Calories-reduced colon cancer depends on genes

[Guest guest]

Hi All,

How CR reduces colon and rectal cancers may depend on our genes.

Now, it seems, the vitamin D receptor (VRD) is important in this

regard

and it seems to me to be of interest that calcium and vitamin D levels

in our diets and blood are involved in the cancers' development.

Calories consumed were apparently reduced in case of colon and

rectal

cancer in the pdf-available below. This is difficult to decipher

from

the

Medline abstract below, but from Table 1 is:

Table 1 .Description of the population

Colon Cases Controls N(%) N(%)

Mean (SD) Mean (SD) p -value

Energy (kcal) 2502 (1190) 2370 (1147) <0.01

PAL (hours vigorous activity/Wk) 2.18 (3.77) 2.56 (4.10) 0.02

BMI (kg/m2) 27.7 (5.3) 26.9 (5.0) <0.01

Rectal Cases Controls N(%) N(%)

Mean (SD) Mean (SD) p -value

Energy (kcal) 2750 (1446) 2591 (1231) <0.01

PAL (hours vigorous activity/Wk) 2.53 (3.67) 3.07 (4.49) <0.01

BMI (kg/m2) 27.8 (5.6) 27.4 (4.8) 0.12

Many among us certainly are more extreme in our CR and the

correlated weights than the cases in the table, it seems to me.

In the below excerpts from the pdf's Results section are the

results

in greatly expanded version, again in a fashion that adds much to the

abstract.

Cancer Causes Control. 2004 Nov;15(9):863-72.

Associations between BMI, energy intake, energy expenditure, VDR

genotype and

colon and rectal cancers (United States).

Slattery ML, Murtaugh M, Caan B, Ma KN, Wolff R, Samowitz W.

... a population-based case-control study of colon (1174 cases and

1174

controls) and rectal (785 cases and 1000 controls) cancer was used to

evaluate

the associations. The Bsm 1, polyA, and Fok 1 VDR polymorphisms were

evaluated.

For colon cancer, those who are obese were at greater risk of colon

cancer if

they had the SS or BB (OR=3.50; 95 CI=1.75-7.03; p interaction 0.03)

or

ff

(OR=2.62; 95 CI=1.15-5.99; p interaction 0.12/) VDR genotypes. On the

other

hand, those who were least physically active were at greater risk of

colon

cancer if they had the ff VDR genotype (OR=3.46; 95 CI=1.58-7.58; p

interaction

0.05. The association between energy intake and colon cancer appears

to

be

driven more by energy intake than Bsm 1 or polyA VDR genotypes,

although there

was a significant interaction between the Fok 1 VDR polymorphism and

energy

intake and risk of both colon and rectal cancer ( p interaction 0.01

for colon

and 0.04 for rectal). These data suggest a relationship between VDR

genotype and

factors related to energy balance in modifying colorectal cancer risk.

PMID: 15577288 [PubMed - in process]

Energy balance,or the ability to maintain body weight by

balancing energy intake with energy expenditure,has

been shown to be an important factor in the etiology of

colon cancer [1 ].Several studies have detected an

increased risk of colon cancer associated with increasing

body mass index (BMI)primarily among men [2 –5 ]and

post-menopausal women who take HRT or are estrogen

positive [6,7 ];physical activity has been shown consis-

tently to reduce risk of colon cancer [8 –10 ].Associa-

tions between energy intake and colon cancer are less

consistent,with case –control studies showing increased

risk while cohort studies generally reporting no associ-

ation [11 –13 ].Animal studies show that restricting energy

intake reduces tumor development [14,15 ].Data on the

effect of energy balance on rectal cancer are less clear,

although most studies do not show obesity as being a risk

factor for rectal cancer [16,17 ].

The vitamin D receptor (VDR)4 is a nuclear

receptor involved in the regulation of many physio-

logical processes,including cell growth and differenti-

ation and metabolic homeostasis [18 ].Some studies

suggest that VDR also may be involved in insulin and

insulin-like growth factor mediated disease pathways

[19 –21 ].Polymorphisms of the VDR gene most fre-

quently studied include two restriction fragment length

polymorphisms (RFLP 's)4 in intron 8 (Bsm I and Apa I)

and one in exon 9 (Taq I).These are in linkage

disequilibrium with each other and with several 3 0

untranslated region (3 0 UTR)polymorphisms,includ-

ing a poly A repeat [22,23 ].The presence of the B,A,

and t RFLP alleles (capital letters denote absence of

restriction site;small letters presence of restriction site

for Bsm I,Apa I,and Taq I RFLP 's respectively)and

the relatively short poly-A alleles are highly correlated.

These alleles,either alone or in combination,have

been associated with increased mRNA expression of

the VDR gene,increased serum levels of 1,25-dihydr-

oxy vitamin D,and increased levels of osteocalcin [24,

25 ].VDR polymorphisms have been examined in

conjunction with colorectal adenomas and cancer and

SS and BB variants have been shown to reduce

adenoma/cancer risk [23,26 –29 ].

At the start site of the gene,a polymorphism detected

with a Fok I digest also has been studied and has been

shown to not be in linkage disequilibrium with the other

variants [23 ].The polymorphism associated with lack of

Fok 1 digestion (F)changes the start site from the #64257;rst

STG to one three codons downstream;thus the F

genotype is associated with a protein that is three amino

acids shorter than that associated with the f genotype.The

ff genotype of the Fok I polymorphism has been reported

in one study to increase risk of colorectal cancer [28 ].

Given the involvement of the VDR in metabolic

homeostasis and insulin-related mechanisms,it is pos-

sible that polymorphisms of the VDR gene are related to

components of energy balance.Studies examining VDR

polymorphisms with energy balance and cancers of the

colon and rectum have not been reported,thus support

for examination of the possible association must come

from other studies.Studies of bone mineral density and

VDR gene have shown that those with the bb VDR

genotype had a greater response to brisk walking than

those with the BB VDR genotype [30 ].Other studies,

focusing primarily on bone density,suggest that physical

activity may interact with VDR genotype to alter fasting

glucose levels [31 ].Studies also have shown that people

with early onset diabetes with the b allele of the VDR

gene were more likely to be obese than people with the B

allele [32 ].Studies examining VDR genotype and diet

have not examined associations with energy intake but

one study suggested that dietary fat,a major energy

contributing nutrient,may interact with the Fok 1

polymorphism [28 ].

Thus,although evidence is limited,it is reasonable to

determine if the associations between BMI,physical

activity,and energy intake,components of energy bal-

ance,and colon and rectal cancer are altered by VDR

genotype.We hypothesize that people with the L,b,or F

alleles of the VDR gene will be at greater risk in the

presence of obesity,physical inactivity,and high energy

intake since these alleles are associated with diabetes.

Using data from two large case –control studies of colon

and rectal cancer,we determine these associations to

obtain a better understanding of the interaction between

energy balance and VDR genotype.

...

Results

In both the colon and rectal cancer studies,the majority

of people were over 60 years of age at time of diagnosis,

were mainly non-Hispanic white (89%of colon controls

and 86%of rectal controls),and there was a slight excess

of men (roughly 56%)(Table 1).The SS or BB VDR

genotype was seen in roughly 19%of controls from the

colon cancer study and 16%of controls from the rectal

cancer study.Both the SS and BB genotypes were

inversely associated with colon cancer relative to the LL

and bb genotypes (OR =0.79;95%CI =0.56 –0.96

and OR =0.84;95%CI =0.70 –1.02 respectively).

The ff Fok 1 genotype was present in roughly 13%of

cases in both the colon and rectal cancer studies.Those

with the [ff] genotype were more likely to develop colon

cancer than those with the FF genotype (OR =1.28;

95%CI =0.97 –1.69).In both colon and rectal cancer

studies,cases ate significantly more calories and per-

formed less vigorous physical activity.BMI was signif-

icantly higher among colon cancer cases compared to

age and gender matched controls.

There was a significant interaction between BMI and

Bsm 1/polyA VDR genotype for colon cancer but not

rectal cancer (RERI p -value =0.06;multiplicative p -

value =0.03;Wald v2=0.04)(Table 2).The SS /BB

VDR genotypes (S and B alleles are in linkage disequi-

librium;see Methods)were associated with a significant

increase in colon cancer risk among obese individuals

(OR =3.50;95%CI =1.75 –7.03).A similar interac-

tion was not observed for BMI and VDR genotype for

rectal cancer.The Fok 1 VDR genotype did not interact

significantly with BMI.

There was no significant interaction between the

BSMI/polyA VDR genotypes and physical activity for

colon cancer,although for rectal cancer there was a

borderline significant interaction (p for multiplicative

interaction =0.08;Wald v2for difference in slopes

0.02)(Table 3).Those at greatest risk of colon cancer

from having no vigorous physical activity were those

with the SS or BB genotypes.There was a significant

multiplicative interaction between physical activity level

and the Fok 1 VDR genotype and colon cancer

(p =0.05;Wald v2for difference in slopes =0.08).

Those who reported high levels of physical activity were

at a two-fold increased risk of developing colon cancer if

they had the FF VDR genotype,while those with the ff

VDR genotype and no long-term vigorous physical

activity were at over a three-fold increased risk of both

colon and rectal cancer.

There was no significant interaction between the BSMI

and polyA VDR genotypes and energy intake for either

colon or rectal cancer (Table 4)while there was a

significant multiplicative interaction for energy intake,

Fok 1 VDR genotype and colon cancer (p =0.01)and a

significant additive interaction between energy intake,

Fok I genotype,and rectal cancer (p =0.04).For colon

cancer the greatest risk was associated with high levels

of energy intake that was slightly greater for those with

the ff VDR genotype.For rectal cancer,low energy

intake was associated with reduced risk of rectal cancer

among those with the ff genotype compared to those

with the ff genotype (RERI p value =0.04).

Further assessment of the colorectal cancer risk

associated with the VDR genotype was done by level of

activity,BMI,and energy intake.There were few clear

differences in VDR genotype by level of physical activity

and BMI,however it appears that rectal cancer risk was

reduced among those with the SS /BB VDR genotypes

who reported low energy intake (Table 5).Both the SS /

BB and ff VDR genotypes reduced risk of proximal

tumors among those with high energy intake;the ff

genotype also was associated with reduced risk of distal

tumors among those with high energy consumption.

Discussion

These data provide some support for an interaction

between the VDR genotype and components of energy

balance.For colon cancer,those who are obese were at

greater risk of colon cancer if they had the SS,BB,or ff

VDR genotypes.On the other hand,those who were

least physically active were at greater risk of rectal

cancer if they had the SL ,Bb ,LL ,bb,or ff VDR

genotypes.For rectal cancer it appeared that those with

the ffVDR enotype were at greatest risk if they were

sedentary.The association between energy intake and

colon cancer appears to be driven more by energy intake

than VDR genotype,although there was a significant

interaction between the Fok 1 VDR polymorphism and

both colon and rectal cancer,again with the greatest risk

associated with the ffgenotype.

Studies in animals suggest that low levels of energy

intake reduce tumor incidence and development [41 ].

Epidemiological studies further suggest that energy

balance,or the maintaining equilibrium between energy

intake and expenditure,is important in the development

of many cancers including colon cancer [42,43 ].

However,the relevant physiological mechanisms asso-

ciated with energy balance and cancer risk are less clear.

Possibilities include that energy balance results in

reduced endogenous free radical formation and oxida-

tive damage,enhanced DNA repair,enhanced immune

response,alterations in the activity of carcinogen-

metabolizing enzymes,or alterations in endogenous

hormone metabolism [43 ].Of these hypothesized mech-

anisms,those related to hormone metabolism,both sex

steroid metabolism and insulin and insulin-like growth

factors (IGF),have received the most attention,espe-

cially in conjunction with colon cancer.

Data have shown that estrogen and hormone replace-

ment therapy (HRT)are involved in colon cancer

etiology [44 ].Studies have shown that estrogen and

HRT also may modify the effect of BMI on colon cancer

risk in women [6,7 ].Other studies suggest the impor-

tance of insulin and IGF in colon cancer etiology [45 –

47 ]and the association of obesity with insulin levels [48,

49 ].Components of energy balance,mainly obesity,

physical activity,and energy intake,may be further

regulated by genetic factors thought to in #64258;uence endog-

enous hormone metabolism.The VDR gene,given its

role in metabolic regulation and its association with

insulin,is therefore one gene that may modify the effects

of obesity,physical activity,and energy intake on risk of

colorectal cancer [19,20,50 ].

Some studies suggest that obesity may be associated

with VDR genotype.Among people with early age onset

of type 2 diabetes,those with the bb VDR alleles had

more obesity [32 ].Another study did not show a

relationship between VDR genotype and body size

[51 ].Our data suggest that those with the SS or BB

VDR alleles who are obese are at an increased risk of

colon cancer.

Studies of the associations between VDR genotype

and physical activity also are limited,but have shown

that people with the bb VDR genotype respond to

physical activity in relationship to bone density more

than those with the BB VDR genotype [52 ].Another

study showed that men who were inactive and had the

BB VDR genotype were more likely to have higher

fasting glucose levels than men with other VDR geno-

types [31 ].Our data suggest the importance of physical

activity on reducing risk of colorectal cancer,but also

suggest risk associated with lack of physical activity was

offset by those with the SS or BB VDR genotypes.On

the other hand,the ffgenotype was protective against

colon cancer amongst those with high levels of physical

activity,but was deleterious in the sedentary.The ff

genotype also was associated with the highest risk of

rectal cancer in the sedentary.

There is some indication of site-specific associations,

especially at different levels of energy intake.In these

data those at low levels of energy intake have reduced

risk of rectal cancer if they also have the SS or BB VDR

genotype;those with high energy intake and the SS ,BB ,

or ffVDR genotypes were at reduced risk of proximal

and distal (#64256;genotype only)tumors.Wong and col-

leagues [28 ]have reported similar associations for

dietary fat in conjunction with the Fok I VDR polymor-

phism;those with the ffgenotype were found to be at

greater risk of colorectal cancer when dietary fat intake

was low,but not at risk in the presence of high dietary

fat.Adjustment for total fat did not alter associations in

the current study.

An intriguing pattern appears to be developing with

respect to VDR genotypes and colorectal cancer risk.

Overall there is a weak protective effect associated with

the BB /SS and ffgenotypes.Also,in a previous study

we detected an interaction between the Bsm I/polyA

VDR genotype and dietary calcium and vitamin D,but

any decreased risk of cancer was always associated with

the BB /SS genotype [53 ].In the current study there are

also many contexts (such as decreased BMI or high

physical activity)in which the SS /BB or ffgenotypes are

protective,but there are other contexts (obesity,seden-

tary life style,high energy intake,either alone or in

combination)in which these genotypes are associated

with the highest risk of colonic or rectal cancer.The fact

that the in some contexts these genotypes are protective

and in other contexts they increase risk suggests the

possibility that VDR may be acting through more than

one pathway to in #64258;uence carcinogenesis.The precise

pathway and the mechanism by which the polymor-

phisms exert effects is difficult to be sure of at this time,

as very little is known about all of the activities of VDR

and how the polymorphisms affect these activities.VDR

is known to in #64258;uence calcium metabolism,however,

and recent studies have suggested that some of its anti-

carcinogenic activity may be related to binding to bile

acids.One could speculate,then,that under conditions

of relatively good energy balance the BB /SS and/or ff

genotypes affect VDR 's actions in calcium/vitamin D

related pathways to decrease the risk of cancer,while

under conditions of poor energy balance these geno-

types affect VDR 's impact on bile acids or insulin-

related pathways.Differences in association by poly-

morphism examined may provide clues to functionality

of the relevant polymorphisms.

This study has several strengths,including the

quality of the data collected and the large sample size

available for analysis.Because of the sample size,we

have been able to assess both site-specific and sex-

specific associations.However,even with our large

sample size,we have limited power to look at both sex-

and site-specific associations simultaneously or with

combinations of BMI,level of activity,and energy

intake.Dietary data and physical activity data were

collected using detailed and validated questionnaires as

described in the methods.This is one of the #64257;rst

reports to look at multiple polymorphisms of the VDR

gene and components of energy balance.Our data

suggest that not all polymorphisms work in the same

manner.The Fok I polymorphism is not in linkage

disequilibrium with the Bsm I and polyA polymor-

phisms and may operate differently than Bsm Iand

polyA polymorphisms.With respect to cancer risk,the

Bsm I and polyA polymorphisms appeared to be more

associated with BMI,while the Fok I appeared to be

more associated with physical activity;both polymor-

phisms appeared to be associated with energy intake.

The reasons for these differences are not well under-

stood,as at the present time the impact of the various

polymorphisms on the perhaps multiple activities of

VDR is not completely understood.

In summary,these data provide some support for an

interaction between obesity and VDR genotype in risk

associated with colon cancer,suggesting some possible

genetic regulation of energy balance as it relates to colon

cancer.However,it appears that physical activity and

energy intake may be less in #64258;uenced by VDR genotype

as they relate to colorectal cancer risk.Energy intake,on

the other hand,may modify the effects of VDR genotype

of rectal cancer risk.

Cheers, Alan Pater