We examined the relationships between folate and methionine intake, serum homocysteine levels (as a biomarker for folate metabolism), and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism genotype and risk of oral cancer in a population-based, case-control study in Puerto Rico. Structured questionnaires were used to collect information on demographic factors, usual adult diet, and tobacco and alcohol use. Oral epithelial cells and blood samples were collected from a subset of subjects. Analyses were conducted by logistic regression, adjusting for age, sex, lifetime smoking and lifetime alcohol intake, with the following numbers of cases/controls, respectively: dietary data (341/521); MTHFR genotype (148/149); and homocysteine (60/90). Although increased folate intake was associated with decreased oral cancer risk [adjusted odds ratio (OR) in highest vs. lowest quartile = 0.6, 95% confidence interval (CI): 0.4, 1.0, P(trend) = 0.05)], this finding was due almost entirely to folate intake from fruit (adjusted OR = 0.4, 95% CI: 0.2, 0.6; P(trend) = 0.0001), whereas other dietary folate sources showed no clear association. Methionine intake and serum homocysteine levels were not associated with oral cancer risk. Subjects with the MTHFR C677T homozygous variant (TT) genotype had a nonsignificantly lower risk, and risk patterns tended to differ by level of folate, methionine, alcohol intake and smoking, although the power to detect significant associations in subgroups of these variables was low. Risks for oral cancer are not folate specific; preventive recommendations for this disease should emphasize the importance of a healthy diet, including substantial intake of fruits.
The HLA region has long been implicated in sporadic and familial Hodgkin disease (HD), with recent case-control studies suggesting that HLA class II loci predispose to sporadic nodular sclerosis HD (NSHD). To determine whether this predisposition extends to familial HD, HLA class II loci (DRB1, DQA1, DQB1, DRB3, DRB4, and DRB5) and transporter associated with antigen processing (TAP) loci (TAP1, TAP2) were investigated in 100 members of 16 families with at least 2 confirmed cases of HD. With the use of the transmission disequilibrium test, evidence for linkage disequilibrium with familial HD and, in particular, familial NSHD was obtained for the DRB1*1501-DQA1*0102-DQB1*0602 haplotype, the TAP1 allele encoding Ile at residue 333, and the DRB5-0101 allele. These 3 markers were in linkage disequilibrium and may not represent independent susceptibility regions. Use of a family-based approach excludes population stratification as an explanation for these findings. The HLA class I region on chromosome 6 (particularly the B5, B8, B18, and A1 alleles) has been weakly but consistently associated with both sporadic and familial HD. [9][10][11] In familial HD, 60% to 70% of cases of which may be linked to this region, 12 there is significant HLA class I haplotype sharing among affected individuals. 11,13 More recent evidence suggests a role of HLA class II antigens. The DPB1*0301 allele was implicated in HD, 14,15 but an analysis of multiple HLA class II loci (eg, DRB1, DQA1, DQB1, and DPB1) discounted an independent role of DPB1. 16 Klitz et al 16 conducted a case-unrelated control study and reported that NSHD (but not other histologic subtypes) is positively associated with the DRB1*1501, DQB1*0602, and DRB1*1104 alleles and negatively associated with the DRB1*1601, DRB1*0404, and DQB1*0303 alleles. They concluded that susceptibility to NSHD was probably due to several HLA class II loci, including DRB1, DQB1, and perhaps other, yet-to-be-identified loci.We investigated whether alleles at HLA class II loci (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5) and transporter associated with antigen processing (TAP) loci (TAP1 and TAP2) play a role in familial HD. We tested for linkage disequilibrium with familial HD and, in particular, with familial NSHD. Study design SubjectsSixteen white families with at least 2 members with histologically confirmed HD (9 sibling pairs; 4 parent-child pairs; 1 sibling-sibling-parent trio; 1 sibling-sibling-cousin trio; and 1 cousin-cousin-uncle trio) were ascertained through self-referral or physician referral to the National Cancer Institute between 1978 and 1993. Thirteen of these families had been studied previously in relation to HLA class I haplotypes 13 or EBV. 5 Four patients were excluded because they did not provide a blood sample for genetic analysis. The present analysis included 28 affected members (23 NSHD, 5 non-NSHD) with at least one parent available for genotyping; 3 affected family members (all non-NSHD) with both parental genotypes unknown; and 69 unaffected family members (27 parent...
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