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T Polymorphism and Distal Colorectal Adenoma Risk1
Department of Preventive Medicine, University of Southern California, Los Angeles, California 90089-9181 [A. J. L., K. D. S., C. M. E., A. D., R. W. H.], and Divisions of Gastroenterology, Bellflower [E. R. L.], and Sunset [H. D. F.], Kaiser Permanente Medical Centers, Los Angeles, California 90027
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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T), is
associated with enzyme thermolability and a reduction in the conversion
of 5,10-methyltetrahydrofolate (5,10-MTHF) into
5-methyltetrahydrofolate. We assessed the association between
homozygosity for the MTHFR 677CT genotype
(TT) and colorectal adenoma risk in a large
sigmoidoscopy-based case-control study of members of a prepaid health
plan in Los Angeles. MTHFR genotype was determined for
471 cases and 510 age-, sex-, clinic-, and sigmoidoscopy-date-matched
controls. Information on RBC and plasma folate levels were analyzed for
331 cases and 350 controls. When compared with the presence of at least
one wild-type allele (CT/CC), the odds ratio (OR) for
the TT genotype was 1.19 [95% confidence interval
(CI), 0.77–1.76] after adjusting for race and the matching factors.
Compared with those in the lowest quartiles of RBC and plasma folate
and a wild-type allele, adenoma risk was increased for
TT homozygotes in the lowest folate quartiles (genotype:
OR, 2.04 and 95% CI, 0.6–7.0; OR, 1.84 and 95% CI, 0.6–7.0 for RBCs
and plasma folate, respectively) and decreased in TT
homozygotes in the highest quartiles (genotype: OR, 0.82 and 95% CI,
0.32–2.10; OR, 0.65 and 95% CI, 0.22–1.95, respectively). There was
also a significant interaction between TT genotype and
the increased adenoma risk associated with alcohol. These data are
consistent with an interaction between MTHFR genotype
and folate availability. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A common polymorphism in the MTHFR gene, in which a cytosine
at position 677 is replaced by a thymine (677CT), causes an
alanine to valine substitution at that position. Those with the
TT genotype have a thermolabile enzyme with about half the
activity of the wild-type enzyme at 46°C (3)
.
Homozygosity for the valine substitution was reported recently to be
associated with increased plasma homocysteine but only in people with
low plasma folate levels (4, 5, 6, 7, 8, 9)
, demonstrating both the
functional consequences of the TT genotype and the
dependence of those consequences on available folates.
Three recent studies have reported on the relationship between the MTHFR TT genotype and CRC risk (10, 11, 12) . Two groups reported a significantly decreased CRC risk in men with the TT genotype, relative to men with either the wild-type (CC) or heterozygous (CT) genotype (10 , 11) . Chen et al. (13) subsequently extended these studies to adenomatous polyps, reporting a nonsignificantly increased risk of adenomas in women with the TT genotype in the Nurses’ Health Study. More recently, Ulrich et al. (14) reported an OR for TT compared with CC individuals of 0.8 (0.5–1.3) and a decreasing relative risk with increasing folate intake (OR, 0.7; 95% CI, 0.3–1.3) for TT homozygotes consuming >434 µg/day compared with CC homozygotes consuming >434 µg/day folate. The Ulrich et al. (14) data also suggested interactions between intakes of vitamins B12, and B6 with MTHFR genotype, with increased adenoma risk among those with lowest B12, and B6 intakes. Thus the relationship between MTHFR genotype and adenomatous polyps remains unclear.
Colorectal adenomas are known to be clinical precursors of CRC (15) , and low folate diets have been associated with an increased risk of colorectal adenomas. There are a number of advantages to studying colorectal adenomas instead of CRCs as the end point of interest in epidemiological studies involving dietary exposures. It is possible to select subjects who are relatively asymptomatic so that symptoms do not cause a change in diet. Similarly, most adenomas are too small to have an effect on blood or plasma nutrient levels. Finally, the induction period for adenomas is substantially shorter than for colon cancer; therefore, nutrient measurements made at the time of an epidemiological study are closer in time to the presumed etiological events.
We report here on a large sigmoidoscopy-based case control study of colorectal adenomas in which we estimated the effect of the MTHFR genotype and assessed modification of this effect by levels of RBC, plasma, and estimated total folate intake from foods and dietary supplements. Our results confirm previous findings of an interaction between MTHFR TT genotype and folate availability risk of colorectal adenomas.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Clinical and Questionnaire Data.
Additional details of subject recruitment and data collection have been
described elsewhere (16)
. Briefly, cases were individuals
diagnosed with their first adenoma during screening sigmoidoscopy, and
controls were drawn from the same population but had no adenomas at
sigmoidoscopy and no history of adenomas. Adenoma data
(e.g., location, size, and number) were obtained from Kaiser
pathology reports. Participants provided nondietary data during a
45-min in-person interview an average of 5 months after sigmoidoscopy.
For dietary data, we used a 126-item, semiquantitative food frequency
questionnaire (17)
that inquired about diet in the year
before sigmoidoscopy. The questionnaire was mailed, to be completed
before the personal interview and then reviewed by the interviewer at
the time of the interview.
Standard methods were used to calculate nutrient intake (18) . We used the Nutrition Data System (base version 21) as a nutrient database for foods (19) . For each subject, the reported frequency of consumption of each item on the questionnaire was multiplied by the nutrient content of the amount generally eaten, and total nutrient intake was obtained by summing, across foods, the amount each nutrient contributed. Data on the nutrient content of supplements were obtained from the Harvard School of Public Health.4 Vitamin and dietary supplement data were self reported by either brand name (for multivitamins) or by the nutrient content/day (for single nutrient supplements) on the food frequency questionnaire.
Red Cell and Plasma Folate.
Details of RBC folate determination are described more completely in
Bird et al. (20)
. Briefly, a fasting blood
sample was drawn in the morning from 500 cases and 533 controls. RBCs,
plasma, and whole blood folate were determined for a subsample of cases
and controls, consisting of the first 368 samples collected from male
subjects and the first 313 samples collected from female subjects.
The first 561 whole blood samples were assayed by using Quantaphase radioassay kits (Bio-Rad Laboratories, Hercules, CA) and a Beckman Gamma 4000 gamma counter (Beckman Instruments, Inc., Fullerton, CA). The last 120 samples were assayed with Quantaphase II kits. A direct comparison of individual folate values obtained by both kits, in our laboratory, indicated that transformation of Quantaphase II values into Quantaphase values could be obtained accurately by the linear regression formula derived by Bio-Rad Laboratories (21) . We calculated red cell folate values from whole blood folate concentrations and corrected for hematocrit and plasma folate levels, according to an established formula (22) .
MTHFR Genotype.
Genotype was determined by the PCR-RFLP method of Frosst et
al. (3)
using their published primer pairs.
Amplification was performed in a total reaction mixture of 15 µl
containing 1.5 µl each of 10x buffer, deoxynucleotide triphosphates,
and each primer; 0.1 µl of DNA polymerase, 0.9 µl of
MgCl2, and 3 µl of template DNA, using an
initial denaturation at 94°C for 5 min, followed by 30 cycles of
94°C for 30 s, 62°C for 30 s, and 72°C for 30 s,
with a final extension at 72°C for 5 min. The reactions were stopped
by chilling to 4°C. Restriction digestion was performed by adding 5
µl of digestion mix [5 units of HinfI (Boehringer
Mannheim, Mannheim, Germany) mixed with 0.5 µ1 of digestion buffer H
(Boehringer Mannheim)] and 4 µ1 of double-distilled
H2O directly to the PCR product and digesting at
37°C for 2 h. Digestion was stopped by chilling to 4°C.
Digested PCR products were visualized by ethidium bromide on a 3.5%
Native Agarose Gel (Life Technologies, Grand Island New York). All
samples with inadequate DNA amplification or unclear results were
genotyped at least three times by the same technician. A random 10%
sample of each 96-well microtiter plate was genotyped twice by a
technician who was blinded to case-control status and the original
genotyping results. All retested samples gave the same genotype
reading.
Statistical Analysis.
Exposure was defined as homozygosity for the valine substitution
(TT). Homozygous wild-type individuals (CC) were
combined with heterozygotes (CT) as a single "unexposed"
group, to increase statistical power in stratified analyses. Initial
analyses in which heterozygotes were removed from the comparison group
were essentially the same as those in which they were combined with
homozygous wild-type individuals and are not presented.
RBC and plasma folate, alcohol consumption, and other stratification variables were categorized into quartiles. Category boundaries were determined from the exposure distribution of the entire sample. Nutritional and physiological exposures, such as calories and BMI were entered into the models as continuous variables.
We used t tests and ANOVA to compare mean plasma and RBC folate between levels of genotype and Pearson product correlation coefficients to determine correlations between the different measures of folate status. Statistical tests for correlations or differences in mean values were done using the natural log scale. Initial estimates of the primary genotype effect were obtained with both conditional logistic regression, controlling for race, and an unconditional logistic regression in which the matching factors, age, sex, clinic, and sigmoidoscopy examination date, as well as race, were included. Because the results were essentially identical, only the results of the unconditional analysis are reported here.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DNA for genotype determination had been used up in prior analyses for 20 of the remaining 1092 subjects (9 cases and 11 controls), leaving a total of 1072 cases for the current analysis. Genotype information was missing for 91 of these subjects (8.5%), 47 cases (9.1%) and 44 controls (7.9%). Missing genotype information generally occurred when subjects had refused to donate blood (n = 59) or when no PCR product was obtained after three tries (n = 30). Genotype could not be clearly assigned for two individuals with amplified DNA. An analysis in which we assumed that all subjects with missing genotypes were either CC or CT (unexposed) or that they were all TT (exposed) did not change the adjusted ORs by >2%. RBC and plasma folate values for stratified analyses were determined as described above.
Among interviewed subjects, the indications for sigmoidoscopy were routine for 45% of cases and 44% of controls, whereas 16% of cases and 13% of controls were referred for sigmoidoscopy for specific minor symptoms. The indication for sigmoidoscopy was not available for the remaining 39% of cases and 43% of controls. The average depth of penetration of the flexible sigmoidoscope was 55 cm for cases (SD, 11 cm) and 59 cm for controls (SD, 5 cm).
Table 1
shows the characteristics of the study population. This Kaiser
Permanente population was predominantly male, white, and had a mean age
>67 years.
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. Table 2
presents the association between TT genotype and
colorectal adenomas in this population. There was no overall effect of
genotype on colorectal adenoma risk (OR, 1.19; CI, 0.78–1.81).
Additional adjustment for alcohol use, estimated methionine intake,
dietary vitamin B12, BMI, or any other adenoma
risk factor identified previously in this study population did not
result in a >10% change in this estimate. We had no data on vitamin
B6. The estimated OR for the TT
genotype in those with adenomas 
10 mm was 1.14 (CI, 0.72–1.81),
whereas in those with adenomas <10 mm, the estimated OR was 1.19 (CI,
0.66–2.17).
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Matching factor-adjusted ORs were computed for each of the four ethnic groups separately. The main effect of genotype was essentially identical for Whites and Hispanics (OR, 1.29 and 95% CI, 0.75–2.20; OR, 1.29 and 95% CI, 0.58–2.90, respectively). Adjusted ORs for Black and Asian subjects were both <1.0 (OR, 0.50 and 95% CI, 0.05–5.3; OR, 0.53 and 95% CI, 0.11–2.49, respectively), but heterogeneity tests were not statistically significant. Excluding Blacks and Asians from the analysis did not materially effect the results of the unstratified analysis, except to broaden the confidence intervals. The small number of exposed cases (3 Blacks and 8 Asians) were insufficient for further stratified analysis.
Table 3
shows the joint effect of MTHFR genotype and folate on
adenoma risk. For those with RBC folate levels in the lowest quartile
(<165 ng/ml), subjects with the TT genotype had
approximately twice the adenoma risk of those with at least one
wild-type allele. At the highest folate levels, adenoma risk was <1.0
for both TT homozygotes and those with a wild-type allele.
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There was a small correlation between dietary folate intake and
either RBC or plasma folate, although at this sample size, all values
were statistically significant (Table 4)
. RBC folate, but not plasma folate, varied significantly by genotype
(Table 5)
.
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. The MTHFR TT genotype significantly modified the effect of
alcohol on adenoma risk (Pinteraction
= 0.012). Neither methionine nor vitamin B12
intakes were associated with adenoma risk in this population, and
MTHFR genotype did not modify these null results.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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150% greater adenoma risk
than those in the lowest quartile of alcohol consumption who had at
least one wild-type allele. However, for those reporting no alcohol
consumption, TT homozygotes appeared to have a 40% lower
adenoma risk than those in the same alcohol group with at least one
wild-type allele. It is important to note that because this was a sigmoidoscopy-based study and the entire colon was not examined in controls, these results are limited to adenomas occurring on the left side of the colon, within reach of the sigmoidoscope. If the MTHFR TT genotype is differentially associated with right-sided adenomas, as reported recently for right-sided CRCs (12) , then we may have underestimated the genotype/folate associations in this population by including a small number of individuals with right-sided adenomas in the control group. Approximately 15–17% of subjects with no family history and no adenomas at sigmoidoscopy may have one or more adenomas beyond the reach of the sigmoidoscope (25 , 26) . Because adenoma prevalence is high in this age group (27) , the use of endoscopically screened controls minimized the likelihood of disease misclassification for left-sided adenomas.
Additionally, only subjects with minor or no symptoms were eligible for this study, and the majority of subjects for whom a reason for sigmoidoscopy referral was recorded were either asymptomatic or had only minor symptoms, implying that symptoms from colorectal disease were not important causes of selection into this study or of changed dietary or other behavior that would bias responses to either the dietary questionnaire or the folate measures. Finally, our response rates were relatively high (84% for cases and 82% for controls). We believe these characteristics helped to minimize any potential selection and information biases in this study population.
A possible interaction between MTHFR genotype and plasma folate on colorectal neoplasia risk has been reported by some groups but not by others. Ulrich et al. (14) reported an OR of 1.5 for those with a TT genotype compared with an OR of 0.9 for those with the CC genotype, relative to those in the highest folate tertile and the CC genotype. Ma et al. (11) studied the association between MTHFR genotype and CRC, reporting a significant decrease in CRC risk in men with plasma folate above 3 ng/ml and a slight increase in risk (OR, 1.33; 95% CI, 0.34–5.17) relative to those with a wild-type allele and plasma folate >3 ng/ml. However, CRC risk was similarly increased, compared with the same baseline, in those with low folate intakes and at least one wild-type allele (OR, 1.49; 95% CI, 0.76–2.94). Neither Chen et al. (10) nor Slattery et al. (12) observed an increase in CRC risk in TT homozygotes in any folate group, whereas both noted a decreased risk among those with the highest folate intakes and two thermolabile alleles in some groups. In a prospective study of colorectal adenoma, Chen et al. (13) reported an increasing risk with increasing dietary folate intake among those with a TT genotype and a decreasing risk with increasing folate among those with a wild-type allele, when both groups were compared with those in the lowest folate tertile and at least one wild-type allele (13) .
A possible interaction between folate status and MTHFR genotype has been reported consistently in studies of plasma tHCY (4 , 5 , 8 , 28) . Although adenoma risk may be etiologically more complex than moderately elevated plasma tHCY, it is possible that these two different outcomes generally reflect a similar set of biological changes in folate metabolism. MTHFR activity is the rate-limiting step in determining the distribution of methyl groups for trans-methylation activities and nucleotide synthesis. The MTHFR product, 5-MTHF, is well known to be a major component in the pathogenesis of moderate homocysteinemia (2 , 29) . Kim et al. (29) recently reported that plasma tHCY was a more efficient measure of functional 5-MTHF deficiency, when compared with either RBC or plasma folate. Recently, Deloughery et al. (4) reported that plasma tHCY reached undetectable levels at significantly lower plasma folate levels in TT homozygotes than in those with at least one wild-type allele. Similar findings were reported by Malinow et al. (8) and Nelen et al. (9) in separate studies of MTHFR genotype and folate supplementation in moderate homocysteinemia. If generalizable, this finding suggests that intracellular homocysteine levels may be controlled with less available folate in those with a thermolabile MTHFR enzyme. If this is also the case in colonic epithelium, then a similar mechanism could also affect the shift from an increased to a decreased risk of colon neoplasia as plasma folate levels increase to moderate levels.
We can only speculate about the biological mechanisms underlying an apparently exaggerated response to folate availability in TT homozygotes. A simple explanation would be that chronic MTHFR inefficiency, over a lifetime, is associated with compensatory mechanisms. An increase in folate absorption, recycling efficiency, MTHFR synthesis, or all three processes could support a higher ratio of available to unavailable intracellular tetrahydrofolate, providing a relative advantage to TT homozygotes when 5-MTHF levels are sufficient or only moderately low. However, as folate levels fall, such compensations would eventually fail. The resulting shortage of 5,10-MTHF for maintaining nucleotide pool balances (30 , 31) and eventually 5-MTHF for controlling the SAM:SAH ratio (2) might become severe, especially in rapidly dividing tissues such as the colon. At this point, we would expect an increase in the adverse outcomes associated with excess uracil incorporation into DNA (32) and, eventually, methylation abnormalities (24) .
The MTHFR TT genotype was associated with significantly higher RBC and nonsignificantly lower plasma folate in this study population, and neither was substantively correlated with dietary folate. This is also similar to associations reported by others (4 , 7 , 11 , 33 , 34) and emphasizes the usefulness of RBC and plasma folate, rather than dietary folate, as indices of folate status in future studies. It is unclear why MTHFR genotype was significantly related only to plasma folate in this population.
Excess alcohol intake is associated with multiple potentially procarcinogenic changes, including the induction of several phase I enzymes (e.g., CYP-2E1) as well as folate inhibition (35) . A significant interaction between MTHFR genotype and increasing alcohol intake, as observed here, implicates folate metabolism as an important intermediate in the higher adenoma risk of individuals with high alcohol intake, because any effect of MTHFR genotype must involve this critical folate metabolic pathway at some level. On the other hand, we did not see either the main effects of, or genotype interactions between, dietary methionine and B12 intakes, (14) or age (12 , 14) on adenoma risk in this study population, most likely because this group of largely older males did not vary enough with respect to these variables.
The thermolabile MTHFR variant may be one of the most common genetic determinants of tHCY levels discovered to date (3 , 4 , 7 , 9 , 28) . In this study, we have observed an increased adenoma risk in those at the lowest plasma and RBC folate quartiles and a decreased adenoma risk in those with higher plasma or RBC Folates. These data are reminiscent of reports that plasma tHCY may reach undetectable levels at significantly lower plasma folate levels in TT homozygotes than in those with at least one wild-type allele (4 , 8 , 9) , providing independent evidence that the functional consequences of the MTHFR genotype are dependent on folic acid levels. Larger studies of populations with a wide range of plasma folate values will be needed to specify the nature of this interaction.
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Acknowledgments |
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Footnotes |
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1 Supported by USPHS Grant 1RO1CA51923 from the
National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at Department of Preventive Medicine, University of Southern
California, Los Angeles, CA 90089-9181.
3 The abbreviations used are: MTHFR,
methylenetetrahydrofolate reductase; 5-MTHF, 5-methyltetrahydrofolate;
5,10-MTHF, 5,10-methylenetetrahydrofolate; SAM,
S-adenosyl methionine; SAH, S-adenosyl
homocysteine; tHCY, plasma total homocysteine; OR, odds ratio; CI,
confidence interval; BMI, body mass index; CRC, colorectal cancer.
4 L. Sampson, personal communication, 1992.
Received 2/26/99; revised 3/15/00; accepted 4/12/00.
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K. Robien and C. M. Ulrich 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview Am. J. Epidemiol., April 1, 2003; 157(7): 571 - 582. [Abstract] [Full Text] [PDF]
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S.-W. Choi, S. Friso, G. G. Dolnikowski, P. J. Bagley, A. N. Edmondson, D. E. Smith, and J. B. Mason Biochemical and Molecular Aberrations in the Rat Colon Due to Folate Depletion Are Age-Specific J. Nutr., April 1, 2003; 133(4): 1206 - 1212. [Abstract] [Full Text] [PDF]
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 T. Marugame, E. Tsuji, C. Kiyohara, H. Eguchi, T. Oda, K. Shinchi, and S. Kono Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas Int. J. Epidemiol., February 1, 2003; 32(1): 64 - 66. [Abstract] [Full Text] [PDF]
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U. B Fallon Commentary: Colon cancer, folate and genetic status Int. J. Epidemiol., February 1, 2003; 32(1): 67 - 70. [Full Text] [PDF]
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T. Keku, R. Millikan, K. Worley, S. Winkel, A. Eaton, L. Biscocho, C. Martin, and R. Sandler 5,10-Methylenetetrahydrofolate Reductase Codon 677 and 1298 Polymorphisms and Colon Cancer in African Americans and Whites Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1611 - 1621. [Abstract] [Full Text] [PDF]
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M. M. de Jong, I. M. Nolte, G. J. te Meerman, W. T. A. van der Graaf, E. G. E. de Vries, R. H. Sijmons, R. M. W. Hofstra, and J. H. Kleibeuker Low-penetrance Genes and Their Involvement in Colorectal Cancer Susceptibility Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1332 - 1352. [Abstract] [Full Text] [PDF]
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E. Giovannucci Epidemiologic Studies of Folate and Colorectal Neoplasia: a Review J. Nutr., August 1, 2002; 132(8): 2350S - 2355. [Abstract] [Full Text] [PDF]
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S. J. James, S. Melnyk, M. Pogribna, I. P. Pogribny, and M. A. Caudill Elevation in S-Adenosylhomocysteine and DNA Hypomethylation: Potential Epigenetic Mechanism for Homocysteine-Related Pathology J. Nutr., August 1, 2002; 132(8): 2361S - 2366. [Abstract] [Full Text] [PDF]
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S.-W. Choi and J. B. Mason Folate Status: Effects on Pathways of Colorectal Carcinogenesis J. Nutr., August 1, 2002; 132(8): 2413S - 2418. [Abstract] [Full Text] [PDF]
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C. M. Ulrich, J. Bigler, R. Bostick, L. Fosdick, and J. D. Potter Thymidylate Synthase Promoter Polymorphism, Interaction with Folate Intake, and Risk of Colorectal Adenomas Cancer Res., June 1, 2002; 62(12): 3361 - 3364. [Abstract] [Full Text] [PDF]
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S. J. Weinstein, G. Gridley, L. C. Harty, S. R. Diehl, L. M. Brown, D. M. Winn, E. Bravo-Otero, and R. B. Hayes Folate Intake, Serum Homocysteine and Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype Are Not Associated with Oral Cancer Risk in Puerto Rico J. Nutr., April 1, 2002; 132(4): 762 - 767. [Abstract] [Full Text] [PDF]
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M. T. Goodman, K. McDuffie, B. Hernandez, L. R. Wilkens, C. C. Bertram, J. Killeen, L. Le Marchand, J. Selhub, S. Murphy, and T. A. Donlon Association of Methylenetetrahydrofolate Reductase Polymorphism C677T and Dietary Folate with the Risk of Cervical Dysplasia Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1275 - 1280. [Abstract] [Full Text] [PDF]
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