149Acta Med Indones - Indones J Intern Med • Vol 53 • Number 2 • April 2021

ORIGINAL ARTICLE

ABSTRAK
Latar belakang: penyakit ginjal diabetik (PGD) sebagai penyebab utama penyakit ginjal tahap akhir 

(PGTA), merupakan komplikasi dari diabetes mellitus (DM). Salah satu kondisi yang menjadi faktor risiko 
PGD yaitu defisiensi vitamin D, dimana polimorfisme reseptor vitamin D (VDR) disinyalir memiliki peran. Studi 
ini bertujuan untuk melihat adanya hubungan antara polimorfisme reseptor vitamin D (VDR) terhadap PGD, 
dan faktor yang memengaruhi hubungan tersebut. Metode: studi dilakukan secara potong lintang pada pasien 
DM Tipe 2 di poliklinik Penyakit Dalam RSUPN Dr. Cipto Mangunkusumo, Jakarta dengan rentang waktu 
November 2014 – Maret 2015. Subjek yang memenuhi kriteria penelitian dilakukan pengumpulan data berupa 
karakteristik subjek, pemeriksaan fisik, dan pemeriksaan darah (polimorfisme BsmI gen reseptor vitamin D). 
Pasien dengan penyakit akut dan berat dieksklusikan dari studi. Selanjutnya dilakukan analisis secara bivariat 
dan multivariat antar variabel. Hasil: dari 93 subjek penelitian, didapatkan 42 (45.2%) subjek tanpa PGD 
dan 51 (54.8%) subjek dengan PGD. Sebagian besar subjek memiliki genotip Bb yaitu sebesar 89.2%, serta 
tidak ada subjek yang memiliki genotip BB. Sebagian besar subjek memiliki alel b, yakni sebesar 55.4%. Tidak 
terdapat hubungan yang berbeda bermakna antara polimorfisme BsmI gen reseptor vitamin D dengan PGD 
(OR = 1.243; CI 95% 0.334-4.621; p = 0.751). Kesimpulan: Genotip Bb pada polimorfisme BsmI didapatkan 
sebesar 89.2% dan genotip bb sebesar 10.8%. Sebagian besar subjek memiliki alel b, yakni sebesar 55.4%. 
Tidak ditemukan adanya hubungan bermakna antara polimorfisme BsmI gen reseptor vitamin D dengan PGD. 
Durasi DM lebih dari lima tahun memengaruhi hubungan antara kedua variabel tersebut.  

Kata kunci: polimorfisme, BsmI, gen reseptor vitamin D, penyakit ginjal diabetik, ras Indonesia-Malay.

ABSTRACT
Background: Diabetic kidney disease (DKD), as a common cause of end-stage renal disease (ESRD), is a 

chronic complication of diabetes mellitus (DM). It has been established that vitamin D deficiency is one of DKD 
risk factors, which may be related to vitamin D receptor (VDR) polymorphisms. This study aimed to analyze the 
association between VDR polymorphisms and DKD in Indonesian population, also risk factors that influence it. 
Methods: a cross-sectional study was conducted in Type 2 DM patients  who visited internal medicine outpatient 
clinic at Dr. Cipto Mangunkusumo Hospital, Jakarta, from November 2014 until March 2015.  Data collection 

Association of BsmI Polymorphisms in the Vitamin D  
Receptor Gene Among Indonesian Population with Diabetic 
Kidney Disease

Pringgodigdo Nugroho1,2, Aida Lydia1, Suhardjono1, Kuntjoro Harimurti2

1 Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, Universitas 
Indonesia—Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
2 Clinical Epidemiology Unit, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia—Dr 
Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

Corresponding Author: 
Aida Lydia, MD, PhD. Division of Nephrology, Department of Internal Medicine, Faculty of Medicine 
Universitas Indonesia - Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71, Jakarta 10430, Indonesia.  
email: aidalydia@gmail.com



Pringgodigdo Nugroho                                                                                Acta Med Indones-Indones J Intern Med

150

INTRODUCTION
Diabetic kidney disease (DKD) is a common 

cause of end-stage renal disease (ESRD). Data 
from the Indonesian Renal Registry (2011) 
revealed that the 25% etiology of patients who 
have undergone hemodialysis is DKD.1 Factors 
that are associated with DKD include blood 
glucose control, hypertension, dyslipidemia, 
duration of diabetes mellitus (DM), high body 
mass index, age, sex, ethnicity, vitamin D 
deficiency, high-sodium diet, high-protein diet, 
and smoking.2–7 

Vitamin D has an anti-calcium effect by 
inhibiting the renin-transcription process, 
angiotensin II, the renal-inflammation process, 
and albumin excretion. It also prevents podocyte 
damage, glomerulosclerosis, and transformation 
from kidney epithelial cells into mesenchymal 
cells.8 Current studies on the association 
between vitamin D deficiency and DKD are still 
controversial. Those controversial results may 
be related to genetic factors, which are vitamin 
D receptor (VDR) polymorphisms. The VDR 
polymorphism is affected by the Cdx2, ApaI, 
BsmI, FokI, and TaqI genes, whereas the Asian 
population is mostly affected by ApaI, FokI, 
and Cdx2.9

Several studies have reported the association 
between BsmI polymorphisms in the vitamin D 
receptor gene and DKD in various populations. 
Zhang et al. (2012) study revealed an association 
between BsmI polymorphisms in the vitamin 
D receptor gene and DKD in Han Chinese 
population, while Vedralova et al. (2012) 

study in Caucasians showed the opposite 
result.10,11 However, the association between 
BsmI polymorphism in the vitamin D receptor 
gene and DKD has not been investigated in the 
Indonesian population. Based on the current 
evidence, we aimed to analyze the association 
between Bsml polymorphism in the vitamin 
D receptor gene and DKD particularly in 
Indonesian population.  In terms of secondary 
objective, we aimed to investigate other risk 
factors that influence the association between 
main variables.  By knowing the potential risk 
factor of BsmI polymorphism in the vitamin D 
receptor gene, it is hoped that the number of 
cases and morbidity of DKD can be prevented. 

METHODS
A cross-sectional study was conducted 

t o  u n d e r s t a n d  t h e  a s s o c i a t i o n  o f  B s m I 
polymorphisms in the vitamin D receptor gene 
with DKD among the Indonesian–Malay race. 
The subjects of this study were patients who 
came to the internal medicine outpatient clinic, 
Dr. Cipto Mangunkusumo Hospital, Jakarta, 
from November 2014 until March 2015. The 
inclusion criteria were patients with type-2 DM, 
of Indonesian–Malay population, who signed the 
informed consent form. Patients with urinary 
tract infection or fever, who were pregnant 
or in their menstrual period, had undergone 
hemodialysis or peritoneal dialysis, had used 
nonsteroid anti-inflammatory drugs (NSAIDs), 
and postexercise were excluded. This study 
has been approved by the Ethical Committee 

includes characteristics of subjects and laboratory examination, including BsmI polymorphisms in the vitamin D 
receptor gene. Patients with acute and severe disease were excluded from the study. Bivariate and multivariate 
analyses were done. Results: of 93 DM subjects, 42 (45.2%) subjects were without DKD and 51 (54.8%) subjects 
had DKD. Most of the subjects had the Bb genotype (89.2%), with no subject having the BB genotype. The 
proportions of the B and b alleles were 44.6% and 55.4%, respectively. There is no association between BsmI 
polymorphisms in the vitamin D receptor gene and DKD (OR = 1.243; CI 95% 0.334-4.621; p value = 0.751). 
Conclusion: the profile of BsmI polymorphisms in the vitamin D receptor gene in the Indonesian population 
were genotypes Bb (89.2%) and bb (10.8%). There was no association between BsmI polymorphisms in the 
vitamin D receptor gene and DKD. Duration of DM more than five years influenced the association between 
those variables.

Keywords: polymorphisms, BsmI, vitamin D receptor (VDR) gene, diabetic kidney disease, Indonesian–
Malay race.



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of Faculty of Medicine Universitas Indonesia 
(Reference no. 756/UN2.F1/ETIK/2014).

D a t a  c o l l e c t i o n  i n c l u d e d  s u b j e c t s ’ 
characteristics, physical examination, and 
laboratory examination, including BsmI 
polymorphisms in the vitamin D receptor 
gene. 5 mL of venous blood was collected in 
a non-fasting state and added to an EDTA-
anticoagulated container. BsmI polymorphisms 
were measured using polymerase chain reaction 
with high resolution melt analysis. Since the 
diabetic kidney disease was defined from 
albuminuria, the mid-stream random urine was 
collected in a urine collector. Albuminuria was 
measured using Nyocacard U-albumin with 
sandwich immunometric assay technique.

The data were then analyzed by SPSS v.16. 
Participants’ characteristics were reported in 
percentages for categorical data, mean (standard 
deviation), or median (range) for continuous 
data. A chi square test was used to analyze the 
association between BsmI polymorphisms in the 
vitamin D receptor gene and DKD. Also, logistic 
regression analysis was performed to investigate 
the role of other risk factors that influence the 
association between BsmI polymorphisms in 
the vitamin D receptor gene and DKD. Bivariate 
and multivariate analyses were presented 
with confidence interval 95% and considered 
statistically significant if the p value was <0.05.   

RESULTS
93 subjects were recruited for the present 

study. There were 51 subjects (54.8%) with 
DKD and 42 subjects (45.2%) without DKD. 
The characteristics of the subjects, which include 
demography and laboratory examination results, 
are presented in Table 1.

Table 1. Characteristics of the subjects.
DKD

(n = 51)
Without DKD

(n = 42)
Sex, n (%)

 - Male 28 (66.7) 14 (33.3)
 - Female 23 (45.1) 28 (54.9)

Age, median (range) 61 (46-73) 61.5 (45–85)
Body mass index (kg/

m2), mean (SD)
26.08 (3.93) 25.40 (3.84)

Duration of DM, n (%)
 - > 5 years 39 (63.9) 22 (36.1)
 - ≤ 5 years 12 (37.5) 20 (62.5)

Systolic BP (mmHg), 
median (range)

137 (88–180) 130 (98–173)

Diastolic BP (mmHg), 
median (range)

74 (52–100) 75 (51–94)

eGFR (mL/min/1.73 
m2), mean (SD)

43.46 (22.46) 73.51 (23.23)

Urea (mg/dL), median 
(range)

39 (17–145) 25.5 (13–54)

Creatinine (mg/dL), 
median (range)

1.5 (0.7–9.6) 0.9 (0.6–1.9)

Fasting blood glucose 
mg/dL), median 
(range)

133 (79–365) 121.5 (75–285)

2-hours postprandial 
blood glucose (mg/
dL), median (range)

199 (60–521) 180.5 (80–479)

HbA1c (%), median 
(range)

7.5 (5.4–11.1) 7.2 (5.9–11.4)

Total cholesterol (mg/
dL), mean (SD)

187.35 (44.66) 175.48 (35.34)

Triglyceride (mg/dL), 
median (range)

115.5 (30–447) 95.5 (52–272)

HDL cholesterol (mg/
dL), mean (SD)

50.57 (18.77) 53.57 (12.76)

LDL cholesterol (mg/
dL), mean (SD)

117.88 (40.46) 108.00 (29.47)

DKD: Diabetic kidney disease; DM: Diabetes mellitus; BP: 
Blood pressure.

The proportion of Genotype and Allele of 
BsmI Polymorphisms in Vitamin D Receptor 
Gene are presented in Table 2. The majority of 
the subjects had the Bb genotype (89.2%), and 
no subject had the BB genotype. The percentage 
of the b allele was 55.4%. 

Table 2. Genotype and allele of the subjects.
Frequency 

n (%)
Genotype

 - Bb 83 (89.2)
 - bb 10 (10.8)

Allele
 - B 83 (44.6)
 - b 103 (55.4)

Association of BsmI Polymorphisms in 
Vitamin D Receptor Gene with DKD

There is no association between BsmI 
polymorphisms in the vitamin D receptor 
gene and DKD (OR = 1.234; CI 95% 0.334–
4.621; p = 0.75). There is also no significant 
association between allele B or allele b on BsmI 
polymorphisms in the vitamin D receptor gene 
and DKD (OR = 1.043; CI 95% 0.584–1.866; p 
= 0.89). (Table 3 and Table 4).



Pringgodigdo Nugroho                                                                                Acta Med Indones-Indones J Intern Med

152

Risk Factors of DKD
Several factors have significant associations 

Table 3. Association of BsmI polymorphisms in vitamin D receptor gene with DKD.

DKD
n (%)

Without 
DKD 
n (%)

Total
n (%) OR

95% Confidence 
Interval 

Min Max
Bb 46 (55.4) 37 (44.6) 83 (100) 1.243 0.334 4.621

bb 5 (50) 5 (50) 10 (100)

Table 4. Association between B allele of BsmI polymorphisms in vitamin D receptor 
gene and DKD.

DKD
n (%)

Without 
DKD
n (%)

Total
n (%) OR

95% Confidence 
Interval 

Min Max

B 46 (55.4) 37 (44.6) 83 (100) 1.043 0.584 1.866

b 56 (54.4) 47 (45.6) 103 (100)

Table 5.  Risk factors of DKD.

DKD
n (%)

Without DKD 
n (%) OR

95% Confidence Interval 

Min Max
Genotype

 - Bb 46 (55.4) 37 (44.6) 1.243 0.334 4.621
 - bb 5 (50) 5 (50)

Duration of DM
 - > 5 years 39 (63.9) 22 (36.1) 2.955 1.218 7.167
 - ≤ 5 years 12 (37.5) 20 (62.5)

Body mass index
 - Overweight and Obese 40 (59.7) 27 (40.3) 2.020 0.806 5.062
 - Normal 11 (42.3) 5 (57.7)

Blood pressure 
 - Hypertension 48 (62.3) 29 (37.7) 7.172 1.883 27.319
 - Without hypertension 3 (18.8) 13 (81.2)

Blood glucose control
 - Uncontrolled 40 (55.6) 32 (44.4) 1.023 0.378 2.769
 - Controlled 11 (55) 9 (45)

Dyslipidemia 
 - Dyslipidemia 28 (57.1) 21 (42.9) 1.217 0.537 2.760
 - Without Dyslipidemia 23 (52.3) 21 (47.7)

Blood pressure control
 - Uncontrolled 23 (62.2) 14 (37.8) 1.643 0.705 3.829
 - Controlled 28 (50) 28 (50)

Kidney function
 - eGFR < 60 41 (75.9) 13 (24.1) 9.146 3.531 23.690
 - eGFR ≥ 60 10 (25.6) 29 (74.4)

with DKD, such as duration of DM being 
more than five years (p value = 0.015), blood 



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153

pressure (p value = 0.001), and kidney function 
(p value < 0.001). From logistic regression 
analysis, confounding factors had effects on the 
association between BsmI polymorphisms in the 
vitamin D receptor gene and DKD with crude 
OR of 1.243 (95% CI 0.334–4.621) and adjusted 
OR of 1.410 (95% CI 0.335–2.296). Duration 
of DM being more than five years influenced 
the association of BsmI polymorphisms in the 
vitamin D receptor gene and DKD. The results 
are presented in Table 5 and Table 6.

Table 6. Crude OR and Adjusted OR Genotype as Risk 
Factor of DKD and Effect from Other Risk Factors

OR 95% CI
Genotype Bb Crude OR: 

1.243
0.334–4.621

Adjusted
(+) eGFR 1.137 0.248–5.216 8.5%
(+) 

Hypertension
1.058 0.219–5.121 6.9%

(+) Duration 
of DM

1.449 0.278–7.551 37%

(+) Body 
Mass Index

1.525 0.283–8.217 5.2%

(+) BP Control 1.410 0.260–7.652 7.5%

DISCUSSION
The studied participants were type-2 DM 

patients who came to the Internal Medicine 
Outpatient Clinic, Dr. Cipto Mangunkusumo 
Hospital, Jakarta. Most of the subjects were 
female with ages ranging from 45 to 85 years old. 
Dewi et al.12 study and Indra et al.13 study showed 
similar participants; most of their subjects were 
female. The duration of DM of most subjects 
was more than five years (65.6%), and most 
subjects had comorbidities, such as hypertension, 
elevated body mass index, and dyslipidemia. 
These findings resembled Indra et al.13 study, 
which had 82.8% patients with hypertension 
and most of them with more than five years’ 
duration of DM. Insulin resistance in type-2 
DM patients causes an increase in angiotensin 
II, inflammatory mediator release, which causes 
endothelial damage, and hyperglycemia, which 
increases sodium reabsorption in renal tubules. 
Hence, plasma volume will increase, which leads 
to hypertension.14

Even though hypertension was the major 
comorbidity among type-2 DM patients in this 

study, the median blood pressure in both groups 
was less than 140/90 mmHg, since 81.7% of 
subjects had already taken antihypertensive 
drugs such as ACE inhibitors or ARBs. More 
than half of the participants belonged to the DKD 
group (54.8%). This finding was related to the 
higher number of patients with comorbidities 
such as hypertension, dyslipidemia, overweight, 
poor glycemic control (HbA1c median = 7.45), 
and more than five years of DM. A total of 
82.8% subjects had a higher body mass index, 
with a mean of 26.08 from the DKD group and 
25.40 from the non-DKD group. It was found 
that obesity leads to oxidative stress conditions, 
which cause endothelial damage and decrease 
adiponectin levels. Such conditions result in 
renal podocyte damage.15

Most subjects with DKD had an estimated 
glomerular filtration rate (eGFR) of less than 
60 mL/min/1.73 m2 (75.9%). Albuminuria 
in DKD causes reduced renal function by 
triggering chemokine expression and activating 
complements of renal tubules, which cause 
infiltration of inflammatory cells in interstitial 
and fibrogenesis. In the end, reduced renal 
function may have resulted in an ESRD state.16 

Based on the results of this study, 10.8% 
of the subjects had the bb genotype, 89.2% 
had the Bb genotype, and none had the BB 
genotype. There were 44.6% subjects with the 
B allele and 55.4% with the b allele. This result 
was different from Zhang et al.10 study, which 
showed the majority of the bb genotype among 
the participants. On the other hand, Vedralova 
et al.11 showed the BB genotype for most of 
the patients. Based on these previous studies, it 
can be concluded that genotype differences are 
influenced by race. Indonesian native citizens, 
most of whom come from the Malay race, are 
different from Han Chinese, who belong to the 
Mongoloid race, and are also different from the 
Caucasian race.

Data suggested an elevated number of DKD 
among BB genotypes (adjusted OR 1.410), but 
the confidence interval was above 1 (CI 95% 
0.260–7.652). This result contradicted Zhang 
et al. (2012),10 who revealed a significant 
correlation between BsmI polymorphisms in the 
vitamin D receptor gene and DKD among Han 



Pringgodigdo Nugroho                                                                                Acta Med Indones-Indones J Intern Med

154

Chinese population.
B e s i d e s  B s m I ,  v i t a m i n  D  r e c e p t o r 

p o l y m o r p h i s m  w a s  i n f l u e n c e d  b y  o t h e r 
investigated genes, such as TaqI, ApaI, and 
FokI. Zhang et al.10 study conducted among  
Han Chinese population stated that there is no 
association between ApaI polymorphisms in the 
vitamin D receptor gene and DKD in the same 
population. A study from Arababadi et al. (2010) 
found that there was no significant association 
between ApaI and TaqI polymorphisms and 
DKD. Arababadi et al. (2010) found that 
vitamin D receptor gene polymorphisms have 
an association with DM, but not with DKD.17 
Vedralova et al.11 also found that the vitamin 
D receptor-gene polymorphism that has an 
association with DKD is FokI.

In the case of the separation of alleles B and 
b, no significant association was found between 
the B allele of BsmI polymorphisms in the 
vitamin D receptor gene and DKD (p value = 
0.89). This result was different from Zhang et al.10 
study, which found that allele B has a significant 
association with DKD among Han Chinese 
population. According to logistic regression 
analysis, more than five years’ duration of DM 
has the greatest influence on the association of 
BsmI polymorphisms in the vitamin D receptor 
gene and DKD. Another study also reported that 
a longer duration of DM increases the prevalence 
of DKD and increases the proteinuria.18

To the best of our knowledge, this is the first 
study to analyze the proportion and association 
of BsmI polymorphisms in vitamin D receptors 
with DKD in the Indonesian–Malay race. This 
study provides a preliminary understanding of 
vitamin D receptor-gene polymorphisms and 
the influence of genetic factors in the therapeutic 
response of DKD. However, this study lacks 
the measurement of both vitamin D and 
vitamin D receptor levels of the subjects which 
might affect the association between variables.   
Hence, there were several confounding factors 
affecting the association between the BsmI 
gene-receptor vitamin D and DKD. Also, this 
study analyzed only the association of the BsmI 
gene as one of the vitamin D receptor-gene 
polymorphisms. Therefore, this study was 
not able to describe the entirety of vitamin D 

receptor-gene polymorphisms. This still warrants 
further studies. 

CONCLUSION
The profiles of BsmI polymorphisms in the 

vitamin D receptor gene in the Indonesian–
Malay race were genotypes Bb (89.2%) and bb 
(10.8%). There was no association between BsmI 
polymorphisms in the vitamin D receptor gene 
and DKD, which might be due to the influence 
of genetic factors among different populations. 
In addition, the duration of DM being more than 
five years influenced the association between 
those variables.

FUNDING
The study was financially supported by the 

Universitas Indonesia Research Grant.

CONFLICT OF INTEREST
The authors declare no conflict of interest

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