[show abstract][hide abstract] ABSTRACT: We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further follow-up of these chromosomal regions is warranted.
[show abstract][hide abstract] ABSTRACT: To determine whether adipose and red blood cell membrane lipids, particularly long-chain polyunsaturated fatty acids such as docosahexaenoic acid and eicosapentaenoic acid, are significantly correlated with phenotype in a family with autosomal dominant Stargardt macular dystrophy (gene locus STGD3). A mutation in the ELOVL4 gene is responsible for the macular dystrophy in this family, and its disease-causing mechanism may be its possible involvement in fatty acid elongation in the retina.
The subjects in this study included 18 adult family members known to have a 2-base pair deletion in the ELOVL4 gene. Control subjects included 26 family members without the mutation. Each subject received a complete eye examination including fundus photographs, the results of which were used to grade the severity of macular dystrophy on a 3-tier scale. Red blood cell membrane and adipose tissue lipids were analyzed as an indication of short-term and long-term dietary fatty acid intake.
When adipose lipids were analyzed, there was a significant inverse relationship between phenotypic severity and the level of eicosapentaenoic acid (r = -0.54; P = .04). When red blood cell lipids were analyzed, there were significant inverse relationships between phenotypic severity and levels of eicosapentaenoic acid (r = -0.55; P = .02) and docosahexaenoic acid (r = -0.48; P = .04).
These results indicate that the phenotypic diversity in this family may be related to differences in dietary fat intake as reflected by adipose and red blood cell lipids.
This study demonstrates that dietary factors can influence the severity of an inherited human macular dystrophy.
Archives of Ophthalmology 03/2006; 124(2):257-63. · 3.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Single-copy variants of the autosomal recessive Stargardt disease (STGD1) gene ABCR (ABCA4) have been shown to confer enhanced susceptibility to age-related macular degeneration (AMD). To investigate the role of ABCR alleles in AMD further, genotype-phenotype analysis was performed on siblings of patients with AMD who had known ABCR variants. This genetically related population provides a cohort of subjects with similar age and ethnic background for genotype-phenotype comparison to the original probands.
All available siblings of 26 probands carrying probable disease-associated ABCR variants were examined clinically. Blood samples were collected from these siblings for genotype analysis to search for the ABCR variant alleles corresponding to the isofamilial proband.
Nineteen of 33 siblings from 15 families carried the respective proband's variant ABCR allele. Some families exhibited concordance of ABCR alleles with macular degeneration phenotype, but others did not. Exudative AMD was uncommon among both probands and siblings.
Although population studies have indicated that some ABCR variant alleles may enhance susceptibility to AMD, investigation of the extent of ABCR involvement by kindred analysis is complicated by a plethora of environmental and other hereditary factors not investigated in the current study that may also play important roles.
[show abstract][hide abstract] ABSTRACT: A 5-bp deletion in ELOVL4, a photoreceptor-specific gene, has been associated with autosomal dominant (ad) macular dystrophy phenotypes in five related families, in which phenotypes range from Stargardt-like macular dystrophy (STGD3; Mendelian Inheritance in Man 600110) to pattern dystrophy. This has been the only mutation identified in ELOVL4 to date, which is associated with macular dystrophy phenotypes. In the current study, the potential involvement was investigated of an ELOVL4 gene variation in adSTGD-like and other macular dystrophy phenotypes segregating in a large unrelated pedigree from Utah (K4175).
The entire open reading frame of the ELOVL4 gene was analyzed by direct sequencing in a proband from the K4175 family. The combination of denaturing high-performance liquid chromatography (DHPLC) analysis and direct sequencing of all available family members was used to further assess segregation of identified ELOVL4 variants in the pedigree.
A complex mutation, two 1-bp deletions separated by four nucleotides, was detected in all affected members of the family. The mutation results in a frameshift and the truncation of the ELOVL4 protein, similar to the effect of the previously described 5-bp deletion.
The discovery of a second mutation in the ELOVL4 gene segregating with macular dystrophy phenotypes confirms the role of this gene in a subset of dominant macular dystrophies with a wide range of clinical expressions and suggests a role for modifying genes and/or environmental factors in the disease process.
[show abstract][hide abstract] ABSTRACT: Some previous studies have reported an improved prognosis in sporadic colon cancers with microsatellite instability, whereas others have not. In addition, relatively few of those reporting an improved prognosis controlled for tumor stage or were population-based. Therefore, we evaluated the relationship between microsatellite instability and prognosis, tumor stage, and other clinical variables in a population-based study of 1026 individuals. Microsatellite instability was determined by the noncoding mononucleotide repeat BAT-26 and the coding mononucleotide repeat in transforming growth factor-beta receptor type II. Significant relationships were seen between microsatellite instability and proximal tumor location, female gender, young and old age at diagnosis, poor histological differentiation, and low tumor stage (P < 0.01). There was a significant relationship between microsatellite instability and improved prognosis, even after adjusting for stage, with a reduction in the risk of death attributable to colon cancer of approximately 60%. Most of this risk reduction occurred in individuals with American Joint Committee on Cancer stage III tumors, although transforming growth factor-beta receptor type II mutations were associated with a significant reduction in colon cancer death in tumors with distant metastases. We conclude that microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.
[show abstract][hide abstract] ABSTRACT: The adenomatous polyposis coli (APC) gene is important in the etiology of colon cancer. Although germ-line mutations of this gene rarely occur in the population, less penetrant variants of the gene have been reported. One variant, producing an aspartate to valine change at codon 1822 (D1822V) [corrected] has been previously reported as having an allele frequency of 10%. The purpose of this study was to determine whether this D1822V [corrected] variant of the APC gene is associated with colon cancer and whether its association is influenced by other genetic or environmental factors. We used data collected as part of a multicenter study of 1,585 incident cases of colon cancer and 1,945 age- and sex-matched population-based controls to evaluate genetic, dietary, and environmental associations with the D1822V [corrected] variant of the APC gene. The frequency of the valine/valine allele at codon 1,822 was 22.8% in this population. In the control population, 61.5% were homozygote wild type, 33.3% were heterozygotes, and 5.2% were homozygote variant. Cases were slightly less likely to have the homozygous variant APC genotype than were controls [odds ratio (OR), 0.8; 95% confidence interval (CI), 0.6-1.1]; for those diagnosed after age 65, the homozygous APC variant was associated with reduced risk of colon cancer (OR, 0.6; 95% CI, 0.4-1.0). Assessment of the homozygous APC variant with dietary, genetic, and environmental factors showed that individuals with this genotype were at lower risk if they consumed a low-fat diet (OR, 0.2; 95% CI, 0.1-0.5) relative to those who were homozygous wild type and ate a high-fat diet. This finding was specific to a low-fat diet and was unrelated to other dietary variables. These results suggest that the codon 1,822 variant of the APC gene may have functional significance. Individuals who have the valine/valine variant of this gene may be at reduced risk of colon cancer if they eat a low-fat diet.
Cancer Research 03/2001; 61(3):1000-4. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ki-ras mutations are thought to be early events in the carcinogenic process leading to colon tumors. Dietary factors associated with colon cancer may be associated with these mutations. Data from a population-based, multicenter, case-control study of colon cancer were used to determine whether dietary factors are associated with Ki-ras mutations. Ki-ras mutations were detected by direct sequencing of codons 12 and 13 of the Ki-ras gene on exon 1 from DNA obtained from archival tissue. Ki-ras data were available for 1428 cases with valid interview data; data from 2410 controls were available for comparison with cases positive and negative for Ki-ras mutations. Mutations in the Ki-ras gene were detected in 32% of tumors. Of these mutations, 32.8% were G-->A transitions in the second base of codon 12 (2G-->A). Other than cruciferous vegetables, there were no nutrients or foods associated specifically with Ki-ras mutations [odds ratio (OR) for high intake relative to low intake, 0.7; 95% confidence interval (CI), 0.5-1.0]. However, evaluation of specific types of Ki-ras mutations revealed that for each of the most common types of mutation, dietary associations existed. Dietary factors involved in DNA methylation pathways were associated with 2G-->A mutations. Comparison of individuals with and without Ki-ras mutations revealed that individuals with low levels of dietary folate (OR, 0.7; 95% CI, 0.4-1.3), vitamin B6 (OR, 0.5; 95% CI, 0.3-1.0), vitamin B12 (OR, 0.6; 95% CI, 0.3-1.1), and high levels of alcohol (OR, 0.7; 95% CI, 0.4-1.1) were less likely to have a 2G-->A mutation. Individuals with high levels of dietary carbohydrate (OR, 2.0; 95% CI, 0.9-4.4) and a high glycemic index (OR, 1.9; 95% CI, 0.8-4.6) were more likely to have a G-->A transition mutation in the second base of codon 13 (5G-->A). Individuals with high levels of dietary fat (OR, 1.6; 95% CI, 0.8-3.2), saturated fat (OR, 1.7; 95% CI, 0.8-3.5), and monounsaturated fat (OR, 1.9; 95% CI, 1.0-3.7) were more likely to harbor a 2G-->T mutation. Low levels of cruciferous vegetable intake and high levels of processed meat intake also were associated with fewer 5G-->A, as reflected by the ORs (OR, 0.4; 95% CI, 0.2-1.0 and OR, 0.4; 95% CI 0.2-0.8, respectively). These data suggest that diet may be involved in disease pathways represented by specific Ki-ras mutations. However, given the limited information currently available on associations between specific genetic mutations in colon tumors and diet, these findings also should be viewed as hypothesis generating.
Cancer Research 12/2000; 60(24):6935-41. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Some previous studies have demonstrated significant results between Ki-ras mutations and tumor stage, survival, and/or other clinical variables, whereas others have not. We therefore evaluated the significance of codons 12 and 13 Ki-ras mutations in a large population-based study of 1413 individuals with colon cancer. Ki-ras mutations were identified in approximately 32% of tumors. Codon 12 mutations were significantly more common in proximal than distal tumors (29.1% versus 20.5%; P < 0.01) and in tumors of advanced stage. Tumors from men were more likely to have transition mutations and codon 12 G-->A mutations. After adjusting for age and stage, the codon 13 G-->A mutation was associated with a 40% (95% confidence interval, 0.95-2.0) increase in short-term mortality from colon cancer. In conclusion, this population-based study demonstrates important relationships between Ki-ras mutations and stage, survival, tumor location, and gender.
[show abstract][hide abstract] ABSTRACT: Microsatellite instability (MSI) has been reported to occur in approximately 10%-15% of colon tumors. MSI is characterized by the presence of mutations in tandemly repeated DNA sequences known as microsatellites. Some individuals with unstable tumors have inherited mutations in mismatch repair genes, but MSI is also observed in sporadic colon cancer. It is unknown whether lifestyle factors associated with colon cancer, such as physical activity, body size, cigarette smoking, or use of aspirin and/or nonsteroidal anti-inflammatory drugs, contribute to MSI in sporadic tumors.
Data from a population-based, case-control study of colon cancer were used. Case subjects were between 30 and 79 years of age at the time of diagnosis and included both men and women. Questionnaire data were used to obtain information on lifestyle factors. Tumor MSI was determined with the use of a panel of 10 tetranucleotide repeats and two mononucleotide repeats. A total of 1510 case subjects had valid questionnaire data and tumor DNA from which we were able to obtain MSI status. Questionnaire data were compared with lifestyle factors reported by 2410 population-based control subjects. All statistical tests were two-sided.
MSI-positive (MSI(+)) tumors were most common in older people and women and in the proximal colon. Patients with MSI(+) tumors were more likely to smoke 20 or more cigarettes a day than case subjects with MSI-negative (MSI(-)) tumors (odds ratio for being a smoker = 1.6 [95% confidence interval = 1.0-2.5] for men and 2.2 [95% confidence interval = 1.4-3.5] for women). The association between MSI(+) tumors and cigarette smoking was strongest among case subjects who started to smoke at a young age, smoked for 35 or more years, and were either current smokers or had stopped fewer than 15 years before diagnosis. A statistically significant linear trend of increased risk of MSI(+) tumors was observed with increasing amount smoked (P<.01).
This study suggests that smoking cigarettes statistically significantly contributes to MSI in colon tumors. We estimate that approximately 21% of MSI in colon tumors may be attributable to cigarette smoking.
JNCI Journal of the National Cancer Institute 11/2000; 92(22):1831-6. · 14.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the association between the angiotensinogen-6 polymorphism (AGT-6) and blood pressure levels.
Data were analysed from the first 4,322 subjects of the NHLBI Family Blood Pressure Program (FBPP), consisting of four networks (GenNet, GENOA, HyperGEN and SAPPHIRe), each conducting a multicentre observational family study to identify and characterize the genetic determinants of hypertension and blood pressure. The four studies use different designs (concordant sibpairs, discordant pairs, sibships, extended pedigrees), target different ethnic groups (Caucasian, African-American, Japanese, Chinese), and have different inclusion/exclusion criteria. However, the protocols and definitions were standardized across networks before data collection to allow maximum poolability.
Each network/racial group was analysed separately, using generalized linear models that accounted for the non-independence of family members and/or the confounding of anti-hypertensive medications as needed. The results were also pooled using a pre-planned meta-analysis technique.
AGT-6 was not significantly associated with blood pressure in any network/racial group. In the meta-analysis, the pooled effect of AGT-6 was small [hazard ratio = 1.10, 95% confidence interval (CI) = 0.99-1.22, P= 0.0647 for systolic; hazard ratio = 1.04, 95% CI = 0.89-1.21, P= 0.6383 for diastolic]. A post-hoc analysis restricting to subjects meeting JNC VI criteria for Stage I hypertension (blood pressure > 140/90 mmHg or medicated) showed a stronger statistically significant relationship for systolic blood pressure (hazard ratio = 1.44, 95% CI = 1.04-2.00, P= 0.0283).
AGT-6 has minimal to no effect on the inter-individual variation of blood pressure levels, and is at best a 'minor gene' for blood pressure in the population as a whole.
Journal of Hypertension 07/2000; 18(7):867-76. · 3.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Rigid spine syndrome is a term first proposed by Dubowitz to describe a subset of patients affected by myopathy with early spinal contractures as a prominent feature. While spinal rigidity is a nonspecific feature, found in Emery-Dreifuss muscular dystrophy and in some congenital myopathies, it is also a prominent feature in a group of patients with merosin-positive congenital muscular dystrophy, where it is generally associated with stable or only slowly progressive weakness and early respiratory insufficiency. Recently, the first locus for congenital muscular dystrophy in association with rigid spine syndrome was mapped to chromosome 1p35-p36 in consanguineous Moroccan, Turkish, and Iranian families. We present here a detailed phenotypic description of the familial syndrome linked to this locus, describing 4 siblings (3 boys and 1 girl) of Northern European-American heritage who are the offspring of a nonconsanguineous marriage. All 4 siblings were affected by hypotonia and prominent neck weakness in infancy, early spinal rigidity, and early scoliosis. After initial improvement, muscle strength stabilizes or slowly declines, and skeletal deformities and respiratory insufficiency supervene. Muscle biopsy in an affected child at age 9 months revealed minimal, nonspecific myopathic changes, leading to a diagnosis of "minimal change myopathy." Muscle biopsy in his sibling, at the age of 14 years, revealed chronic and severe myopathic (dystrophic) changes, with normal staining for laminin-2 and for proteins of the dystrophin-glycoprotein complex. A possible explanation for these biopsy findings is that magnetic resonance imaging of the thighs reveals stereotyped selective muscle involvement, with the selectivity more pronounced early in the disease course followed by widespread muscular signal abnormalities in the late stages of the disease. In this family, linkage to the chromosome 1p rigid spine syndrome locus (RSMD1) is supported by maximum LOD scores for several markers of 1.81 at theta = 0, representing the maximum statistical power possible for this family. In combination with the previous report, this syndrome is linked to the RSMD1 locus with a summated maximum LOD score of 6.29, and analysis of recombination events in our family narrows the previously reported RSMD1 locus to 3 centiMorgans.
Annals of Neurology 03/2000; 47(2):152-61. · 11.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous recessive disease characterized primarily by atypical retinitis pigmentosa, obesity, polydactyly, hypogenitalism, and mental retardation. Despite the presence of at least five loci in the human genome, on chromosomes 2q, 3p, 11q, 15q and 16q, as many as 50% of the mutations appear to map to the BBS1 locus on 11q13. The recessive mode of inheritance and the genetic heterogeneity of the syndrome, as well as the inability to distinguish between different genetic loci by phenotypic analyses, have hindered efforts to delineate the 11q13 region as a first step toward cloning the mutated gene. To circumvent these difficulties, we collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis, using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in two consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. The identification of multiple recombinants at the same position forms the basis for physical mapping efforts, coupled with mutation analysis of candidate genes, to identify the gene for BBS1.
The American Journal of Human Genetics 01/2000; 65(6):1672-9. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: In this study we examine the combined effects of Western diet, age at diagnosis, and genetic susceptibility.
We use data collected as part of an incident case-control study of colon cancer. Family history of colorectal cancer, N-acetyltransferase (NAT2), and glutathione-S-transferase (GSTM-1) are studied with Western diet and age at diagnosis.
A significant interaction between age at time of diagnosis, Western dietary pattern, and family history of colorectal cancer (p for interaction = 0.03) was detected. Those with a family history of colorectal cancer who ate a predominantly Western diet were at increased risk of colon cancer (OR 14.0, 95% CI 3.9-50.1 for < or = 55 years; OR 7.7, 95% CI 2.0-29.1 for 56-66 years; OR 1.6, 95% CI 0.8-3.2 for > or = 67 years) compared to those without a family history of colorectal cancer and low levels of a Western diet. Associations with the Western diet were stronger than individual components of the dietary pattern. Neither NAT2 nor GSTM-1 showed significant interaction with Western diet.
The extent to which diet comprising a Western dietary pattern influences risk of colon cancer is dependent on age. This dietary pattern also appears to modulate the colon cancer risk associated with a family history of colon cancer.
Cancer Causes and Control 01/2000; 11(1):1-8. · 3.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inherited mutations of the APC gene predispose carriers to multiple adenomatous polyps of the colon and rectum and to colorectal cancer. Mutations located at the extreme 5' end of the APC gene, however, are associated with a less severe disease known as attenuated adenomatous polyposis coli (AAPC). Many individuals with AAPC develop relatively few colorectal polyps but are still at high risk for colorectal cancer. We report here the identification of a 5' APC germline mutation in five separately ascertained AAPC families from Newfoundland, Canada. This disease-causing mutation is a single basepair change (G to A) in the splice-acceptor region of APC intron 3 that creates a mutant RNA without exon 4 of APC. The observation of the same APC mutation in five families from the same geographic area demonstrates a founder effect. Furthermore, the identification of this germline mutation strengthens the correlation between the 5' location of an APC disease-causing mutation and the attenuated polyposis phenotype.
Human Genetics 12/1999; 105(5):388-98. · 4.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: Febrile seizures are the most common form of childhood seizures, occurring in 2% to 5% of North American children. We report a large Utah family with 21 members affected by febrile seizures inherited as an autosomal dominant trait. All had generalized tonic-clonic seizures with onset associated with fever, consistent with the consensus febrile seizure phenotype, and none had febrile seizures beyond 6 years of age. Eighteen affected individuals had recurrent febrile seizures. Eight individuals developed afebrile seizures between ages 5 and 13 years. Afebrile seizures consisted of generalized tonic-clonic, generalized tonic, generalized atonic, simple partial, and partial complex seizure types and were associated with abnormal electroencephalographic findings in 5 individuals, all of whom were intellectually normal. We undertook linkage analysis in this family, defining the disease phenotype as febrile seizures alone. Linkage analysis in epilepsy candidate gene/loci regions failed to show evidence for linkage to febrile seizures. However, a genomewide scan and subsequent fine mapping revealed significant evidence for a new febrile seizure locus (FEB3) on chromosome 2q23-24 with linkage to the marker D2S2330 (LOD score 8.08 at theta = 0.001). Haplotype analysis defined a critical 10-cM region between markers D2S141 and D2S2345 that contains the FEB3 locus.
Annals of Neurology 11/1999; 46(4):671-8. · 11.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ABCR gene encodes a rod photoreceptor specific ATP-binding cassette transporter. Mutations in ABCR are associated with at least four inherited retinal dystrophies: Stargardt disease, Fundus Flavimaculatus, cone-rod dystrophy, and retinitis pigmentosa. A statistically significant increase in heterozygous ABCR alterations has been identified in patients with age-related macular degeneration (AMD). A pedigree is described which manifests both Stargardt disease and AMD in which an ABCR mutation cosegregates with both disease phenotypes. These data from this case report support the hypothesis that ABCR is a dominant susceptibility locus for AMD. Recent work regarding ABCR is reviewed and a model is presented in which decreased ABCR function correlates with severity of retinal disease.
Vision Research 08/1999; 39(15):2537-44. · 2.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dentinogenesis imperfecta type III (DGI-III) is an autosomal-dominant disorder of dentin formation which appears in a tri-racial southern Maryland population known as the "Brandywine isolate". This disease has suggestive evidence of linkage to the long arm of human chromosome 4 (LOD score of 2.0) in a family presenting with both juvenile periodontitis and DGI-III. The purpose of this study was to screen a family presenting with only DGI-III to determine if this locus was indeed on chromosome 4q. Furthermore, we wanted to determine if DGI-III co-localized with dentinogenesis imperfecta type II (DGI-II), which has been localized to 4q21-q23. Therefore, a large kindred from the Brandywine isolate was identified, oral examination performed, and blood samples collected from 21 family members. DNA from this family was genotyped with 6 highly polymorphic markers that span the DGI-II critical region of chromosome 4q. Analysis of the data yielded a maximum two-point LOD score of 4.87 with a marker for the dentin matrix protein 1 (DMP1) locus, a gene contained in the critical region for DGI-II. Our results demonstrated that the DGI-III locus is on human chromosome 4q21 within a 6.6 cM region that overlaps the DGI-II critical region. These results are consistent with the hypothesis that DGI-II is either an allelic variant of DGI-III or the result of mutations in two tightly linked genes.
Journal of Dental Research 07/1999; 78(6):1277-82. · 3.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12.