Vitamin D receptor gene polymorphism(s) and breast cancer risk in north Indians.
BACKGROUND
Vitamin D (1,25-dihydroxyVitamin D3) has shown experimentally anticarcinogenic effects and is thought to protect against breast cancer. The actions of Vitamin D are mediated via the Vitamin D receptor (VDR), and the polymorphisms at 3'UTR region of this gene are associated with the risk and progression of breast carcinoma. The current study is an attempt to examine the association of these variations with breast cancer risk in north Indians.


METHODS
A total of 160 cases and 140 control subjects were studied for the polymorphisms at 3' end of the VDR gene. A polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method and fragment analysis was performed to determine ApaI and TaqI polymorphisms and variable length poly-A microsatellite repeats. Linkage disequilibrium (LD) was calculated for each pair of polymorphisms. Unadjusted and adjusted odds ratios for breast cancer with genotypes comprising the polymorphic sites were calculated to understand their role towards breast cancer susceptibility.


RESULTS
Patient's with long poly-A repeat showed a significant association with disease (chi 2 = 9.52, df = 2, P <or= 0.01). Compared to subjects having two S alleles (SS), odds ratios (and 95% CI) were 0.75 (0.45-1.23) and 2.49 (1.18-5.27) for subjects having genotypes SL and LL, respectively. Among matched pairs (age), the poly-A LL genotype was found significantly associated with increased risk of breast cancer among early-onset cases (P = 0.02). The unconditional logistic regression analysis demonstrated a significant association between grade and LL genotype [(unadjusted odds ratio (95% CI): 4.45 (1.87, 10.63); adjusted odds ratio: 4.66 (1.88, 11.53)]. No significant association was observed for the VDR ApaI (chi 2 = 1.00, df = 2, P = 0.60) and TaqI polymorphism (chi 2 = 0.35, df = 2, P = 0.83). Although, strong LD was not observed among these polymorphic sites, it denies the total equilibrium at the same time. Based on haplotype distribution, the most common one observed among cases and controls was ATS while, genotype AATTLL had shown a significant association with the breast cancer risk (P = 0.02).


CONCLUSIONS
The results indicate that the VDR poly-A polymorphism is significantly associated with breast cancer risk in north Indians especially with early onset disease. Although, ApaI and TaqI did not show any significant association with the disease when analyzed in isolation, but TaqI might modulate the risk associated with L alleles. Further, understanding the functional role of these variants residing on the VDR haplotype associated with disease susceptibility may suggest novel approaches for breast cancer prevention and therapy.
Chakraborty
Anurupa
A
Institute of Pathology, Safdarjang Hospital Campus, New Delhi 110029, India.
Mishra
Ashwani K
AK
Soni
Abha
A
Regina
Thodum
T
Mohil
R
R
Bhatnagar
D
D
Bhatnagar
A
A
Chintamani
Chintamani
C
Sharma
P C
PC
Saxena
Sunita
S
D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007194:India / Q000453:epidemiology; D015810:Linkage Disequilibrium; D016015:Logistic Models; D018895:Microsatellite Repeats; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D012150:Polymorphism, Restriction Fragment Length; D018167:Receptors, Calcitriol / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
D020413:3' Untranslated Regions; D018167:Receptors, Calcitriol