Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

BACKGROUND: Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. METHODS: To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. RESULTS: There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.80 and OR = 1.34, 95% CI: 1.00-1.79 respectively). CONCLUSION: This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility

SNPLINK: multipoint linkage analysis of densely distributed SNP data incorporating automated linkage disequilibrium removal.

SUMMARY: SNPLINK is a Perl script that performs full genome linkage analysis of high-density single nucleotide polymorphism (SNP) marker sets. The presence of linkage disequilibrium (LD) between closely spaced SNP markers can falsely inflate linkage statistics. SNPLINK removes LD from the marker sets in an automated fashion before carrying out linkage analysis. SNPLINK can compute both parametric and non-parametric statistics, utilizing the freely available Allegro and Merlin software. Graphical outputs of whole genome multipoint linkage statistics are provided allowing comparison of results before and after the removal of LD

Causation of chronic lymphocytic leukemia - Insights from familial disease

Causation of chronic lymphocytic leukemia - insights from familial disease. In Western countries B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia. Evidence from epidemiological studies and family studies strongly supports the notion that a subset of CLL involves inherited susceptibility. Identification of genes predisposing to CLL should be useful for diagnosis and treatment, as well as serving as a model for B-cell tumorigenesis in general. Here, we review the current status of knowledge about inherited susceptibility to CLL. (C) 2003 Elsevier Science Ltd. All rights reserved

Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia.

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

The predicted impact of coding single nucleotide polymorphisms database.

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

Dominantly inherited cutaneous small-vessel lymphocytic vasculitis maps to chromosome 6q26-q27.

Outside the context of hereditary deficiencies of complement and IgA, Mendelian inherited predisposition to small vessel lymphocytic vasculitis (SVLV) has rarely been documented. Here we report a large, multigenerational family segregating symmetrical cutaneous SVLV affecting the cheeks, thighs and hands. In all affected family members the disease presented in early infancy and there was no evidence for an association with systemic disease. Skin biopsy of lesions showed a lymphocytic vasculitis with red blood cell extravasation. Complementary studies, with extensive investigation focused on dysfunction of the immunological system were negative. The pattern of inheritance of SVLV in the family was compatible with an autosomal dominantly acting disease gene with incomplete penetrance. To localize the disease causing gene in the family a genome-wide linkage search was conducted using a high-density SNP array. Haplotype construction and analysis of recombination events permitted the minimal interval defining the disease locus to be refined to a 4.7 Mb region on chromosome 6q26-q27. The genes CCR6 and GPR31, which map to the linked region represent plausible candidates for the disease on the basis of their biological function. Extensive screening of both genes by mutational analysis failed to identify a deleterious mutation in the family

Genomewide linkage searches for Mendelian disease loci can be efficiently conducted using high-density SNP genotyping arrays

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

Variants in the GH-IGF axis confer susceptibilityto lung cancer

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 = 5.4 × 10(−5)), AKAP9 M463I (OR = 1.32, P = 1.0 × 10(−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