide abstract]
ABSTRACT: Early-onset lung cancer diagnosed up to the age of 50 is a very rare disease, with an increasing incidence rate. Differences in aetiology, characteristics and epidemiology of early and older onset lung cancer have been described previously, suggesting the importance of genetic factors in early-onset lung cancer aetiology. A case-control study was conducted to investigate the effects of genetic polymorphisms in the MPO, EPHX1, GSTT1, GSTM1, GSTP1 and NQO1 genes on the risk of early-onset lung cancer development. Six hundred thirty-eight Caucasian patients under the age of 51 with confirmed primary lung cancer and 1,300 cancer free control individuals, matched by age and sex, were included in this analysis. Seventeen single nucleotide polymorphisms and two deletion polymorphisms were genotyped. No significant association was found for any of the analyzed polymorphisms and overall lung cancer risk. Nonsignificantly decreased risk of lung cancer was observed for carriers of 1 or 2 copies of GSTM1. Subgroup analysis revealed gender- and/or smoking-specific effects of EPHX1 rs2854455 (IV-1464C > T) and rs2234922 (His139Arg), GSTT1 deletion, GSTP1 rs1695 (Ile105Val), rs947895 (+991C > A) and rs4891 (Ser185Ser) and NQO1 rs1800566 (Pro187Ser) polymorphisms. However, none of the observed effects were confirmed by interaction tests nor were they significant after Bonferroni correction for multiple testing. In summary, our study suggested a modifying effect of polymorphisms in EPHX1, GSTP1, GSTT1, GSTM1 and NQO1 genes on the risk of early-onset lung cancer. To confirm these observations and to eliminate possible bias in our analyses, larger studies are warranted.
International Journal of Cancer 10/2010; 127(7):1547-61. · 5.44 Impact Factor
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Florian Lederbogen,
Christine Kühner,
Clemens Kirschbaum,
Christa Meisinger,
Josefine Lammich,
Rolf Holle,
Bertram Krumm,
Thomas von Lengerke, Heinz-Erich Wichmann,
Michael Deuschle,
Karl-Heinz Ladwig
[show abstract]
[hide abstract]
ABSTRACT: Analysis of salivary cortisol concentrations and derived indices is increasingly used in clinical and scientific medicine. However, comprehensive data on these parameters in the general population are scarce. The aim of this study was to evaluate the concentrations of salivary cortisol in a large middle-aged community sample and to identify major factors associated with altered hormone levels.
We conducted a cross-sectional study within the Cooperative Health Research in the Region of Augsburg (KORA)-F3 study. A total of 1484 participants aged 50-69 years (52% women) had agreed to provide four saliva samples during a regular weekday.
We measured salivary cortisol concentrations at wake-up (F0), (1/2) h (F(1/2)), 8 h (F8), and 14 h (F14) after waking. We calculated cortisol awakening response (CAR), slope, and area under the curve (AUC(G)) of the circadian cortisol secretion. Sociodemographic and clinical characteristics were evaluated by interview and questionnaires, sampling conditions by protocol. In total, 1208 participants returned saliva samples, exclusion criteria left 990 subjects for final analyses.
Salivary cortisol levels were (means+/-s.d.) F0=13.7+/-7.6, F(1/2)=20.5+/-9.8, F8=5.4+/-3.3, and F14=2.0+/-1.8 nmol/l. Earlier sampling times were associated with higher CAR and smaller slope. Cortisol secretion was also influenced by gender and smoking habits. Higher perceived social support was associated with lower AUC(G) and smaller slope.
We provide data on salivary cortisol concentrations in a large middle-aged community sample. Gender, sampling time, smoking habits, and perceived social support appeared as determinants of cortisol secretion.
European Journal of Endocrinology 09/2010; 163(3):443-51. · 3.42 Impact Factor
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[show abstract]
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ABSTRACT: Understanding factors associated with death wishes and suicidal ideation (SID) may help to improve identification of subjects at risk in the general population. We assessed SID in a population-based sample of 3079 subjects, 35 to 84 years and examined multiple sex- and age-adjusted affective and bio-behavioral covariates. Anxiety and a high level of somatic complaints, particularly dyspnea, contributed to the SID risk. However, the clinical picture of subjects suffering from SID was dominated by a 6-fold adjusted increased risk of a depressive syndrome followed by impaired self perceived health (3-fold risk) in both sexes. In men, unemployment status and living alone also increased SID risk substantially. These factors open new insights for our understanding of the multifaceted etiology of suicide risks offering new strategies for early detection of subjects at risk.
The Journal of nervous and mental disease 01/2010; 198(1):52-8. · 1.77 Impact Factor
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Carolien G F de Kovel,
Holger Trucks,
Ingo Helbig,
Heather C Mefford,
Carl Baker,
Costin Leu,
Christian Kluck,
Hiltrud Muhle,
Sarah von Spiczak,
Philipp Ostertag, [......],
Andre Franke,
Stefan Schreiber,
Peter Nürnberg,
Christian E Elger,
Holger Lerche,
Ulrich Stephani,
Bobby P C Koeleman,
Dick Lindhout,
Evan E Eichler,
Thomas Sander
[show abstract]
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ABSTRACT: Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
Brain 10/2009; 133(Pt 1):23-32. · 9.46 Impact Factor
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Ursula Krämer,
Dorothea Sugiri,
Ulrich Ranft,
Jean Krutmann,
Andrea von Berg,
Dietrich Berdel,
Heidrun Behrendt,
Thomas Kuhlbusch,
Matthias Hochadel, Heinz-Erich Wichmann,
Joachim Heinrich
[show abstract]
[hide abstract]
ABSTRACT: Traffic-related air pollution (TAP) impairs respiratory health and could influence the development of allergies, as was demonstrated in urban areas with relatively high pollution. Whether eczema is affected by TAP was rarely investigated.
To investigate whether exposure to TAP affects eczema and respiratory allergies also in small-town areas with lower concentrations of pollution.
Between 1995 and 1999, we recruited 3390 newborns from small-town areas. Diagnoses and symptoms of eczema and respiratory allergies were recorded by annual questionnaires. Seventy-seven percent of families participated until the child's 6th birthday, when a clinical test for eczema and IgE-sensitization was performed. Individual exposure to traffic-related soot and NO(2) at the children's home addresses was determined by land-use-regression. We used Cox-regression/log-binomial-regression to determine its confounder-adjusted association with incidence and prevalence of eczema and respiratory allergies.
The prevalence of eczema at age 6 was significantly higher in children who resided in areas where TAP was higher. The adjusted relative risk for doctor diagnosed eczema for instance was 1.69 (95% confidence interval 1.04-2.75) per 90%-range of soot concentration. Current eczema at the 6 year clinical investigation was likewise associated, children with parental allergies showed significantly stronger effects (p<0.05). Incidence of eczema was not affected. No associations between TAP and asthma, hay fever, or allergic sensitization emerged.
Eczema was sensitive to TAP, effects emerged even in lower polluted small-town areas of Germany. They could be seen for prevalence but not incidence of eczema. This is equivalent to a longer duration of eczema in exposed children.
Journal of dermatological science 09/2009; 56(2):99-105. · 3.71 Impact Factor
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Maria N Timofeeva,
Silke Kropp,
Wiebke Sauter,
Lars Beckmann,
Albert Rosenberger,
Thomas Illig,
Birgit Jäger,
Kirstin Mittelstrass,
Hendrik Dienemann,
Helmut Bartsch,
Heike Bickeböller,
Jenny C Chang-Claude,
Angela Risch, Heinz-Erich Wichmann
[show abstract]
[hide abstract]
ABSTRACT: Cytochrome P450 (CYP) enzymes, involved in metabolism of tobacco carcinogens, are also involved in estrogen metabolism and many are regulated by estrogens. These genes may thus be of relevance to gender-specific differences in lung cancer risk, particularly in early-onset lung cancer, where a high proportion of women is observed. We conducted a case-control study to investigate genetic polymorphisms in cytochromes that might modify the risk of developing early-onset lung cancer. In total, 638 Caucasian patients under the age of 51 with primary lung cancer and 1300 cancer-free control individuals, matched by age and sex, were included in this analysis. Thirteen polymorphisms in the CYP1A1, CYP1B1, CYP2A13, CYP3A4 and CYP3A5 genes were analyzed. No significant association was found for any of the analyzed polymorphisms and lung cancer risk overall. However, among women, a significantly increased risk of early-onset lung cancer was observed for carriers of the minor allele of CYP1B1 SNP rs1056836 [odds ratio (OR) 1.97; 95% confidence interval (CI) 1.32-2.94; P < 0.001]. Also, a non-significant increase in lung cancer risk was observed in the group of women carriers of the minor allele of CYP2A13 SNP rs1709084 (OR 1.64; 95% CI 1.00-2.70; P = 0.05). The effect of these two polymorphisms was shown to be modified by smoking. Haplotype analysis was performed for CYP1B1 and CYP2A13. No differences between cases and controls were observed for both genes (P = 0.63 and P = 0.42 for CYP1B1 and CYP2A13, respectively). Our results suggest that the CYP1B1 and the CYP2A13 genotypes may contribute to individual susceptibility to early-onset lung cancer in women.
Carcinogenesis 05/2009; 30(7):1161-9. · 5.70 Impact Factor
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Timothy Tehua Lu,
Oscar Lao,
Michael Nothnagel,
Olaf Junge,
Sandra Freitag-Wolf,
Amke Caliebe,
Miroslava Balascakova,
Jaume Bertranpetit,
Laurence Albert Bindoff,
David Comas, [......],
André Gerardus Uitterlinden,
Christian Gieger, Heinz-Erich Wichmann,
Andreas Ruether,
Stefan Schreiber,
Christian Becker,
Peter Nürnberg,
Matthew Roberts Nelson,
Manfred Kayser,
Michael Krawczak
[show abstract]
[hide abstract]
ABSTRACT: Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309,790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.
European journal of human genetics: EJHG 02/2009; 17(7):967-75. · 3.56 Impact Factor
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[show abstract]
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ABSTRACT: Deletion polymorphisms of Glutathione-S-transferase (GST) M1 and T1 are considered risk factors for various diseases. However, most previous studies only distinguished "null" and "non-null" genotypes. Our aim was to develop a reliable, high-throughput GSTM1/T1 genotyping method able to determine allele copy numbers.
We developed a multiplex real time PCR method to distinguish between heterozygous (1/0) and homozygous (1/1) GSTM1 and GSTT1 genotypes. The principle of relative quantification was applied and an expectation-maximisation (EM) algorithm was developed to assign one of 3 possible genotypes: 1/1, 1/0 or 0/0 for each of the two genes.
1320 Caucasians were genotyped using the newly developed method. The observed genotype distributions did not deviate from the expected and were in Hardy-Weinberg equilibrium. GSTM1 duplication was detected in one sample.
This new semiquantitative genotyping method is a sensitive and promising tool for large-scale molecular epidemiological and clinical studies.
Clinical biochemistry 01/2009; 42(6):500-9. · 2.02 Impact Factor
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[show abstract]
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ABSTRACT: Among risk factors for suicide, suicidal ideation (SID) is of paramount importance. This study sought to determine sex- and age-related SID point prevalence rates in the general population. A population-based survey of 3154 subjects, 35 to 84 years, conducted in 2004/05 in southern Germany, identified 170 subjects (5.4%; 95% CI 4.6-6.2) suffering from SID within the last 14 days. Age-adjusted short-term period prevalence in women (6.0%, 95% CI 4.9.-7.2) was higher than in men (4.0%, 95% CI 3.1-5.1). Among 10-year age groups, sex-related differences were only significant in middle-aged subjects (55-64 years). Prevalence increased significantly with age, leading to a prevalence of >10% in the oldest age group (75-84 years). The population-based approach demonstrates a substantial proportion of subjects suffering from SID, particularly in older age groups.
Psychiatry Research 10/2008; 161(2):248-52. · 2.52 Impact Factor
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Oscar Lao,
Timothy T Lu,
Michael Nothnagel,
Olaf Junge,
Sandra Freitag-Wolf,
Amke Caliebe,
Miroslava Balascakova,
Jaume Bertranpetit,
Laurence A Bindoff,
David Comas, [......],
André G Uitterlinden,
Christian Gieger, Heinz-Erich Wichmann,
Andreas Rüther,
Stefan Schreiber,
Christian Becker,
Peter Nürnberg,
Matthew R Nelson,
Michael Krawczak,
Manfred Kayser
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ABSTRACT: Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry.
Current Biology 09/2008; 18(16):1241-8. · 9.65 Impact Factor
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Wiebke Sauter,
Albert Rosenberger,
Lars Beckmann,
Silke Kropp,
Kirstin Mittelstrass,
Maria Timofeeva,
Gabi Wölke,
Angelika Steinwachs,
Daniela Scheiner,
Eckart Meese,
Gerhard Sybrecht,
Florian Kronenberg,
Hendrik Dienemann,
Jenny Chang-Claude,
Thomas Illig, Heinz-Erich Wichmann,
Heike Bickeböller,
Angela Risch
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ABSTRACT: Matrix metalloproteinases (MMP) play a key role in the breakdown of extracellular matrix and in inflammatory processes. MMP1 is the most highly expressed interstitial collagenase degrading fibrillar collagens. Overexpression of MMP1 has been shown in tumor tissues and has been suggested to be associated with tumor invasion and metastasis. Nine haplotype tagging and additional two intronic single nucleotide polymorphisms (SNP) of MMP1 were genotyped in a case control sample, consisting of 635 lung cancer cases with onset of disease below 51 years of age and 1,300 age- and sex-matched cancer-free controls. Two regions of linkage disequilibrium (LD) of MMP1 could be observed: a region of low LD comprising the 5' region including the promoter and a region of high LD starting from exon 1 to the end of the gene and including the 3' flanking region. Several SNPs were identified to be individually significantly associated with risk of early-onset lung cancer. The most significant effect was seen for rs1938901 (P = 0.0089), rs193008 (P = 0.0108), and rs996999 (P = 0.0459). For rs996999, significance vanished after correction for multiple testing. For each of these SNPs, the major allele was associated with an increase in risk with an odds ratio between 1.2 and 1.3 (95% confidence interval, 1.0-1.5). The haplotype analysis supported these findings, especially for subgroups with high smoking intensity. In summary, we identified MMP1 to be associated with an increased risk for lung cancer, which was modified by smoking.
Cancer Epidemiology Biomarkers & Prevention 06/2008; 17(5):1127-35. · 4.12 Impact Factor
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Kirstin Mittelstrass,
Wiebke Sauter,
Albert Rosenberger,
Thomas Illig,
Maria Timofeeva,
Norman Klopp,
Hendrik Dienemann,
Eckart Meese,
Gerhard Sybrecht,
Gabi Woelke, [......],
Gerd Hoeffken,
Christine Schmidt,
Bettina Jilge,
Wilhelm Schmidt,
You-Dschun Ko,
Dagmar Taeuscher,
Jenny Chang-Claude, Heinz-Erich Wichmann,
Heike Bickeboeller,
Angela Risch
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ABSTRACT: The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis.We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking. Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7-1.5) and 1.0 (95% CI: 0.7-1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.
BMC Cancer 02/2008; 8:113. · 3.01 Impact Factor
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ABSTRACT: Some studies have suggested that particulate matter (PM) levels during pregnancy may be associated with birth weight. Road traffic is a major source of fine PM (PM with aero-dynamic diameter < 2.5 microm; PM(2.5)).
We determined to characterize the influence of maternal exposure to atmospheric pollutants due to road traffic and urban activities on offspring term birth weight.
Women from a birth cohort [the LISA (Influences of Lifestyle Related Factors on the Human Immune System and Development of Allergies in Children) cohort] who delivered a non-premature baby with a birth weight > 2,500 g in Munich metropolitan area were included. We assessed PM(2.5), PM(2.5) absorbance (which depends on the blackness of PM(2.5), a marker of traffic-related air pollution), and nitrogen dioxide levels using a land-use regression model, taking into account the type and length of roads, population density, land coverage around the home address, and temporal variations in pollution during pregnancy. Using Poisson regression, we estimated prevalence ratios (PR) of birth weight < 3,000 g, adjusted for gestational duration, sex, maternal smoking, height, weight, and education.
Exposure was defined for 1,016 births. Taking the lowest quartile of exposure during pregnancy as a reference, the PR of birth weight < 3,000 g associated with the highest quartile was 1.7 for PM(2.5) [95% confidence interval (CI), 1.2-2.7], 1.8 for PM(2.5) absorbance (95% CI, 1.1-2.7), and 1.2 for NO(2) (95% CI, 0.7-1.7). The PR associated with an increase of 1 microg/m(3) in PM(2.5) levels was 1.13 (95% CI, 1.00-1.29).
Increases in PM(2.5) levels and PM(2.5) absorbance were associated with decreases in term birth weight. Traffic-related air pollutants may have adverse effects on birth weight.
Environmental Health Perspectives 09/2007; 115(9):1283-92. · 7.04 Impact Factor
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ABSTRACT: Recommendations for primary prevention of allergic diseases in high-risk children include feeding with hydrolyzed formulas if breast-feeding is insufficient.
The primary objective of the German Infant Nutritional Intervention study was to investigate the allergy preventive effect of 3 hydrolyzed formulas compared with cow's milk formula in the first 3 years of life in a randomized, double-blind trial.
Between 1995 and 1998, 2252 newborns with atopic heredity were allocated to a group receiving cow's milk formula, partially or extensively hydrolyzed whey formula, or extensively hydrolyzed casein formula as a milk substitute for the first 4 months if breast-feeding was insufficient. Main outcome parameters were allergic manifestations, atopic dermatitis (AD), and asthma.
After 3 years, 396 of 2252 children (17.6%) had dropped out. Breast-fed infants without formula feeding during the intervention (n = 889) were considered separately. A significant reduction of the incidence of AD was achieved with the extensively hydrolyzed casein formula in the intention-to-treat (ITT; n = 1363) and per protocol (PP; n = 904) analyses (ITT: population odds ratio [95% CI], 0.67 [0.45-0.99]; PP: adjusted odds ratio [OR(adj)], 0.53 [0.32-0.88]), and with the partially hydrolyzed whey formula in the PP analysis (ITT: population odds ratio, 0.76 [0.52-1.11]; PP:OR(adj), 0.60 [0.37-0.97]). None of the formulas reduced the incidence of asthma.
The risk for AD, but not for asthma, can be reduced with certain cow's milk hydrolyzates in high-risk infants when breast-feeding is insufficient.
Early nutritional intervention in high-risk children has significant influence on the incidence of AD, but not of asthma.
Journal of Allergy and Clinical Immunology 04/2007; 119(3):718-25. · 11.00 Impact Factor
