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Articles by T Illig
Total Records ( 8 ) for T Illig
  M. N Timofeeva , S Kropp , W Sauter , L Beckmann , A Rosenberger , T Illig , B Jager , K Mittelstrass , H Dienemann , Bartsch The LUCY Consortium , H Bickeboller , J. C Chang Claude , A Risch and H. E. Wichmann

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.

  B Frank , M Hoffmeister , N Klopp , T Illig , J Chang Claude and H. Brenner

RecQ helicase family members are involved in multiple DNA repair pathways, protecting the genome from incorrect recombination during mitosis and maintaining its stability. Deficiencies in genes encoding the RecQ helicases WRN and BLM lead to rare autosomal recessive diseases, Werner and Bloom syndromes, which have been implicated in early onset of aging, and predisposition to various types of cancer. We investigated associations of WRN, BLM and BLM-associated protein (BLAP75/RMI1) gene polymorphisms and risk of colorectal cancer (CRC), genotyping WRN V114I (rs2230009), WRN L1074F (rs2725362), WRN C1367R (rs1346044), RMI1 S455N (rs1982151) and BLM P868L (rs11852361). A large population-based case–control study, including 1795 CRC cases and 1805 controls, found no evidence for an association between the selected allelic variants in DNA repair-related genes and CRC risk. However, we detected a significant association of BLM P868L with an increased rectal cancer risk (odds ratio = 1.29, 95% confidence interval 1.02–1.64 and P = 0.04), suggesting a potential cancer-site specificity. This is the first study to analyze the associations between polymorphisms in WRN, BLM and RMI1 and CRC risk. Although none of them showed a significant association with CRC, the association of BLM P868L with rectal cancer risk requires further investigation.

  T Truong , W Sauter , J. D McKay , H. D Hosgood , C Gallagher , C. I Amos , M Spitz , J Muscat , P Lazarus , T Illig , H. E Wichmann , H Bickeboller , A Risch , H Dienemann , Z. F Zhang , B. P Naeim , P Yang , S Zienolddiny , A Haugen , L Le Marchand , Y. C Hong , J. H Kim , E. J Duell , A. S Andrew , C Kiyohara , H Shen , K Matsuo , T Suzuki , A Seow , D. P. K Ng , Q Lan , D Zaridze , N Szeszenia Dabrowska , J Lissowska , P Rudnai , E Fabianova , V Constantinescu , V Bencko , L Foretova , V Janout , N. E Caporaso , D Albanes , M Thun , M. T Landi , J Trubicka , M Lener , J Lubinski , Wang EPIC lung , A Chabrier , P Boffetta , P Brennan and R. J. Hung

Background. Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). Methods. Genotype data from 15 ILCCO case–control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. Results. Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10–4). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11 722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89–0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85–0.95), P = 1 x 10–4]. Conclusion. This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.

  B Frank , M Hoffmeister , N Klopp , T Illig , J Chang Claude and H. Brenner

It is well known that ~90% of colorectal cancer (CRC) cases originate from the constitutive activation of the canonical Wnt signaling pathway. There is increasing evidence that genetic variation both in Wnt and apoptotic pathway genes affects CRC susceptibility and progression. This population-based case–control study, including 1795 CRC cases and 1805 controls, investigates the association between common, putative functional polymorphisms in DNFA5, HIF1A, NDRG1, PYGO1, SFRP2, SFRP4, WISP1 and WISP3 genes and CRC risk. We found no evidence for an association between the selected allelic variants and risk of CRC. Subsite analyses, however, revealed a significant association of HIF1A c.*191T>C with rectal cancer risk [odds ratio (OR) = 1.25, 95% confidence interval (CI), 1.03–1.51, P = 0.03] comparing minor allele carriers with major allele homozygotes. In addition, homozygosity for the minor allele of SFRP4 P320T was significantly associated with rectal cancer risk (OR = 1.37, 95% CI, 1.06–1.79, P = 0.02) and early-stage CRC (OR = 1.33, 95% CI, 1.05–1.69, P = 0.02). This study does not support the hypothesis that Wnt signaling- and apoptosis-related polymorphisms contribute to CRC risk. However, our results provide evidence that CRC subsets may be affected. If confirmed, this knowledge may be used to assess individual susceptibility and to target potential measures of cancer prevention.

  A Dehghan , Q Yang , A Peters , S Basu , J. C Bis , A. R Rudnicka , M Kavousi , M. H Chen , J Baumert , G. D.O Lowe , B McKnight , W Tang , M de Maat , M. G Larson , S Eyhermendy , W. L McArdle , T Lumley , J. S Pankow , A Hofman , J. M Massaro , F Rivadeneira , M Kolz , K. D Taylor , C. M van Duijn , S Kathiresan , T Illig , Y. S Aulchenko , K. A Volcik , A. D Johnson , A. G Uitterlinden , G. H Tofler , C Gieger , Psaty Wellcome Trust Case Control Consortium , D. J Couper , E Boerwinkle , W Koenig , C. J O`Donnell , J. C Witteman , D. P Strachan , N. L Smith and A. R. Folsom

Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

Methods and Results— We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0x10–8). These included a single-nucleotide polymorphism located in the fibrinogen β chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8x10–30), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3x10–15), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9x10–10), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04x10–8).

Conclusions— Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

  D Teupser , R Baber , U Ceglarek , M Scholz , T Illig , C Gieger , L. M Holdt , A Leichtle , K. H Greiser , D Huster , P Linsel Nitschke , A Schafer , P. S Braund , L Tiret , K Stark , D Raaz Schrauder , G. M Fiedler , W Wilfert , F Beutner , S Gielen , A Grosshennig , I. R Konig , P Lichtner , I. M Heid , A Kluttig , N. E El Mokhtari , D Rubin , A. B Ekici , A Reis , C. D Garlichs , A. S Hall , G Matthes , C Wittekind , C Hengstenberg , F Cambien , S Schreiber , K Werdan , T Meitinger , M Loeffler , N. J Samani , J Erdmann , H. E Wichmann , H Schunkert and J. Thiery

Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).

Methods and Results—

A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6x10–50 and 6.2x10–25, respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10–13). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2x10–6; rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4x10–6), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3x10–5).


Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

  E Org , S Eyheramendy , P Juhanson , C Gieger , P Lichtner , N Klopp , G Veldre , A Doring , M Viigimaa , S Sober , K Tomberg , G Eckstein , Kelgo KORA , T Rebane , S Shaw Hawkins , P Howard , A Onipinla , R. J Dobson , S. J Newhouse , M Brown , A Dominiczak , J Connell , N Samani , M Farrall , Caulfield BRIGHT , P. B Munroe , T Illig , H. E Wichmann , T Meitinger and M. Laan

Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395 912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10–5, effect –1.40 mmHg; SBP, P = 0.007, effect –1.56 mmHg; HYP, P = 5.30 x 10–8, OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.

  T Truong , R. J Hung , C. I Amos , X Wu , H Bickeboller , A Rosenberger , W Sauter , T Illig , H. E Wichmann , A Risch , H Dienemann , R Kaaks , P Yang , R Jiang , J. K Wiencke , M Wrensch , H Hansen , K. T Kelsey , K Matsuo , K Tajima , A. G Schwartz , A Wenzlaff , A Seow , C Ying , A Staratschek Jox , P Nurnberg , E Stoelben , J Wolf , P Lazarus , J. E Muscat , C. J Gallagher , S Zienolddiny , A Haugen , H. F. M van der Heijden , L. A Kiemeney , D Isla , J. I Mayordomo , T Rafnar , K Stefansson , Z. F Zhang , S. C Chang , J. H Kim , Y. C Hong , E. J Duell , A. S Andrew , F Lejbkowicz , G Rennert , H Muller , H Brenner , L Le Marchand , S Benhamou , C Bouchardy , M. D Teare , X Xue , J McLaughlin , G Liu , J. D McKay , P Brennan and M. R. Spitz

Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.


Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case–control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided.


Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, Ptrend = 2 x 10–26), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, Ptrend = 1 x 10–10) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, Ptrend = 5 x 10–8) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, Ptrend = 2 x 10–5; rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, Ptrend = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer.


In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

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