Contribution of the positional candidate gene OXR1 to premature coronary heart disease
and to type 2 diabetes in the Mauritian population
Paper Presenter: Nathalie Lan Heng SEM FA, SSR Resource Centre Department of Medicine
Author(s):

Lan Heng SEM FA, Department of Medicine, Faculty of Science

Meera MANRAJ, Department of Medicine, Faculty of Science

Annick HEBE, SSR Resource Centre, Department of Medicine, Faculty of Science

M Y LEE KWAI YAN, SSR Resource Centre, Department of Medicine, Faculty of Science

Sarojini JANKEE, Resource Centre, Department of Medicine, Faculty of Science

Asha DOOKUN-SAUMTALLY, Mauritius Sugar Industry Research Institute
Paper type: Oral presentation
Keywords: coronary heart disease, Type 2 diabetes, OXR1 gene, SNP,
Abbreviations: CHD: coronary heart disease; T2D: Type 2 diabetes; SNP: single nucleotide
polymorphism; OXR1: Oxidation Resistance 1: NI: North Indian; MAF: minor allele frequency; OR:
odds ratio; CI: confidence interval; MS: metabolic syndrome; CONT: control; MSIRI: Mauritius Sugar
Industry Research Institute.
Background: Previous genome scan carried out in Mauritian families affected by CHD and/or T2D
unveiled several chromosomal regions harbouring positional candidate genes for these complex traits
(Francke et al, 2001). The chromosomal 8q23 region was a region where microsatellite markers showed
simultaneous co-segregation with premature CHD and T2D in the families studied. A strong positional
candidate gene within that region appears to be the OXR1 gene, given the role of oxidative stress in the
patho-physiology of T2D (Gopaul et al, 2001) or CHD (Ceriello, 2004), the role of mitochondrial
metabolism in oxidative stress and the putative role of OXR1 protein in protection against oxidative stress
when it is localised to the mitochondrion (Elliot & Volkert, 2004).
Objective: The aim of our study was to evaluate the contribution of variants in OXR1 gene to
susceptibility to the premature CHD and to T2D in North Indian Mauritian population.
Research design and methods: We genotyped 6 tagging SNPs spanning the OXR1 gene with minor
allele frequency (MAF) above 0.20 using TaqMan SNP Genotyping Assays (Applied Biosystems, Foster
City, USA) in unrelated case-control cohorts from the North-Indian (NI) ethnic group. The patients group
included 380 unrelated NI patients affected by premature CHD with or without T2D and the control group
included 268 unrelated healthy NI individuals (matched for age) with a normal glucose metabolism and
who had no CHD. Genotyping assays were carried out using a real-time PCR apparatus (MJ Research
PTC 200, Chromo4 System) found at the Department of Biotechnology of the MSIRI. Genotypes were
analysed individually using Epi 2000 (CDC, Atlanta; Jul 2007) and in haplotypes using Haploview v3.32
(Broad Institute, Cambridge, USA; 21 June 2006).
Results: Statistical analyses were carried out separately for men and women on 5 out of the 6 SNPs for
which reliable genotyping results were available. No allelic/genotypic association was observed between
the 4 SNPs: rs2282509, rs1681886, rs1681904, rs6983111 and CHD or T2D.
One SNP, rs776959 in
intron 9 of the OXR1 gene, however, showed a trend towards association with both CHD and T2D in
women only. Major allele T showed allelic association with CHD: OR=1.61(95% CI: 1.0-2.59), pvalue<0.048 and T2D: OR= 1.71 (95% CI: 1.03-2.85), p-value<0.037. Homozygous TT genotype seems
to confer a higher risk of CHD: OR=2.15 (95%CI: 1.09-4.25), p-value<0.02 and T2D: OR=2.34 (95%CI:
1.16-4.74), p-value<0.016. Interestingly, further analysis with respect to metabolic syndrome (MS) and
its different components showed similar trends of allelic association with allele T: MS: OR=1.75 (1.062.89), p-value<0.03; hypertriglyceridaemia: OR=1.83 (95%CI: 1.04-3.22), p-value<0.035; hypertension:
OR=1.69 (1.05-2.71), p-value<0.028. Haplotype analysis of the 5 SNPs showed that haplotype TACGC
tend to be protective against CHD in females: OR: 0.60 (95% CI: 0.37-0.96), p-value<0.025.
Conclusion: A trend was found towards association between SNP rs776959 and both CHD and T2D
phenotypes in the NI female group. Similar results were observed with metabolic syndrome and several
of its components. Further replication studies with larger sample size in the female group are needed to
confirm evidence of association with this SNP.
References:

Ceriello Antonio, Motz Enrico (2004). Is Oxidative Stress the pathogenic mechanism underlying
insulin resistance, diabetes and cardiovascular disease? The Common soil Hypothesis revisited.
Artreioscler Thromb Vasc Biol 2004;24; 816–823.

Elliott N.A. & Volkert M.R. (2004). Stress Induction and Mitochondrial Localization of Oxr1
Proteins in Yeast and Humans. Molecular and Cellular Biology, 24: 3180-3187.

Francke S, Manraj M, Lacquemant C, Lecoeur C, Lepretre F, Passa P, Hebe A, Corset L, Lee Kwai
Yan S, Lahmidi S, Jankee S, Gunness TK, Ramjutun US, Balgobin V, Dina C, Froguel P (2001). A
genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on
chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Gen 10:
2751-2765.

Gopaul NK, Manraj M, Hébé A, Lee Kwai Yan S, Johnston A, Carrier MJ, Änggard EE: (2001)
Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians
with impaired glucose metabolism. Diabetologia 44: 706-712.
Table 1: Comparison of allelic frequencies between CHD patients and control group
Male (M)
SNP
Associated
Allele
Frequency
CHD
CONT
Female (F)
OR
(95% CI)
P value
rs2282509
C
0.483
0.464
1.08
(0.82-1.43)
0.62
rs1681886
G (M)
A (F)
0.433
0.393
1.18
(0.89-1.56)
0.26
rs776959
T
0.654
0.635
1.09
(0.81 -1.51)
rs1681904
A
0.503
0.469
rs6983111
C (M)
T (F)
0.850
0.846
Frequency
CHD
CONT
0.48
0.414
OR
(95% CI)
P value
1.31
(0.83-2.06)
0.27
1.07
(0.67-1.72)
0.86
0.653
0.638
0.61
0.680
0.569
1.61
(1.0-2.58)
0.048
1.15
(0.87-1.51)
0.36
0.473
0.441
1.14
(0.72-1.80)
0.63
1.03
(0.70-1.52)
0.95
0.133
1.59
(0.85-2.97)
0.16
0.196
Table 2: Genotypic association between SNP rs776959 and CHD in NI case-control group
T/T
C/T
C/C
NI Male
CHD
CONT
n=306
n=167
--------------------129(42%) 68(41%)
142(47%) 76(45%)
35(11%) 23(14%)
T/T v/s (C/T & C/C)
C/T v/s (T/T & C/C)
C/C v/s (C/T & T/T)
OR (95%CI)
1.06 (0.70-1.59)
1.04 (0.70-1.54)
0.81 (0.44-1.48)
SNP rs776959
Genotypes
p-value
<0.76
<0.84
<0.93
<0.55
NI Female
CHD
CONT
n=76
n=95
--------------------36(47%) 28(29%)
31(41%) 53(56%)
9(12%) 14(15%)
OR (95%CI)
2.15 (1.09-4.25)
0.55 (0.28-1.05)
0.78 (0.29-2.06)
p-value
<0.05
<0.02
<0.07
<0.74
Table 3: Genotypic association between SNP rs776959 and T2D in NI case-control group
NI Male
No
p-value
T2D
n=161
n=311
---------------------67(42%) 130(42%) <0.68
77(48%) 140(45%)
17(11%) 41(13%)
SNP rs776959
Genotypes
NI Female
No
T2D
n=57
n=114
---------------------29(51%) 35(31%)
22(39%) 62(54%)
6(10%) 17(15%)
T2D
T/T
C/T
C/C
T/T v/s (C/T & C/C)
C/T v/s (T/T & C/C)
C/C v/s (C/T & T/T)
OR (95%CI)
0.99 (0.66-1.49)
1.12 (0.75-1.67)
0.78 (0.41-1.47)
T2D
p-value
<0.04
OR (95%CI)
2.34 (1.16-4.74)
0.53 (0.26-1.06)
0.67 (0.20-1.93)
<0.95
<0.63
<0.50
<0.016
<0.07
<0.58
Table 4: Haplotypes in OXR1 gene with frequency >0.01 in NI case-control group
Male
Haplotype
Frequency
OR
(95%CI)
CHD
CONT
CGTAC
0.387
0.376
1.05 (0.79-1.40)
TACGC
0.320
0.347
TATGT
0.139
CATAC
Female
P
value
Frequency
OR
(95%CI)
P
value
CHD
CONT
0.75
0.340
0.346
0.97 (0.60-1.57)
0.91
0.88 (0.66-1.18)
0.40
0.307
0.425
0.60 (0.37-0.96)
0.025
0.152
0.90 (0.61-1.34)
0.59
0.187
0.122
1.65 (0.87-3.13)
0.104
0.083
0.073
1.18 (0.70-2.02)
0.56
0.120
0,064
2.0 (0.88-4.59)
0.07
TGTAC
0.019
0.009
2.22 (0.59-12.34)
0.24
-
-
-
-
TATGC
0.008
0.021
0.39 (0.10-1.43)
0.10
0.020
0.011
1.90 (0.21-22.96)
0.48
TGCGC
0.016
0.004
5.56 (0.78-242.2)
0.10
-
-
-
-
A. Male
B. Female
Figure 1: Analysis of linkage disequilibrium (LD) showed that the 5 SNPs were highly correlated. LD
patterns between the 5 SNPs were derived from genotyping data of NI male and female case control
cohorts. The pairwise correlation between the SNPs was measured as D’ and shown (x100) in each
diamond.