Genetic studies:
Genetic variations in the genes of vitamin D synthesis and its
metabolism have been linked with many diseases in the world populations
(114, 115, 116).
Vitamin D receptor (VDR) is a type of nuclear receptor that after
binding its ligand calcitriol (active form of vitamin D) regulates
expression of many genes (117, 118). The variations in the VDR gene have
been associated with several disease conditions in different populations
(119, 120, 121, 122).
Many studies in Pakistani population showed the association of some
diseases with certain types of SNPs in VDR gene. The Apa1 SNP present in
the 3สน intronic region of VDR may affects the stability of mRNA of VDR
(123). Some SNPs in VDR gene were found to be associated with Type 1
diabetes (T1D) (124). Another study was conducted to probe a link
between T1D and two SNPs of VDR (Fok1 and Apa1) in children (125). The
results of this study showed vitamin D deficiency was prevalent in
studied group but no significant association was found of any of these
SNPs with T1D. It may be due to very small sample size (44 cases and 44
controls).
SNPs in VDR gene have been studied with the relevance of vitamin D
levels in healthy women of Pakistani population (126). Two SNPs (Fok1
and Taq1) were found significantly associated with vitamin D deficiency
and insufficiency.
Vitamin D circulates in the body after binding with vitamin D binding
protein (VDBP); a type of transporter protein (127). A case control
study showed significant association of group-specific 1-2 (Gc 1-2)
genotype with the risk of T2DM in the subjects (128). Another study
found a significant link between vitamin D deficiency and IF-IF genotype
of VDBP gene with acute myocardial infarction (AMI) in Pakistani
population (74). Breast cancer is quite prevalent in Pakistani women
(83). The analyses of 360,933 breast cancer cases revealed that Asian
Pakistani/Indian women had higher frequency of breast cancer than
Caucasians (129). Meta analyses of some studies carried out to probe the
role of variation in VDR gene with the onset of breast cancer, showed
its positive correlation in different world populations (130). Many
studies in Pakistani population revealed the association of variations
in VDR gene with breast cancer. A case-control study (103 cases and 161
controls) showed the GG genotype of cdx-2 SNP may increase the risk of
breast cancer in young females belonged to the Southern Punjab (131).
The Tru9I SNP in VDR gene was studied in 228 patients and 503 controls
and found that this SNP could be associated with the risk of this
disease (132). It found from the same study that the mutant Tru9I was
found significantly associated with grade IV carcinoma in the study
group.
The b allele of Bsm1 polymorphism of VDR gene showed positive
association with breast cancer (133). This study included 463 cases with
known BRCA1/2 status and 1012 controls. Sub-group analysis of the study
revealed that BRCA1/2 non-carriers and subjects with a family history of
breast and/or ovarian cancer had significant association of this allele
with this disease condition.
The overall results of many studies showed that the variations in VDR
gene are not associated with some disease conditions in Pakistani
population. The results of a study conducted by our group showed that
only TT genotype of TaqI polymorphism was significantly associated with
T2DM in Karachi, Pakistan (Mahmood et al., unpublished data).