By Traci Pantuso, ND, MS

Adjunct Faculty, Bastyr University, Seattle; Owner, Naturopathic Doctor, Harbor Integrative Medicine, Bellingham, WA

Dr. Pantuso reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • The vitamin D receptor gene encodes the nuclear hormone vitamin D3 receptor protein, which is a transcriptional regulatory factor and affects mineral metabolism and other pathways involved in immune response and cancer.
  • The effect of vitamin D supplementation on the risk of advanced colorectal adenomas may vary because of the vitamin D receptor genotype rather than the magnitude of change in circulating 25(OH)D levels.
  • Consuming 1,000 IU vitamin D3 per day increased the risk of advanced adenoma in participants with a homozygous or heterozygous G allele at rs7968585 by 41%, but in participants who had a homozygous AA genotype at rs7968585, vitamin D3 reduced the risk of advanced adenomas by 64%.

SYNOPSIS: In a follow-up study, researchers investigated whether single nucleotide polymorphism (SNP) genotypes in the vitamin D and calcium pathways are associated with the authors’ previous findings that daily intake of 1,000 IU vitamin D3 and/or 1,200 mg calcium did not reduce colorectal adenoma risk. The authors concluded that vitamin D3 supplementation benefits in the prevention of advanced colorectal adenomas may vary depending on vitamin D receptor genotype status.

SOURCE: Barry EL, et al. Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: A randomized clinical trial. JAMA Oncol 2017;3:628-635.

Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States and is ranked as the fourth cause of cancer death worldwide.1 In the United States, CRC is the third leading cause of cancer deaths in women and the second in men.1 Since the 1980s, the overall rates of CRC diagnosis in the United States have been dropping, which is attributed to increased screening.1 However, CRC diagnosis in young adults has increased compared to people born in 1950, with people born in 1990 having two times the risk of colon cancer (incidence rate ratio [IRR], 2.40; 95% confidence interval [CI], 1.11-5.19) and four times the risk of rectal cancer (IRR, 4.32; 95% CI, 2.19-8.51).1 People who are younger than 55 years of age have a 58% likelihood of being diagnosed with late-stage disease.1 Risk factors for CRC include obesity, drinking alcohol, eating red meat, physical inactivity, and smoking.1 In other studies, body mass index (BMI), physical activity, smoking, diet, and use of other supplements have been correlated with circulating 25(OH)D levels.2

In 2015, Baron et al published findings from the Vitamin D/Calcium Polyp Prevention Study investigating the chemopreventive effects of daily intake of 1,000 IU vitamin D3 and/or 1,200 mg calcium supplementation compared to placebo on colorectal adenoma risk.3 The results were contrary to their hypothesis, in that they found that neither vitamin D nor calcium taken daily alone or in combination reduced colorectal adenoma risk.

The Vitamin D/Calcium Polyp Prevention Study was a double-blind, placebo-controlled trial conducted at 11 academic medical centers and outpatient clinics in the United States between 2004 and 2008. The study included male and female participants aged 45-75 years who had at least one large bowel adenoma removed within 120 days prior to enrollment and no known polyps remaining after complete colonoscopy. Exclusion criteria included serious intestinal disease, familial colorectal cancer syndromes, serum calcium outside the normal range, 25(OH)D levels < 12 ng/mL or > 90 ng/mL, creatinine > 20% above the upper normal limit, and contraindications to the study treatment. The physician recommended the colonoscopic follow-up interval, which was either three or five years. The study sample size was determined by the hypothesized treatment effect on adenoma recurrence. Participants were instructed to avoid personal calcium and vitamin D supplement use during the trial. To determine which participants were unlikely to follow study procedures, the investigators performed a blind placebo run-in period, after which time participants were randomized to 1,000 IU vitamin D3, 1,200 mg calcium carbonate, both, or placebo. Women could elect to be given calcium and randomized to calcium alone or calcium and vitamin D3. Every six months, participants were contacted by telephone and interviewed regarding adherence to study treatment, medication and supplement use, dietary calcium and vitamin D intake, colorectal procedures, and any illnesses. The study endpoint was all adenomas diagnosed at the planned three- to five-year follow-up colonoscopy. Serum 25(OH)D levels were measured at baseline and at one year.

To further elucidate the relationship between vitamin D, calcium, and colorectal cancer, the authors analyzed associations between their previously identified single nucleotide polymorphism (SNP) genotypes and colorectal adenoma risk among the eligible participants from the Vitamin D/Calcium Polyp Prevention Study. An SNP is a variation in the nucleotide sequence at a single position in the gene. SNPs have the potential to alter the amino acid sequence of a protein and in turn affect the structure and activity of a protein. SNPs are referred to by relative SNP ID number (rs) and/or may have other names associated with them.

Of the 2,259 randomized participants, 2,088 had colonoscopic outcome data and were eligible for this study; 386 of the 2,088 participants were not eligible either because genotype data were missing (n = 39) or self-identification at time of enrollment was of non-white race or Hispanic identification (n = 347), leaving 1,702 participants for genotype analysis. The 1,702 participants had an average age of 58 years, were 65% male, and 57% had one adenoma < 1 cm on colonoscopy and 19% had at least one advanced adenoma.

The three- to five-year risk of advanced colorectal adenomas differed significantly among participants in the vitamin D3 group based on genotype at two SNP locations (rs731236 and rs7968585) in the VDR gene. Participants who had a homozygous AA genotype, which means they had the nucleotide adenine (A) on both strands of DNA at rs7968585 (n = 436; 25.8%) in the vitamin D group, had reduced risk of advanced adenomas by 64% (relative risk [RR], 0.36; 95% CI, 0.19-0.69; P = 0.002) with an absolute risk reduction of 9.3%. (See Table 1.) Individuals with one or two guanine (G) alleles (74.1%; n = 1,251) had a 41% increased colorectal adenoma risk with vitamin D supplementation (RR, 1.41; 95% CI, 0.99-2.00; P = 0.05) with an increased absolute risk of 3.4%.

Table 1: Vitamin D3 Supplementation and Risk of Adenoma by rs7968585 Genotype

SNP

VDR GENOTYPE

Relative Risk (RR) and Absolute Risk (AR)

Rs7968585

(n = 1,687)

AA (n = 436)

64% reduced colorectal adenoma risk with vitamin D3 supplementation
(RR, 0.36; 95% CI, 0.19-0.69; P = 0.002) with an absolute risk reduction of 9.3%.

AG or GG

(n = 1,251)

41% increased colorectal adenoma risk with vitamin D3 supplementation
(RR, 1.41; 95% CI, 0.99-2.00; P = 0.05) with an increased absolute risk of 3.4%.

Adapted from: Barry EL, Peacock JL, Rees JR, et al. Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: A randomized clinical trial. JAMA Oncol 2017;3:628-635.

Vitamin D3 supplementation was found to interact significantly with rs7968585 genotype (IRR, 3.88; P < 0.001 for interaction). An association of low serum 25(OH)D level with risk of advanced adenoma in participants who were not assigned to the vitamin D3 supplementation group was significantly modified by the rs7968585 status. (See Table 2.) Participants who had one or two G alleles at rs7968585 and were in the lowest season-specific quintile of serum 25(OH)D level had an 82% higher risk (RR, 1.82; 95% CI, 0.99-3.34) of advanced adenoma, while those with AA genotype were associated with a 69% lower risk of advanced adenoma (RR, 0.31; 95% CI, 0.08-1.19; P = 0.02 for interaction). (See Table 2.) The polymorphisms mentioned here do not alter the VDR amino acid sequence; however, these SNPs may affect mRNA, protein levels, or protein isoforms.

Table 2: Significant Interactions With rs7968585 Genotype and Lowest Season-specific Quintile of Serum 25(OH)D and Risk of Adenoma

SNP

VDR GENOTYPE

Relative Risk (RR) and Absolute Risk (AR)

P value

interaction

Rs7968585

AA

69% lower risk of colorectal adenoma (RR, 0.31; 95% CI, 0.08-1.19)

P = 0.02

AG or GG

82% higher risk of colorectal adenoma (RR, 1.82; 95% CI, 0.99-3.34)

Adapted from: Barry EL, Peacock JL, Rees JR, et al. Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: A randomized clinical trial. JAMA Oncol 2017;3:628-635.

COMMENTARY

Decreased colorectal adenoma risk has been shown to be associated with increased intake of both vitamin D and calcium and with increased vitamin D serum levels in both epidemiological and preclinical studies.3,4 The results of this study demonstrating that a 41% increased risk of advanced adenoma in participants with a homozygous or heterozygous G allele at rs7968585 with vitamin D3 supplementation is interesting. Particularly interesting is the low serum 25(OH)D level and 82% increased risk of advanced adenoma in the non-supplemented group with the G allele at rs7968585. Understanding the relationship between rs7968585 genotype and advanced adenoma risk will require more research.

In a 2014 Cochrane Review, which included 18 randomized trials with 50,623 participants, vitamin D supplementation did not appear to decrease or increase cancer occurrence.5 The participants in the studies included were mostly elderly community-dwelling women.5 The bulk of the epidemiological evidence has demonstrated that increased circulating 25(OH)D levels decreases risk for colorectal cancer.3 However, other studies have shown that higher 25(OH)D levels increased colorectal cancer risk in Finnish men.6

Recent research including data from the Vitamin D/Calcium Polyp Prevention Study demonstrated the emergence of a much more complicated picture between vitamin D and cancer risk.7

A nested case control study investigating VDR gene polymorphism and CRC risk in Asians also found that SNPs in the VDR gene were associated with CRC risk and were modified by 25(OH)D serum levels.8 Another recent study investigating the levels of free and bioavailable 25(OH)D in CRC patients in China found that low levels of free and bioavailable 25(OH)D were associated with poor overall survival, and free 25(OH)D was an independent prognostic factor for overall survival.9 Total 25(OH)D was found not to be associated with overall survival in CRC patients, as had been stated previously in the literature.9,10

A number of variables may be involved in vitamin D and CRC risk. Participant populations selected for studies may be more nuanced than previously thought, as we learn more about genetic variation in the VDR gene and also in the vitamin D metabolism pathway. Also, whether the participants included in a study have precancerous adenomas or cancerous adenomas may be an important factor in how vitamin D supplementation and 25(OH)D levels interact with the VDR in the transcription of genes.

The strengths of the Vitamin D/Calcium Polyp Prevention Study are its randomized trial design and large sample size. There was a high follow-up rate and good adherence to the trial. Limitations to this study included the low dose of vitamin D3 (1,000 IU per day); some critics have mentioned that perhaps a higher dose may have decreased risk. Also, the authors conceded that their approach to identifying the SNP was not comprehensive and the power was limited to advanced adenoma outcomes for rare variants. In addition, the study population included non-Hispanic/white men and women. SNP frequency has been shown to differ between races and ethnic groups, which limits the generalizability of the findings of this study. African Americans have the highest incidence of CRC and in studies have had lower serum levels of 25(OH)D.8 Another limitation was the exclusion of participation by individuals who had a serum 25(OH)D level of < 12 ng/mL; these individuals potentially could have shown the greatest benefit to supplementation.8

Recommending vitamin D3 supplements is further complicated by the variation in the actual vitamin D3 dose in supplements compared to label claims. According to Labdoor, a company that tests supplements, an analysis of 19 of the best-selling vitamin D supplements in the United States found that all the products exceeded their vitamin D label claims by 22% and six products exceeded their label claims by 40%.11 This makes it difficult for providers to recommend an exact dose of vitamin D3, especially since genetic variation in the vitamin D3 pathway is a major factor.

Bottom Line

The implications of vitamin D supplementation in individuals at higher risk of colorectal cancer is complicated. Providers should discuss the risks and benefits with patients so they can make educated decisions regarding supplementation. More research is needed before clinicians confidently can recommend vitamin D supplementation to patients at risk for CRC or currently diagnosed with CRC. This study demonstrates that rs7968585 VDR SNP genotype modifies CRC risk and interacts with 25(OH)D serum levels. It also demonstrated that 1,000 IU of vitamin D could modify adenoma risk, which deserves more thorough consideration of vitamin D dosages that are recommended, particularly when vitamin D supplements exceed their label claims by 22-40%. Further research and guidelines are needed to understand the risks and benefits of vitamin D supplementation in this population.

REFERENCES

  1. Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974-2013. J Natl Cancer Inst 2017;109:djw322.
  2. Gong C, Long Z, Yu Y, et al. Dietary factors and polymorphisms in vitamin D metabolism genes: the risk and prognosis of colorectal cancer in northeast China. Sci Rep 2017;7:8827.
  3. Baron JA, Barry EL, Mott LA. Et al. A trial of calcium and vitamin D for the prevention of colorectal adenomas. N Engl J Med 2015;373:1519-1530.
  4. Barry EL, Rees JR, Peacock JL, et al. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab 2014;99:E2133-E2137.
  5. Bjelakovic G, Gluud LL, Nikolova D et al. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev 2014;(6):CD000085.
  6. Weinstein SJ, YuK, Horst RL, et al. Serum 25-hydroxyvitamin D and risks of colon and rectal cancer in Finnish men. Am J Epidemiol 2011;173:499-508.
  7. Rai V, Abdo J, Agrawal S, Agrawal DK. Vitamin D receptor polymorphism and cancer: An update. Anticancer Res 2017;37:3991-4003.
  8. Sheng S, Chen Y, Shen Z. Correlation between polymorphism of vitamin D receptor TaqI and susceptibility to colorectal cancer. A meta-analysis. Medicine 2017;96:e7242.
  9. Yang L, Chen H, Zhao M, Peng P. Prognostic value of circulating vitamin D binding protein, total free and bioavailable 25-hydroxy vitamin D in patients with colorectal cancer. Oncotarget 2017;8:40214-40221.
  10. Kupfer SS, Chun Li Y, Bissonnette M. Vitamin D and calcium for colorectal adenoma chemoprevention. Nutr Cancer 2017;69:167.
  11. Labdoor. Top 10 vitamin D supplements. Available at: http://bit.ly/2ysDVmY. Accessed Aug. 31, 2017.