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Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.

ABSTRACT: BACKGROUND:Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between APC genotype and phenotype but there remains significant intrafamilial variation. In the Min mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes. AIMS:To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of modifier genes. METHOD:We systematically examined polyp numbers in colectomy specimens from patients with classical FAP. Variation both between and within families was analysed. Formal modelling of the segregation of disease severity in families was performed RESULTS:There was strong evidence for a relationship between site of mutation and the number of colorectal polyps, with germline mutations in the "cluster region" causing the most severe disease and those with mutations between codons 1020 and 1169 having the mildest disease. In addition to this genotype-phenotype relationship, we found evidence for non-APC linked genetic modifiers of disease expression. First degree relatives had more similar polyp counts than more distant relatives. Formal modelling of the segregation of disease severity in families revealed further evidence for the action of modifier genes, with a best fit to a mixed model of inheritance. CONCLUSION:Our data provide good evidence to support the hypothesis that modifier genes influence the severity of FAP in humans.

SUBMITTER: Crabtree MD

PROVIDER: S-EPMC1773342 | biostudies-literature | 2002 Sep

REPOSITORIES: biostudies-literature

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Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.

Crabtree M D MD Tomlinson I P M IP Hodgson S V SV Neale K K Phillips R K S RK Houlston R S RS

Gut 20020901 3

<h4>Background</h4>Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between APC genotype and phenotype but there remains significant intrafamilial variation. In the Min mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes.<h4>Aims</h4>To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of ...[more]

PMID: 12171967

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Project description:BACKGROUND:We have recently shown that the severity of human colonic familial adenomatous polyposis (FAP) varies in a manner consistent with the action of modifier genes. These modifier genes may harbour common alleles which increase the risk of colorectal cancer (CRC) in the general population. Analyses have suggested several common polymorphisms as risk alleles for CRC. METHODS:We determined the association between the severity of colonic FAP (151 patients) and polymorphisms in MTHFR, NAT1, NAT2, GSTM, GSTT, cyclin D1, E-cadherin, and APC. All of these loci have been suggested as influencing the risk of CRC. Colonic FAP severity was quantitated as the number of polyps per colectomy specimen, standardised for colon size. We analysed the relationship between disease severity and genotype at the polymorphic site, making allowance for the position of the germline APC mutation. RESULTS:We identified significant associations between more severe disease and the absence of the NAT1*10 genotype in the whole group of patients. In a subset of patients with germline mutations in the so-called "mutation cluster region", there was an association between more severe disease and the presence of NAT2*fast alleles. In the whole patient set, a relatively strong association existed between more severe disease and possession of both the NAT1*non-10 and NAT2*fast genotypes. There was weak evidence for an association between the APCT1493C allele and more severe disease in the whole patient group. No consistent association with disease severity was found for the other polymorphisms. CONCLUSION:The severity of colonic FAP may be modified by alleles at the NAT1 and/or NAT2 loci. The identity of any functional variation remains unknown as NAT1*10 appears to be non-functional and there is linkage disequilibrium between alleles at multiple sites within these loci which are adjacent on chromosome 8p22. While evidence from this study cannot be conclusive, our data suggest that NAT1 and NAT2 variants may explain an approximately twofold increase in polyp number in the FAP colon.

Dataset Information

Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.

Publications

Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.

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