Stacey S.N.,DeCODE Genetics Inc. |
Sulem P.,DeCODE Genetics Inc. |
Jonasdottir A.,DeCODE Genetics Inc. |
Masson G.,DeCODE Genetics Inc. |
And 116 more authors.
Nature Genetics | Year: 2011
To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 ×-10 -17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 ×-10 -20). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 ×-10 -6), glioma (OR = 2.35, P = 1.0 ×-10 -5) and colorectal adenoma (OR = 1.39, P = 1.6 ×-10 -4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27). © 2011 Nature America, Inc. All rights reserved.
Kiemeney L.A.,Biostatistics and Health Technology Assessment |
Kiemeney L.A.,Radboud University Nijmegen |
Kiemeney L.A.,Comprehensive Cancer Center East |
Sulem P.,DeCODE Genetics Inc. |
And 80 more authors.
Nature Genetics | Year: 2010
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10 12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC. © 2010 Nature America, Inc. All rights reserved.
Rothman N.,U.S. National Cancer Institute |
Garcia-Closas M.,U.S. National Cancer Institute |
Chatterjee N.,U.S. National Cancer Institute |
Malats N.,Spanish National Cancer Research Center |
And 120 more authors.
Nature Genetics | Year: 2010
We conducted a multi-stage, genome-wide aSociation study of blaDer cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies foLowed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified thrE new regions aSociated with blaDer cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8-10-12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2-10-11) on 19q12 maps to CNE1 and rs11892031 (P = 1-10-7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide aSociations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate aSociations for the GSTM1 deletion (P = 4-10-11) and a tag SNP for NAT2 acetylation status (P = 4-10-11), and found interactions with smoking in both regions. Our findings on coMon variants aSociated with blaDer cancer risk should provide new insights into the mechanisms of carcinogenesis. © 2010 Nature America, Inc. All rights reserved.
Gorog K.,London School of Hygiene and Tropical Medicine |
Pattenden S.,London School of Hygiene and Tropical Medicine |
Niciu E.,Institute of Public Health Bucharest |
Rudnai P.,National Institute of Environmental Health |
And 6 more authors.
Maternal and Child Health Journal | Year: 2011
Childhood obesity is a worldwide public health concern. Recent studies from high income countries have demonstrated associations between maternal smoking during pregnancy and children's excess body weight. We examine associations between maternal smoking during pregnancy and children's overweight or obesity, in six countries in the less affluent Central/Eastern European region. Questionnaire data were analysed, for 8,926 singleton children aged 9-12 years. Country-specific odds ratios for effects of maternal smoking during pregnancy on being overweight, and on obesity, were estimated using logistic regression. Heterogeneity between country-specific results, and mean effects (allowing for heterogeneity) were estimated. Positive associations between maternal smoking and overweight were seen in all countries but Romania. While not individually statistically significant, the mean odds ratio was 1.26 (95% CI 1.03-1.55), with no evidence of between-country heterogeneity. Obese children were few (2.7%), and associations between obesity and maternal smoking during pregnancy were more heterogeneous, with odds ratios ranging from 0.71 (0.32-1.57) in Poland to 5.49 (2.11-14.30) in Slovakia. Between-country heterogeneity was strongly related to average persons-per-room, a possible socioeconomic indicator, with stronger associations where households were less crowded. Estimates of dose-response relationships tended to be small and non-significant, even when pooled. Our results provide evidence of a link between maternal smoking in pregnancy and childhood overweight. Associations with obesity, though strong in some countries, were less consistent. Maternal smoking may confer an addition to a child's potential for obesity, which is more likely to be realised in affluent conditions. © Springer Science+Business Media, LLC 2009.
Rafnar T.,DeCODE Genetics Inc. |
Vermeulen S.H.,Biostatistics and HTA |
Sulem P.,DeCODE Genetics Inc. |
Thorleifsson G.,DeCODE Genetics Inc. |
And 76 more authors.
Human Molecular Genetics | Year: 2011
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 3 10 -11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. © The Author 2011. Published by Oxford University Press. All rights reserved.
PubMed | Karolinska Institutet, Danish Cancer Society, Finnish National Institute for Health and Welfare, International Agency for Research on Cancer IARC and 57 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
Hough R.L.,London School of Hygiene and Tropical Medicine |
Hough R.L.,Macaulay Institute |
Fletcher T.,London School of Hygiene and Tropical Medicine |
Leonardi G.S.,London School of Hygiene and Tropical Medicine |
And 9 more authors.
International Archives of Occupational and Environmental Health | Year: 2010
Objective Methods and results are presented for an arsenic exposure assessment integral to an epidemiological case-control study of arsenic and cancer-the European Commission funded ASHRAM (Arsenic Health Risk Assessment and Molecular Epidemiology) study carried out in some counties of Hungary, Romania and Slovakia. Methods The exposure history of each participant (N = 1,392) was constructed by taking into account how much water they consumed (as water, in drinks and in food), sources of drinking water in their various residences over their lifetime, and the concentrations of arsenic in their various water supplies measured by Hydride Generation-Atomic Absorption Spectrometry (HG-AAS). Concentrations of arsenic in previous water supplies were either derived from contemporary analyses of the same source, or from routine historical data from measurements performed by the authorities in each country. Using this approach, 80% of the recorded lifetime residential history was matched to an arsenic concentration. Seven indices of current, life time, and peak exposure were calculated. Results The exposure indices were all log-normally distributed and the mean and median lifetime average concentrations were in Hungary 14.7 and 13.3 μg l-1, Romania 3.8 and 0.7 μg l-1 and in Slovakia 1.9 and 0.8 μg l-1, respectively. Overall 25% of the population had average concentrations over 10 μg l-1 and 8% with exposure over 50 μg l-1. Conclusions Careful assessment of arsenic in drinking water supplies (both current and previous) enabled the majority of study participants' cumulative lifetime of potential exposure to arsenic in residential water to be characterised. © Springer-Verlag 2010.