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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 4, July/August 2016

AFRICA

213

Sirtuin 1

rs1467568

and

rs7895833

in South African

Indians with early-onset coronary artery disease

Prithiksha Ramkaran, Alisa Phulukdaree, Sajidah Khan, Devapregasan Moodley, Anil A Chuturgoon

Abstract

Background:

Sirtuin 1 (SIRT1), a class III histone deacetyl-

ase, has been identified as a candidate molecule affecting

the epigenetic mechanisms of cardiovascular disease (CVD).

Previous studies have shown that some SIRT1 single-nucle-

otide polymorphisms (SNPs) are associated with body mass

index, diabetes, blood pressure, cholesterol metabolism and

coronary artery calcification. We investigated two A

>

G SIRT1

SNPs,

rs1467568

and

rs7895833

, in young South African (SA)

Indians with coronary artery disease (CAD) and compared

them to Indian and black controls.

Methods:

For

rs1467568

, a total of 287 subjects were recruit-

ed into this study (104 CAD patients, 99 age-, gender- and

race-matched controls, and 84 age- and gender-matched black

controls). For

rs7895833

, a total of 281 subjects were recruit-

ed into this study (100 CAD patients, 99 age-, gender- and

race-matched controls, and 82 age- and gender-matched black

controls). All patients were male, of Indian ethnicity, stable CAD

confirmed on angiography, mean age 37.5 years; range 24–45. All

subjects were genotyped using TaqMan SNP genotyping assays.

Results:

The variant allele for both SNPs was found at a higher

frequency in the total Indian group compared to the total

black population (

rs1467568

: 41 vs 18.5%, respectively,

p

<

0.0001, OR

=

3.190, 95% CI: 2.058–40943; and

rs7895833

: 41

vs 22%, respectively,

p

<

0.0001, OR

=

2.466, 95% CI: 1.620–

3.755). Indian controls presented with a higher frequency

for both SNPs compared to black controls (

rs1467568

: 40 vs

18.5%, respectively,

p

<

0.0001, OR

=

2.996, 95% CI: 1.850–

4.853; and

rs7895833

: 41 vs 22%, respectively,

p

<

0.0001, OR

=

2.513, 95% CI: 1.578–4.004). No difference was seen in the

distribution of both SNPs between CAD patients and either

control group. We did not observe any association between the

SNPs and clinical parameters in CAD patients and controls.

Conclusion:

Both SNP variant alleles occurred more frequent-

ly in SA Indians than in SA blacks. A larger study group and

further analysis is required to assess whether these SIRT1

SNPs may serve as risk factors that contribute to Indians

developing early-onset CAD.

Keywords:

sirtuin 1,

rs1467568

,

rs7895833

, single-nucleotide

polymorphism, premature coronary artery disease, South

African Indians

Submitted 22/4/15, accepted 14/11/15

Cardiovasc J Afr

2016;

27

: 213–217

www.cvja.co.za

DOI: 10.5830/CVJA-2015-085

Sirtuins are a class of NAD

+

-dependent proteins involved in a

wide range of biological processes such as aging, transcription,

apoptosis and inflammation.

1

Sirtuin 1 (SIRT1) is located in

the nucleus and cytoplasm, and plays an important role in

epigenetic regulation by deacetylating a range of transcription

factors to control downstream gene expression.

2

The targets

of SIRT1 include Forkhead box O (FOXO)1, (FOXO)3,

peroxisome proliferator-activated receptor gamma coactivator

1-alpha (PGC-1

α

), tumour suppressor p53, nuclear factor-

kappa B (NF-

κ

B), Notch, hypoxia-inducible factor (HIF) 1

α

,

liver X receptor (LXR), farnesoid X receptor (FXR) and sterol

regulatory element-binding protein (SREBP)1c.

3

Recent studies have demonstrated a protective role of SIRT1

in atherosclerosis, the underlying process of coronary artery

disease (CAD).

4

SIRT1 performs an anti-inflammatory function

by downregulating the expression of several pro-inflammatory

cytokines by interfering with the NF-

κ

B signalling pathway.

By deacetylating NF-

κ

B, SIRT1 suppresses the expression of

lectin-like oxidised low-density lipoprotein receptor-1 (Lox-

1), a scavenger receptor for oxidised low-density lipoproteins

(oxLDL), therefore preventing foam cell formation.

4

SIRT1

controls the activity of LXR, an important regulator of lipid

homeostasis and inflammation.

4

Activation of LXR results in

expression of ATP-binding cassette (ABC) transporter ABCA1,

which regulates the removal of cholesterol into high-density

lipoproteins (HDL), a process known as reverse cholesterol

transport (RCT). Dysfunctional RCT could lead to accumulation

of cholesterol, thus stimulating foam cell production and the

progression of atherosclerosis.

4,5

Given the important role of

SIRT1 in cardiovascular disease, research on genetic variation in

the SIRT1 gene has become of interest.

Genetic variations such as single-nucleotide polymorphisms

(SNPs) in the SIRT1 gene have been associated with

inflammation, body mass index, type 2 diabetes, blood pressure

and dyslipidaemia, all of which are well-established risk factors

for CAD.

2,6-9

Coronary artery disease remains a leading cause of

mortality worldwide, with an unusually high prevalence of early-

onset disease among the Indian population. South African (SA)

Indians have a much higher prevalence of CAD compared to SA

blacks.

10

There are currently no studies on SIRT1 SNPs in SA

Indians with CAD. We therefore investigated the SIRT1 A

>

G

SNPs,

rs1467568

and

rs7895833

in young SA Indians with CAD

and compared them to Indian and black controls.

Discipline of Medical Biochemistry and Chemical Pathology,

University of KwaZulu-Natal, Durban, South Africa

Prithiksha Ramkaran, BMedSc Hons

Devapregasan Moodley, PhD

Anil A Chuturgoon, PhD,

chutur@ukzn.ac.za

Department of Physiology, School of Medicine, Faculty of

Health Sciences, University of Pretoria, South Africa

Alisa Phulukdaree, PhD

Department of Cardiology, Nelson R Mandela School of

Medicine, University of KwaZulu-Natal, Durban, South Africa

Sajidah Khan, MB ChB, FCP (SA), PhD