**7. VDR gene polymorphisms and breast cancer**

VDR gene polymorphism is associated with the breast cancer risk [117–125] but insufficient data are available to find the relationship with breast cancer risk [126]. The studies have pointed out allelic variations in VDR gene, such as *Cdx*2, *Fok*1, *Bsm*1, *Taq*1, *Apa*1 and *Poly* A in different ethnic groups with breast cancer incidence with contradictory results [117, 118, 121, 126].

#### **7.1.** *Cdx2* **polymorphism and breast cancer**

binding domain, which results in a formation of more active transcription factor that is three amino acids shorter [103, 112]. Those individuals who have ACG sequence in the start codon, the initiation of translation occurs at the second ATG site which results in a formation of three less amino acids at NH2 terminus containing 424 amino acids. If the initiation occurs at first ATG sequence, it produces full-length VDR protein containing 427 amino acids. In the presence of restriction site, alleles are designated as 'f', whereas its absence is designated as 'F' (active form) [113]. The restriction recognition site of *Fok*1 is 5'-GGATG\*-3'; 3'-CCTAC\*-5' and enzyme

Most of the functional sequence variants identified near the 3' region of VDR gene were *Bsm*1, *Apa*1 and *Taq*1 SNP. These SNPs are in linkage disequilibrium with each other and are located in the same haplotype block. Therefore, these SNPs may have the potential to influence the mRNA stability. The *Apa*1 and *Bsm*1 are located at intron 8, whereas *Taq*1 is located at exon 9

The presence of restriction enzyme site in these SNPs is designated as lower case letter such as b, a and t, whereas absence is designated as upper case letter including B, A, T. The restriction site for Bsm1 is 5'-GAATGCN\*-3', Apa1 is 5'-GGGCC\*C-3' and Taq1 is 5'-T\*CGA-

*Poly* (A) tail is a variable number of tandem repeats (VNTR) or short tandem repeats (STR) containing variable numbers of adenine nucleotide present at the 3' UTR of VDR. *Poly* (A) is also linked with Bsm1, Apa1 and Taq1 polymorphisms and also involved in the mRNA stability

Because all four polymorphisms (*Bsm*1, *Apa*1, *Taq*1 and *Poly* (A)) are present in close proximity on the VDR gene, strong linkage disequilibrium exists among them. The two most common

**1.** baTL haplotype in which *Bsm*1 and *Apa*1 restriction sites are present, whereas *Taq*1 site is

**2.** BAtS haplotype *Bsm*1 and *Apa*1 restriction sites are absent, whereas *Taq*1 site is absent

The baTL haplotype is reported to be associated with the increase incidence of breast cancer

**1.** The long (L) *Poly* (A) sequence in which 18–24 adenine nucleotide is present, and

**2.** The short (S) *Poly* (A) sequence in which 13–17 adenine nucleotide is present.

cleaves 9/13 nucleotide downstream of the recognition site.

of VDR. It varies in length and can be divided into two types:

absent along with the presence of long *Poly* (A) repeats.

along with the presence of short *Poly* (A) repeats [115].

**6.4.** *Bsm***1‐***Apa***1‐***Taq***1 SNP**

146 A Critical Evaluation of Vitamin D - Clinical Overview

[114].

3'.

**6.5.** *Poly* **(A) repeats**

haplotypes are:

[116].

The contradictory observations were reported on the association of *Cdx*2 polymorphism and breast cancer susceptibility [125]. Recently, a meta-analysis has documented that *Cdx*2 polymorphism is linked with breast cancer susceptibility only in Africans [127]. However, no profound relations was observed between *Cdx*2 polymorphism and breast cancer risk among Pakistani population [126].

#### **7.2.** *Fok***1 polymorphism and breast cancer**

*Fok*1 polymorphism contain large consensus sequence has no relationship with breast cancer incidence [116, 117]. But the association between *Fok*1 polymorphism and breast cancer was reported in several ethnic groups [113, 120], mainly in Caucasians [128, 129]. Nemenqani et al. [121] found that *Fok*1 polymorphism is associated with the ER and PR status of breast cancer and described that *Fok*1 polymorphism has a significant interaction with the ER status but not with PR status of breast cancer.

#### **7.3.** *Bsm***1 polymorphism and breast cancer**

*Bsm*1 polymorphism is the most important functional VDR gene polymorphism, which is found to be associated with the risk of developing breast cancer [124]. However, it has also been documented that there is no relation between *Bsm*1 and breast cancer [119]. Rollison et al. [123] describe that *Bsm*1 is involved to alter the vitamin D intake and overall breast cancer risk. McCullough et al. [130] found that B allele of *Bsm*1 decreases breast cancer incidence by 20%.

#### **7.4.** *Taq***1 polymorphism and breast cancer**

Many case-control studies suggested that *Taq*1 polymorphism is not associated with breast cancer risk [119–121]. But it has been reported that *Taq*1 is one of the functional polymorphisms which is linked with increased breast cancer incidence [131, 132]. A meta-analysis on large ethnic groups revealed that the *Taq*1 polymorphism increases the risk of breast cancer development in Caucasians; however, no profound association was observed among Asians [133].

#### **7.5. Other polymorphisms and breast cancer**

Positive association of poly A [118] or Apa1 [119] was found to be reported with breast cancer risk, showing a connection between polymorphism and likelihood of having a tumour.
