RESUMO
Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c --> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.
Assuntos
Glicosilfosfatidilinositóis/deficiência , Manosiltransferases/genética , Mutação , Regiões Promotoras Genéticas , Sequência de Aminoácidos , Sequência de Bases , Feminino , Genes Recessivos , Hemoglobinúria/genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Convulsões/genética , Trombose/genéticaRESUMO
Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family. Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1alpha, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development, and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a(-/-) mice.
Assuntos
Cromossomos Humanos Par 10/genética , Diabetes Mellitus/genética , Mutação/genética , Fenótipo , Fatores de Transcrição/genética , Animais , Sequência de Bases , Western Blotting , Cerebelo/patologia , Biologia Computacional , Consanguinidade , Ligação Genética , Técnicas Histológicas , Humanos , Lactente , Escore Lod , Camundongos , Camundongos Mutantes , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Pâncreas/patologia , Linhagem , Análise de Sequência de DNARESUMO
Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Família , Ligação Genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 3 , Análise Mutacional de DNA , Saúde da Família , Dosagem de Genes , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We report the genetic analysis of a large multi-generational family composed of 144 individuals in which 11 members have been diagnosed with chronic lymphocytic leukaemia (CLL). The observation of a significant over-representation of monoclonal B-cell lymphocytosis (MBL) in unaffected family members strongly supports MBL being a surrogate marker of carrier status. A genome-wide linkage scan of the family using high-density 10K single nucleotide polymorphisms provided no significant evidence for a single gene model of disease susceptibility, inviting speculation that susceptibility to CLL has a more complex basis. The absence of a correlation in IGHV usage between affected family members does however argue strongly against exposure to a single super-antigen in disease development.
Assuntos
Linfócitos B/imunologia , Mapeamento Cromossômico , Família , Ligação Genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Linfocitose/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Análise Mutacional de DNA/métodos , Citometria de Fluxo , Genes de Cadeia Pesada de Imunoglobulina/genética , Estudo de Associação Genômica Ampla , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/imunologia , Linfocitose/imunologia , Pessoa de Meia-IdadeRESUMO
Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas.
Assuntos
Adenoma/etiologia , Neoplasias Colorretais/etiologia , Ácido Fólico/metabolismo , Recidiva Local de Neoplasia/etiologia , Polimorfismo Genético , Adenoma/genética , Adenoma/metabolismo , Adulto , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Ferredoxina-NADP Redutase/genética , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , RiscoRESUMO
The role of inherited genetic factors in the etiology of chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs) is now well established. Significant familial aggregation of CLL and B-cell LPDs has been demonstrated, but the mode of inheritance is unknown. Identifying genes that when mutated confer an increased risk of these diseases is of immediate clinical relevance in terms of primary and secondary interventions. Furthermore, their identification provides for a greater understanding of the mechanisms of B-cell tumorigenesis in general. Here we review the current status of knowledge relating to inherited susceptibility to CLL and the strategies that are being employed to identify disease-causing mutations.
Assuntos
Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Feminino , Humanos , Masculino , Mutação , LinhagemRESUMO
ARLTS1, a member of the Ras superfamily and putative tumor-suppressor gene resides at chromosome 13q14, a region commonly deleted in hematopoietic and solid tumors. Previously, the truncating single nucleotide polymorphism (SNP) of ARLTS, G446A (W149X) has been reported to act as a multi-site tumor susceptibility allele. To explore the relationship between polymorphic variation in ARTLS1 and risk of chronic lymphocytic leukemia (CLL) we analyzed germline DNA from 413 cases and 471 healthy controls for W149X and five additional coding SNPs, S99S, P131L, L132L, C148R, and E164K. A high proportion of the cases were familial, thereby empowering detection of an association. None of the SNPs were individually significantly associated with risk of CLL and there was no evidence for epistatic interaction between loci. Our study does not support the postulate that variants of ARLTS1 influence the risk of CLL.
Assuntos
Fatores de Ribosilação do ADP/genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Genomewide linkage searches aimed at identifying disease susceptibility loci are generally conducted using 300-400 microsatellite markers. Genotyping bi-allelic single nucleotide polymorphisms (SNPs) provides an alternative strategy. The availability of dense SNP maps coupled with recent technological developments in highly paralleled SNP genotyping makes it practical to now consider the use of these markers for whole-genome genetic linkage analyses. Here, we report the findings from three successful genomewide linkage analyses of families segregating autosomal recessively inherited neonatal diabetes, craniosynostosis and dominantly inherited renal dysplasia using the Affymetrix 10K SNP array. A single locus was identified for each disease state, two of which are novel. The performance of the SNP array, both in terms of efficiency and precision, indicates that such platforms will become the dominant technology for performing genomewide linkage searches.
Assuntos
Predisposição Genética para Doença , Genômica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Polimorfismo de Nucleotídeo Único , Sequência de Aminoácidos , Craniossinostoses/genética , Diabetes Mellitus/genética , Feminino , Ligação Genética , Genoma Humano , Genótipo , Humanos , Nefropatias/genética , Masculino , Dados de Sequência Molecular , Linhagem , Alinhamento de SequênciaRESUMO
We report a family with an unusual form of autosomal dominant spondyloepiphyseal dysplasia characterized by infantile-onset disproportionate short stature with relative shortening of the spine, thoracic kyphosis, lumbar lordosis, scoliosis and premature osteoarthritis of the joints especially of the hips. Radiological findings include mild platyspondyly, vertebral end plate irregularity, irregular femoral necks, and dysplasia of the capital femoral epiphyses with flattening and irregularity present from childhood and mild variable epiphyseal dysplasia elsewhere in the skeleton. Intrafamilial variability is observed in the degree of short stature, severity of spinal and hip involvement and the age of onset of symptoms and complications. We demonstrate that this dysplasia is due to a glycine to alanine substitution in the COL2A1 gene (p.Gly862Ala), thereby expanding the phenotypic spectrum of dysplasias associated with defects in type II collagen.
Assuntos
Colágeno Tipo II/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Idade de Início , Idoso , Substituição de Aminoácidos , Sequência de Bases , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , DNA/genética , Análise Mutacional de DNA , Feminino , Genes Dominantes , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/patologia , Linhagem , Fenótipo , Mutação PuntualRESUMO
We report a genomewide linkage analysis of a large consanguineous family segregating autosomal recessively inherited neonatal diabetes and the identification of a novel neonatal diabetes locus. Neonatal diabetes was characterized by low levels of circulating C-peptide with very low to undetectable levels of insulin in the presence of severe hyperglycemia unresponsive to insulin infusion. A dense genomewide linkage search of the family was undertaken using a first generation 10K single nucleotide polymorphism chip containing 10,044 markers. A region of homozygosity harboring the neonatal diabetes disease gene on chromosome 10p12.1-p13 was identified (multipoint logarithm of odds score 3.25). There is a strong history of type 2 diabetes in carriers of the disease gene. It is likely that chromosome 10p12.1-p13 may harbor a maturity-onset diabetes of the young or type 2 diabetes gene.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 10/genética , Diabetes Mellitus/genética , Alelos , Consanguinidade , Frequência do Gene , Genes Recessivos , Ligação Genética , Genoma Humano , Genótipo , Haplótipos , Heterozigoto , Humanos , Recém-Nascido , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Nonsynonymous single nucleotide polymorphisms (nsSNP) have the potential to affect the structure or function of expressed proteins and are, therefore, likely to represent modifiers of inherited susceptibility. We have classified and catalogued the predicted functionality of nsSNPs in genes relevant to the biology of cancer to facilitate sequence-based association studies. Candidate genes were identified using targeted search terms and pathways to interrogate the Gene Ontology Consortium database, Kyoto Encyclopedia of Genes and Genomes database, Iobion's Interaction Explorer PathwayAssist Program, National Center for Biotechnology Information Entrez Gene database, and CancerGene database. A total of 9,537 validated nsSNPs located within annotated genes were retrieved from National Center for Biotechnology Information dbSNP Build 123. Filtering this list and linking it to 7,080 candidate genes yielded 3,666 validated nsSNPs with minor allele frequencies > or =0.01 in Caucasian populations. The functional effect of nsSNPs in genes with a single mRNA transcript was predicted using three computational tools-Grantham matrix, Polymorphism Phenotyping, and Sorting Intolerant from Tolerant algorithms. The resultant pool of 3,009 fully annotated nsSNPs is accessible from the Predicted Impact of Coding SNPs database at http://www.icr.ac.uk/cancgen/molgen/MolPopGen_PICS_database.htm. Predicted Impact of Coding SNPs is an ongoing project that will continue to curate and release data on the putative functionality of coding SNPs.
Assuntos
Algoritmos , Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Bases de Dados Genéticas , Humanos , Prognóstico , RNA Mensageiro/biossínteseRESUMO
The P2X7 receptor, a plasma membrane ATP-gated ion channel that plays a role in lymphocyte apoptosis, has been suggested to be involved in the development of chronic lymphocytic leukemia (CLL). P2X7 is polymorphic with 1513A and 1513C alleles encoding fully active and nonfunctional proteins, respectively. We evaluated the significance of the P2X7-A1513C polymorphism on CLL risk by genotyping 424 patients and 428 healthy controls. To empower detection of an association, we included in our analysis 106 familial cases. Allele frequencies were identical in cases and controls irrespective of whether cases were familial or sporadic (frequency of the C allele was 0.17 and 0.17, respectively). The odds ratio of CLL associated with the C allele was 1.03 (95% confidence interval: 0.80-1.31). A meta-analysis of this study and five other smaller published studies provides no evidence of relationship between this P2X7 polymorphism and risk of CLL (odds ratio = 0.99, 95% confidence interval: 0.74-1.32).
Assuntos
Predisposição Genética para Doença/epidemiologia , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo Genético , Receptores Purinérgicos P2/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Receptores Purinérgicos P2X , Reino Unido/epidemiologiaRESUMO
Folate availability is critical for DNA integrity, required for the transfer of methyl groups in the biosynthesis of thymidilate. Reduction of 5,10-methylenetetrahydrofolate, a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate, the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). The MTHFR polymorphisms C677T and A1298C have been shown in some studies to alter the risk of a range of different malignancies. We evaluated the role of the C677T and A1298C polymorphisms on chronic lymphocytic leukemia (CLL) risk by genotyping 832 patients and 886 healthy controls. The odds ratio of CLL associated with 677CT and 677TT genotypes were 1.02 [95% confidence interval (95% CI), 0.83-1.24] and 0.90 (95% CI, 0.66-1.24), respectively. The odds ratio of CLL associated with 1298AC and 1298CC genotypes were 0.97 (95% CI, 0.79-1.18) and 0.88 (95% CI, 0.62-1.24), respectively. This data indicate that the MTHFR polymorphisms C677T and A1298C do not significantly contribute to an inherited genetic susceptibility to CLL.
Assuntos
Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de RiscoAssuntos
Fatores de Ribosilação do ADP/genética , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RiscoAssuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Idoso , Quinase do Ponto de Checagem 2 , Dano ao DNA , Análise Mutacional de DNA , Feminino , Deleção de Genes , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P = .03), IL19 S213F (P = .001), LILRA4 P27L (P = .004), KLRC4 S29I (P = .007), and CD5 V471A (P = .002); and DNA response genes POLB P242R (P = .04) and TOPBP1 S730L (P = .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (IgV(H)) mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available.
Assuntos
Ensaios Clínicos Fase III como Assunto , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Dano ao DNA/genética , Feminino , Genótipo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Taxa de SobrevidaRESUMO
Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders display familial aggregation. To identify a susceptibility gene for CLL, we assembled families from the major European (ICLLC) and American (GEC) consortia to conduct a genome-wide linkage analysis of 101 new CLL pedigrees using a high-density single nucleotide polymorphism (SNP) array and combined the results with data from our previously reported analysis of 105 families. Here, we report on the combined analysis of the 206 families. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. After the removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage (NPL) score of 3.02 (P = .001) on chromosome 2q21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a common recessive model of disease susceptibility (HLOD = 3.11; P = 7.7 x 10(-5)), which was significant at the genome-wide level. In addition, 2 other chromosomal positions, 6p22.1 (corresponding to the major histocompatibility locus) and 18q21.1, displayed HLOD scores higher than 2.1 (P < .002). None of the regions coincided with areas of common chromosomal abnormalities frequently observed in CLL. These findings provide direct evidence for Mendelian predisposition to CLL and evidence for the location of disease loci.
Assuntos
Mapeamento Cromossômico , Família , Ligação Genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos , Análise Mutacional de DNA/métodos , Feminino , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , LinhagemRESUMO
We conducted a large-scale association study to identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), analyzing 992 patients and 2707 healthy controls. To increase the likelihood of identifying disease-causing alleles we genotyped 1467 coding nonsynonymous single nucleotide polymorphisms (nsSNPs) in 865 candidate cancer genes, biasing nsSNP selection toward those predicted to be deleterious. Preeminent associations were identified in SNPs mapping to genes pivotal in the DNA damage-response and cell-cycle pathways, including ATM F858L (odds ratio [OR] = 2.28, P < .0001) and P1054R (OR = 1.68, P = .0006), CHEK2 I157T (OR = 14.83, P = .0008), BRCA2 N372H (OR = 1.45, P = .0032), and BUB1B Q349R (OR = 1.42, P = .0038). Our findings implicate variants in the ATM-BRCA2-CHEK2 DNA damage-response axis with risk of CLL.
Assuntos
Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Idoso , Proteínas Mutadas de Ataxia Telangiectasia , Estudos de Casos e Controles , Ciclo Celular/genética , Quinase do Ponto de Checagem 2 , Dano ao DNA/genética , Reparo do DNA/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR=1.72, P=0.0075) and XRCC4 I137T (OR=1.31, P=0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer.
Assuntos
Hormônio do Crescimento Humano/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Somatomedinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Apoptose/genética , Estudos de Casos e Controles , Reparo do DNA/genética , Feminino , Predisposição Genética para Doença , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Penetrância , Transdução de Sinais , Somatomedinas/metabolismo , Reino UnidoRESUMO
To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97). To validate associations, we performed a kin-cohort analysis on the 14 704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publicly available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses.