ASSOCIATION OF VDR GENE VARIANT (rs1544410)
WITH TYPE 2 DIABETES IN A PAKISTANI COHORT
Khan A1, Khan S2, Aman A1, Ali Y1, Jamal M3, Rahman B4, Ahmad M4, Aasim M4, Jalil F1,*, Shah AA4
*Corresponding Author: Dr. Fazal Jalil, Department of Biotechnology, Abdul Wali Khan University
Mardan, Toru Road, Near Sheikhmaltoon Twon 23300, Mardan, Khyber-Pakhtunkhwa Province, Pakistan.
E-mail: fazaljalil@awkum.edu.pk
page: 59
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RESULTS
Prevalence of Study Subjects. Clinical and demographic
data such as family history, gender, and ages of the
patients, associated diseases and Hb A1c levels of 917 study
subjects (459 T2DM, 145 T1DM, 303 controls) were analyzed.
The upper and lower ranges of these variables along
with the mean/average were calculated at gender level. In
male T1DM patients, the mean age was 40 years (5-57),
mean BMI was 22.3 (12.7-32.2), mean FBS/RBS was
196.7 (122-384) and Hb A1c was 9.4 (6.8-15.5). Whereas
in female T1DM patients, the mean age was 43.1 years
(15-62), mean BMI was 24.6 (16-37.2), RBS/FBS was
219.8 (161-402) and HbA1c was 9.6 (7.3-12.7). In male
T2DM patients, the mean age was 57.4 years (32-100),
mean BMI was 23.4 (13.5-39.8), mean FBS/RBS was 245 (135-510) and Hb A1c mean was 9.6 (6.7-13.7). Similarly,
in female T2DM patients, the mean age was 55.4 (29-91),
mean BMI was 22.1 (12.3-37.3), mean FBS/RBS was
269.7 (144-510) and Hb A1c was 9.8 (6.9-12.7). In the
control samples, the mean age was 44 years (10-100), the
mean BMI was 21.2 (14.5-33.7) and the mean FBS/RBS
was 112.3 (70-168) (Table 1).
Association of VDR gene with T2DM. A genetic variant
(rs1544410) in the VDR gene was mapped in 250 T2DM
patients and 250 controls, as shown in Figures 1 (A) and
(B). The frequencies of genotype and allelic distribution and
the effect of homozygous dominant and recessive models
were determined in cases vs. controls. It was found that 65
(26.0%) cases and 32 (12.8%) controls had homozygous
AA, while 69 (27.6%) cases and 139 (55.6%) controls had
heterozygous AG, and 116 (46.4%) cases and 79 (31.6%)
controls had homozygous GG (χ2 = 41.81, p = 0.0001).
However, through allele frequency distribution analyses,
we determined that 199 (39.8%) cases and 203 (40.6%)
control individuals had allele A and 301 (60.2%) cases and
297 (59.4%) control individuals had allele G [OR = 0.967
(0.751-1.246); RR= 0.984 (0.866-1.116); p value = 0.846]
(Table 2). The effect of the major allele on the association
of VDR with T2DM was checked through homozygous
dominant model analysis. Homozygous AA was found in
65 (26.0%) cases and 32 (12.8%) in controls. Similarly,
AG+GG was found 185 (74.0%) and 218 (87.20%) in cases
and controls, respectively (OR = 2.394 (1.501-3.816); RR
= 1.46 (1.225-1.740); p = 0.003). Moreover, the effect of
the minor allele on the association of VDR with T2DM
was assisted through recessive model analysis. Where homozygous
GG was observed in 116 (46.4%) cases and 79
(31.28%) controls and AG+AA was seen in 134 (53.6%)
cases and 271 (68.3%) controls (OR = 2.970 (2.086-4.227);
RR = 1.798 (1.501-2.154); p = <0.0001) (Table 2). It is predicted that there will be an alarming increase
in the incidence of diabetes from 382 million (8.3%) in
2013 to 592 million (10.1%) in 2035. The previous study
has shown a strong correlation between the VDR polymorphisms
and T2DM-associated metabolic parameters
[12]. To briefly explain, the human VDR gene is located on
chromosome 12q13.1. The VDR gene consists of coding
and non coding exons that is spliced alternatively [13-
15]. Genetic polymorphism in the VDR gene may play an
important role in increased β cells capacity of secretion,
and thus have an association with T1DM and T2DM [16].
In this study, a total of 917 samples, which included
614 DM patients (469 T2DM and 145 T1DM) and 303
control samples’ data were collected from different hospitals
of District Swat, Khyber Pakhtunkhwa Province,
Pakistan. A questionnaire was designed, and the patients
were visited at hospitals to record various information
such as RBS/FBS, BMI, age, family history and associated
disease of these patients. For each variable, the upper and
lower ranges and the mean/average was calculated in both
males and females. Then a genetic variant rs1544410 in the
VDR gene was genotyped in 250 T2DM patients and 250
control subjects using the (amplification refractory mutation
system) ARMS-PCR method. In the current study, we
determined the mean/average values for certain variables
in our data stated at the gender level. Our findings are
consistent with the observations who studied the association
of BMI with T2D in the health records’ system in the
United States. They recruited 12,179 T2DM and 25,177
healthy controls and concluded that BMI is strongly associated
with the risk of being diagnosed with T2DM [17].
In another case-control study, the risks of T2DM focused
on the physical activity of individuals. This study was
conducted on 279 males and 119 females in Tokyo and was
reported that family history of diabetes and smoking are
the risk factor for the prevalence of T2DM [18]. Through
genotype distribution, we found that 65 (26%) cases had
homozygous AA, 69 (27.6%) cases had heterozygous AG,
116 (46.4%) cases had homozygous GG. Whereas, in control
subjects, AA was found in 32 (12.8%), AG in 139
(55.6%), GG in 79 (31.6%). A significant difference was
observed at the genotype level in cases and controls (χ2
= 41.81, p = 0.0001). However, through allele frequency
distribution analysis, we determined an insignificant difference
between T2DM cases and controls (p value = 0.866;
OR = 0.967; RR = 1.034).
The effect of the major allele on the association of the
VDR gene with T2DM was checked through homozygous
dominant model analysis. Homozygous AA was found
in 65 (26.0%) cases and 32 (12.8%) in controls. Similarly,
AG+GG was found in 185 (74.0%) cases and in
controls that was 218 (87.20%). Thus, a significant effect
of <0.05 was observed (OR = 2.394 (1.501-3.816); RR
= 1.46 (1.225-1.740); p = 0.003). Moreover, the effect
of the minor allele on the association of the VDR gene
with T2DM was assisted through recessive model analysis.
Homozygous GG was present in 116 (46.4%) cases
and 79 (31.28%) controls, whereas, AG+AA was 134
(53.6%) in cases and 271 (68.3%) in controls (OR = 2.970
(2.086-4.227); RR = 1.798 (1.501-2.154); p = <0.0001).
Our data suggest that the VDR gene BsmI (rs1544410)
genetic variant is associated with the risk of T2DM in a
Pakistani cohort.
To date, more than 25 different polymorphisms have
been mapped to the VDR locus. There are several reports
that these VDR polymorphisms are associated with T2DM
and insulin secretion [19-21]. In addition, VDR polymorphisms
are related to metabolic syndrome, metabolic
changes related to obesity [22]. The association of the
VDR gene polymorphisms and T2DM in older people
living in a community of Santiago de Chile, Chile, were
previously established through a case-control study on 138
T2DM patients and 172 control subjects with ages ranging
from 60-79 years. They further suggested that the C
allele (TC+ CC) of the VDR-FokI gene is a possible risk
factor for T2DM in older people living in a community in
Santiago de Chile, Chile [10].
In conclusion, the findings of the current study suggest
that genotype GG of genetic variant rs1544410 of the
VDR gene is the most susceptible genotype to T2DM, and
thus, obesity in patients of the Pakistani cohort. Although,
the sample size of our study cohort was small, an extensively
large case-control study with a huge sample set is
needed to further confirm these findings and to be applied
for the management and proper therapeutic intervention
by the clinicians.
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