Transcript VDR AND ACE GENE POLYMORPHISM IN SOUTH ASIAN …

1986/T
Association Analysis of VDR, a-2-Macroglobulin, TNFRII, FcgRIIIA and ACE gene
polymorphism in South Asian Rheumatoid Arthritis patients of the East Midlands, UK.
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A. Ghelani , A. Pacynko , A. Gilmour , L. Goh , A. Jones , A. Samanta , J.I. Robinson , A.W. Morgan ,
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Isaacs , S.S. Mastana .
J.D.
1) Human Sciences, Loughborough University, Loughborough,UK; 2) Leicester Royal Infirmary, Leicester, UK; 3) City
Hospital, Nottingham,UK; 4) St. James' University Hospital, Leeds,UK; 5) University Medical School, Newcastle Upon Tyne,
UK.
Groups
A2M
TNFRII
FcgRIIIA
ACE
No 1 1 1 2 2 2 No MM RM RR No V V V F F F No II ID DD No
131 83 37 13 133 49 57 23 129 48 28 11 87 48 53 30 131
145 105 37 4 146 40 85 17 142 26 31 8 65 50 63 31 144
VDR
Bb bb
60 24
108 16
BB
RA
47
Control 21
Figure 2: A2M Ge notype s
Figure 1: VDR Ge notype s
80%
80%
60%
60%
RA
40%
RA
40%
Control
20%
Frequency
Frequenc
y
Frequency
Frequency
Control
20%
n = 131 - 145
0%
n = 133 - 146
0%
BB
Bb
bb
11
80%
80%
60%
60%
RA
40%
Control
20%
12
22
Figure 4: Fcg RIIIA Ge notype s
Figure 3: TNFRII Ge notype s
Frequency
Frequency
Rheumatoid Arthritis (RA) is a polygenic disease characterised
by localised joint destruction and osteoporosis.
The
pathogenesis of RA is not completely understood but genetic
factors may play a significant role. The genetic polymorphism
in the vitamin D receptor (VDR) gene has been described as a
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significant determinant of bone turnover and mass . A number
of studies have shown contradictory results, but there are no
studies on Asiatic Indian RA patients. Alpha-2-macroglobulin
(A2M) is involved in modulation of cytokines.
TNFRII is
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involved in tissue destruction . FcgRIIIA has an important role
in the clearance of immune complexes and polymorphism from
low affinity phenylalanine (F) to high affinity valine (V) binding
site has been reported to increase susceptibility/severity of RA
in UK Caucasian and North Indo-Pakistani groups3. One of the
biological roles for the angiotensin-converting enzyme (ACE) is
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pro-inflammatory .
ACE is expressed in the synovial
membranes
from
patients
with
RA
suggesting
pathophysiological role in the joint angiogenesis with a
possibility of localised hypertension.
The aim of this study is to assess the role of VDR, TNFRII, A2M
and ACE genotypes in the development of RA amongst South
Asians. This is a part of our ongoing genetic epidemiological
studies on South Asian RA patients.
Table 1: VDR, A2M, TNFRII, FcgRIIIA and ACE genotypes
Frequency
Frequency
Background
RA
40%
Control
20%
n = 129 - 142
n = 65 - 87
0%
0%
MM
RM
V V
RR
V F
FF
Table 2: Odds Ratio and c2 values for each genotype
Methods
The blood samples from 133 South Asians (33 males, 100
females; Age range 29 to 75 years old) with established RA
attending Rheumatology referral Clinics in the East Midland
hospitals and their siblings (brothers and/or sisters) and
random controls from same ethnic groups were collected.
Extracted DNA was amplified and analysed for VDR(Bsm1),
A2M, TNFRII(196R/M), FcRIIIgA(158V/F) and ACE(I/D) loci. The
association analysis was performed by computing Odds Ratios
and Chi Square values (P <0.05).
Results
Our results (Tables 1-Genotypes & 2-Case vs. Control comparison,
Figures 1 to 4-Genotype Frequency) indicate an increased
frequency of BB genotypes of VDR gene in Asian RA patients
compared to controls leading to highly significant differences
(c2 = 24.61, DF 2, P<0.01). Similarly A2M-22 genotype was
prominent in RA patients compared to controls (c2 = 6.75, DF 2,
P<0.05).
TNFRII loci also showed significant chi-square
differences (c2 = 6.72, DF 2, P<0.05) but the Odds Ratios were
not significant or high. The ACE I/D polymorphism was not
associated in the present sample (c2 = 0.305, DF 2, P>0.05). The
BB genotype of VDR locus was associated with RA in Asian
patients (Odds ratio = 3.30 (95% CI 1.78 – 6.24), c2 = 16.97,
P<0.005). Similarly A2M 22 genotype was associated with RA
(Odds ratio = 3.85 (95% CI 1.14 – 136.55), c2 = 4.85, P<0.005).
Groups
Odds
Ratio
( 95% CI )
c2
BB
VDR
Bb
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A2M
12
bb
22
3.3
0.29
1.81
0.65
1.14
(1.78 6.24)
(0.17 0.5)
(0.87 3.83)
(0.38 1.11)
16.97
22.58
2.39
P=
P=
0.000
0.000
[3.8 E-5] [2.0 E-6]
MM
TNFRII
RM
VV
FcgRIIIA
VF
II
ACE
ID
RR
FF
DD
3.85
1.56
0.53
1.6
1.85
0.52
1.03
1.09
0.87
1.06
(0.64 2.00)
(1.14 16.55)
(0.91 2.69)
(0.32 0.89)
(0.74 3.36)
(0.92 3.74)
(0.254 1.07)
(0.35 3.16)
(0.64 1.84)
(0.53 1.45)
(0.58 1.96)
2.45
0.11
4.85
2.52
6.04
1.41
2.85
3.14
0.00
.04
0.19
0.00
P=
P=
P=
P=
P=
P=
P=
P=
P=
p=
P=
P=
P=
0.122
0.118
0.74
0.028
0.112
0.014
0.236
0.092
0.076
1
0.837
0.667
0.947
Conclusions
Our results suggest that the VDR BB and A2M 22 genotypes
were associated with RA among South Asians. The mechanism
by which the VDR polymorphism is associated with RA is
unknown, but they could be related to immuno-regulatory
properties of vitamin D. A2M association may be due to
cytokine binding affinity which could modulate the progression
of RA. TNFRII and FcRIIIgA did not achieve statistical
significance. ACE (I/D) polymorphism was also not associated
with RA among South Asians. Additional samples are being
analysed for these loci and other RA candidate genes to
evaluate their role in pathogenesis of RA among Asiatic Indians.
References
1. Morrison et al., Nature 1994; 367: 284-7.
2. Barton et al., Arth & Rheum 2001; 44, 61-65.
3. Morgan et al. Arth & Rheum 2000; 43,2328-2334
4. Zapico et al., J Rheumatol 2000; 27, 2308-2311.
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