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Relative transcriptional activities of SAA1 promoters polymorphic atposition 713(T/C): Potential association between increasedtranscription and amyloidosis
MASATO MORIGUCHI1,2, HIROTAKA KANEKO1, CHIHIRO TERAI1, YUMI KOSEKI1,
HIROSHI KAJIYAMA1, SHINICHI INADA3, YUTAKA KITAMURA1, &
NAOYUKI KAMATANI1
1Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, 2Omiya Medical Center, Jichi Medical
School, Saitama, Japan, and 3Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan
(Received 2 March 2004; accepted 21 September 2004)
Keywords: Serum amyloid A, AA-amyloidosis, polymorphism, luciferase reporter gene assay
Abbreviations: RA, rheumatoid arthritis; FMF, familial Mediterranean fever; SAA, serum amyloid A; SNP, singlenucleotide polymorphism; A-SAA, acute phase serum amyloid A
AbstractThe risk associated with the serum amyloid A (SAA) 1 gene and developing AA-amyloidosis is still controversial. In familialMediterranean fever or Caucasoid rheumatoid arthritis (RA), the SAA1.1 allele is a risk factor for the development of AA-amyloidosis. However, individuals with the SAA1.3 allele are susceptible to AA-amyloidosis in the Japanese RA population,but those with the SAA1.1 are not. Previous reports have indicated that the7 13T/C single nucleotide polymorphism (SNP)at the 5’-flanking region of SAA1 appears to be a better marker of AA-amyloidosis than the exon-3 based haplotype, i.e.,SAA1.1 or SAA1.3, in both Japanese and American Caucasian populations. So far, it is unknown why the 7 13T SNPincreases the amyloidogenicity of the patients. In the present study, a luciferase reporter gene assay showed that thetranscriptional activity of the SAA1 having the 7 13T-containing promoter was significantly higher than activities of thosewith 7 13C-containing promoters (Fisher’s protected least significance difference test). We suggest that having the 7 13TSNP in the SAA1 promoter correlates with the amyloidogenicity in part as a result of this increased transcriptional activity.
Introduction
Reactive AA-amyloidosis is a serious complication of
both rheumatoid arthritis (RA) and familial Medi-
terranean fever (FMF). The precursor protein in
AA-amyloidosis is serum amyloid A (SAA), which is
an acute phase protein mainly synthesized in the liver
by stimulation with proinflammatory cytokines, such
as IL-1, TNF-a and IL-6 [1]. The SAA1 and SAA2
genes on the short arm of chromosome 11 code acute
phase SAA (A-SAA) proteins, SAA1 and SAA2,
respectively. While an MEFV missense mutation,
M694V, is associated with a severe course of FMF
and developing AA-amyloidosis [2–8], the risk
associated with the SAA1 gene and developing AA-
amyloidosis is still controversial. Although homo-
zygosity for SAA1.1 is reported to be a risk factor for
the development of AA-amyloidosis in patients with
FMF [9–11] and in Caucasians with RA [12,13], this
is not the case in the Japanese RA population. The
SAA1.3 allele and not the SAA1.1 allele was closely
associated with AA-amyloidosis in Japanese RA
patients [14–17], with the SAA1.1 allele frequency
being significantly less in Japanese AA-amyloidosis
patients than in controls. In order to resolve this
discrepancy, we searched for new single nucleotide
polymorphisms (SNPs) in the 5’-flanking region of
the SAA1 sequence. We found one SNP, 7 13T/C
SNP, which correlated with the presence of AA-
amyloidosis in Japanese RA patients more strongly
than the SAA1.3 allele [18]. In that study, we
suggested that the 7 13T/C SNP represented a
superior marker of AA-amyloidosis than the exon-3
based haplotype SAA1.1 or SAA1.3. Recently, two
Correspondence: Dr. Masato Moriguchi, Omiya Medical Center, Jichi Medical School, 1-847 Amanuma-cho, Omiya-ku, Saitama-shi, 330-8503, Japan.
Tel: 81-48-647-2111. Fax: 81-48-648-5188. E-mail: mmorigu@omiya.jichi.ac.jp
Amyloid, March 2005; 12(1): 26–32
ISSN 1350-6129 print/ISSN 1744-2818 online ª 2005 Taylor & Francis Group Ltd
DOI: 10.1080/13506120500032394
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different papers were published regarding the asso-
ciation between the 7 13T/C SNP and AA-
amyloidosis. Gershoni-Baruch et al. examined the
7 13T/C SNP in a population of FMF patients in
Israel [11] and found no association between the
7 13T/C SNP and the susceptibility to renal
amyloidosis. The other study, by Yamada et al.,
established a positive association between the 7 13T
SNP and AA-amyloidosis in both American Cauca-
sian and Japanese populations [13]. In that paper,
they found significantly higher allele frequencies of
both SAA1.1 and the 7 13T SNP in American
Caucasian patients with AA-amyloidosis compared
to controls. In addition, the relation between the
7 13T SNP and AA-amyloidosis was much closer
than that between the SAA1.1 allele and AA-
amyloidosis in the American Caucasian population
(w2 = 12.30, p5 0.001 versus w2 = 7.33, p5 0.01,
respectively).
We suspect that functional differences between the
7 13T-containing SAA1 promoter and the 7 13C-
containing promoter affect the susceptibility to AA-
amyloidosis in both the American Caucasian and
Japanese populations. To elucidate this issue, we
have compared the activity of the promoter between
the 7 13T-containing cis-regulating element and the
7 13C-containing one using a luciferase reporter
gene assay.
Materials and methods
Determination of the haplotypes of the SAA1 promoter
and SAA1 genotypes
Each SNP at 7 2A/G, 7 13T/C and 7 61C/G in the
SAA1 promoter region was determined in genomic
DNA samples from 157 Japanese individuals,
including 44 RA patients with AA-amyloidosis, 55
RA patients without AA-amyloidosis and 58 healthy
controls, according to methods previously described
[18]. The haplotype frequencies of SAA1 SNPs
containing 3 SNPs at the promoter region and 2
SNPs at exon-3 were determined by the LDSupport
program developed in our laboratory [19,20]. This
program was designed for haplotype typing using a
maximum likelihood estimation method based on
the expectation-maximization algorithm.
Cells and reagents
Human hepatoma cell line, HepG2, was purchased
from DAINIPPON PHARMACEUTICAL CO.,
LTD. (Osaka, Japan). The cells were maintained in
5% CO2 at 378C in Eagle’s minimum essential
medium (MEM) with 10% fetal bovine serum and
supplemented with 1 mM sodium pyruvate, 1%
MEM nonessential amino acids, 2% L-glutamine,
100 U/ml penicillin and 100 mg/ml streptomycin.
Human recombinant IL-1b and IL-6 were purchased
from R&D Systems (Minneapolis, MN).
SAA1 promoter-luciferase construct
Using primers 5’-GTG CAG TGG CGT GAT
TAT AG-3’ and 5’-GAA GAT CTT CGT GCT
GTA GCT GAG CTG CGG-3’, the PCR
products of the promoter region of SAA1 were
obtained from the patient’s genomic DNA. In-
formed consent was obtained from all DNA
donors. After digestion with Bgl II, the PCR
fragments (560 bp of the promoter region of
SAA1, 7 534 to + 26) were subcloned into the
Bgl II site of the pGL-3 basic vector, which has a
down stream luciferase (Promega Madison, WI).
The insertion direction was confirmed by DNA
sequencing. We prepared 4 types of SAA1 pro-
moter-luciferase constructs based on 3 SNPs, at
7 61, 7 13 and – 2, of the SAA1 promoter region,
and designated them the 7 13C1(C-C-G),
7 13C2(G-C-G), 7 13C3 (G-C-A) and 7 13T(C-
T-G) promoter constructs (Figure 1A).
Transient transfection and luciferase assay
HepG2 cells were transfected with 0.25 mg of the
SAA1 promoter-luciferase construct and 0.006 mgof the pRL-TK vector (Promega), using FuGENE6
(Roche, Indianapolis, IN) according to the manu-
facture’s instructions. At 12 h after transfection,
the cells were stimulated with IL-1b (10 ng/ml)
and IL-6 (10 ng/ml) and harvested in the provided
lysis buffer, 0, 4, 6, 8, 16 and 24 h later. After
centrifugation of the cell solutions, the super-
natants were assayed for Firefly and Renilla
luciferase activity, using a TD-20/20 Luminometer
(Promega). The Firefly luciferase activity was
normalized to Renilla luciferase activity.
The relative luciferase activity of the 7 13C2,
7 13C3 or 7 13T promoter was expressed as a ratio
to the luciferase activity of the 7 13C1 promoter.
Data were obtained in duplicate from each experi-
ment, which was repeated 3 times. Relative luciferase
activity data for cultures harvested at 6 h after
stimulation with cytokines were subjected to analysis
of variance (ANOVA), and the differences were
determined by the one-way ANOVA followed by
Fisher’s protected least significance difference
(PLSD) test and other methods of post-hoc compar-
isons (Dunnett’s test and Tukey’s tests). For the
non-parametric analyses of time course luciferase
activity data, we applied Friedman’s test and after-
wards ran the Nemenyi’s test for multiple
comparisons to check which of the 2 groups was
significant.
SNPs at SAA1 and transcriptional activities 27
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Figure 1. Comparison of transcriptional activity between the 713C-containing SAA1 promoter and the 713T-containing SAA1
promoter. As described in ‘‘Materials and methods,’’ HepG2 cells were cotransfected with the SAA1 promoter-luciferase construct and
pRL-TK. Twelve h after transfection, cells were stimulated with IL-1b (10 ng/ml) and IL-6 (10 ng/ml). Cells were harvested and tested for
Firefly and Renilla luciferase activity at 6 h (B) or the indicated times (C). The Firefly luciferase activity was normalized to the Renilla activity.
(A) Schematic of 4 SAA1 promoter-luciferase constructs generated from 4 haplotypes of SAA1 promoter based on 3 SNPs 761C/G,
713T/C and7 2 A/G. Each SAA1 promoter construct was inserted into the pGL3 basic vector. (B) Transcriptional function of each SAA1
promoter. Each relative luciferase activity of the7 13C2,713C3 or 713T promoter is expressed as a ratio to that of the 713C1 promoter.
Each bar represents the mean of triplicate relative luciferase activities calculated as above, whilst the error bar represents SD of 3
experiments. (C) Comparison of time course data for the transcriptional function of each promoter. X-axis indicates duration of stimulation
with IL-1b (10 ng/ml) and IL-6 (10 ng/ml). The relative luciferase activity at each time point was expressed as a ratio to that at the point 0-h
in each promoter construct. We used Friedman’s test to analyze the effect of allelic variances on the luciferase reporter gene activities. Each
bar represents the mean of triplicate experiments whilst the error bar represents SD.
28 M. Moriguchi et al.
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Results
Haplotype frequencies of SNPs in the SAA1 promoter
and exon-3
In the analysis of 157 Japanese, we found 4 major
haplotypes of the SAA1 promoter based on 3 SNPs
at 7 61, 7 13 and 7 2 of the SAA1 promoter
region, and designated them 7 13C1(C-C-G),
7 13C2(G-C-G), 7 13C3 (G-C-A) and 7 13T(C-
T-G). The SAA1 allelic variants were determined
using a combination of 2 SNPs (2995C/T and
3010C/T) from the exon-3 region of the SAA1 gene
as previously reported [14,16]. The combinations of
SNPs at 2995 and 3010 of SAA1.1, SAA1.3 and
SAA1.5 are T-C, C-C and C-T, respectively. The
7 13C1 and 7 13T promoters were found to be
mainly linked to SAA1.1 and SAA1.3, respectively,
and both the 7 13C2 and 7 13C3 promoters to
SAA1.5 (Table I). The 7 13T/SAA1.3 haplotype
was the most frequent of all haplotypes found in the
Japanese AA-amyloidosis population.
Luciferase reporter gene assay
To compare the transcriptional activities of the 4
haplotypes of the SAA1 promoter, i.e., the 7 13C1,
7 13C2, 7 13C3 and 7 13T promoters, we pre-
pared 4 luciferase reporter gene constructs, each
including one of the SAA1 promoters (Figure 1A).
A-SAA is mainly synthesized by the liver, so we
chose the hepatocellular carcinoma cell line HepG2
for transfection. These cells have been shown to
produce significant amounts of A-SAA after treat-
ment with IL-1 and IL-6, the principal cytokines
involved in the up-regulation of A-SAA production
[21].
The luciferase activity of each SAA1 promoter
reached a maximum 6 h after stimulation with IL-1band IL-6 in a preliminary experiment (data not
shown). As shown in Figure 1B, after 6-h stimulation
with cytokines the relative luciferase activities of the
7 13C1, 7 13C2, 7 13C3 and 7 13T constructs
were 1, 0.88+ 0.15, 0.61+ 0.13, and 1.31+ 0.25
(mean+SD), respectively. By one-way ANOVA, we
found significant differences in transcriptional activ-
ity among the 4 luciferase reporter gene constructs
(F=9.97, p5 0.01), and so we applied post-hoc
analyses to determine which of each two groups was
significant. The relative luciferase activity of the
7 13T haplotype was significantly higher than the
other 3 haplotypes by Fisher’s PLSD test (p-values
for 7 13T versus 7 13C1, 7 13C2, and 7 13C3
were 5 0.05, 5 0.02, and 5 0.001, respectively).
Additionally, the transcriptional activity of 7 13C1
was higher than that of 7 13C3 (p5 0.02). Other
post-hoc tests, Dunnett’s and Tukey’s tests, also
indicated significant differences (p5 0.05) between
7 13T versus 7 13C2 and 7 13T versus 7 13C3.
Figure 1C illustrates a time course of the relative
promoter activities of the 7 13C1, 7 13C2, 7 13C3
and the 7 13T haplotypes. In this experiment, we
stimulated each group of cells with IL-1 and IL-6 for
4, 8, 16, or 24 hours. For each promoter construct
the relative luciferase activity at each time point was
measured and expressed as a ratio to that at the 0-h
time point. We used Friedman’s test to analyze the
effect of allelic variances on the luciferase reporter
gene activities. The factor of allelic variances
influenced the luciferase activity with an overall
significance (Friedman’s w2 = 10.69 with 3 degrees of
freedom, p5 0.02), indicating that there were
significant differences in the transcriptional activities
among the different SNPs in the SAA1 promoter
region. Further analysis using Nemenyi’s test for
multiple comparisons determined that only the
difference between 7 13T and 7 13C3 was signifi-
cant (p5 0.05).
Discussion
It is clear that the genotypes at the SAA1 locus are
associated with a susceptibility to develop AA-
Table I. Haplotype frequencies of the SAA1 promoter linked to the exon-3 based SAA1 allele.
Promoter haplotype/SAA1 allele Rheumatoid Arthritis Control
Amyloid ( + ) Amyloid (7)
(Number of alleles) (88) (110) (116)
713C1/SAA1.1 6.1% 31.6% 29.7%
713C2/SAA1.5 20.2 26.6 20.3
713C3/SAA1.5 1.4 6.2 4.2
713T/SAA1.3 60.9 26.3 38.1
713T/SAA1.1 1.2 1.8 –
713T/SAA1.5 4.1 4.5 6.0
713C1/SAA1.3 1.2 0.9 –
713C2/SAA1.3 – – 0.9
Others 4.9 2.0 0.8
SNPs at SAA1 and transcriptional activities 29
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amyloidosis, although it appears that the susceptible
alleles differ amongst different ethnic populations
[9–17]. So far, there has been no reported study
indicating the mechanism whereby the allelic
variants at the SAA1 locus influence amyloidogeni-
city.
In cases of long-standing inflammatory diseases
like RA or FMF, amyloid A proteins derived from
the N-terminal of the A-SAA protein form amyloid
fibrils and deposit in the extra cellular region of
multiple organs. After a period of several years to
decades, the patient’s condition may be complicated
by multiple organ failure. Several processes, includ-
ing the production of the A-SAA protein, its
conversion to amyloid A protein, and the rate of
tissue deposition, are thought to correlate with the
susceptibility to AA-amyloidosis.
Our previous data suggested that an SNP in the 5’-
flanking region of SAA1, 7 13T/C, was more closely
associated with AA-amyloidosis than 2 SNPs in the
coding region (2995C/T and 3010C/T). Another
group also confirmed this association and its useful-
ness as a predictor of AA-amyloidosis in an
American Caucasian population [13]. We focused
on the transcription of SAA1 in the present study.In
luciferase reporter gene assays, we demonstrated that
the 7 13T promoter exhibited greater transcrip-
tional activity compared to the other cis-regulating
elements, 7 13C1, 7 13C2 and 7 13C3, after a 6-hr
stimulation with IL-1b and IL-6 (Figure 1B).
In the Japanese population, the promoter SNPs
7 13T and 7 13C1, in the 5’-flanking region of
SAA1, exhibit strong linkage disequilibrium to the
SAA1.3 and SAA1.1 alleles, respectively, and both
7 13C2 and 7 13C3 are linked to the SAA1.5 allele
as shown in Table I. Previous studies have demon-
strated that, in different ethnic populations, the
SAA1.1 or SAA1.3 allele exhibits stronger amyloi-
dogenicity than SAA1.5 [9–17]. This may result
from a greater transcriptional activity of the promo-
ters, SAA1.1 or SAA1.3 (i.e., 7 13C1 or 7 13T)
compared to that of SAA1.5 (i.e., 7 13C2 or
7 13C3).
According to Yamada et al., the serum A-SAA
protein concentration appeared to vary among the
3 SAA1 genotypes [16]. The serum concentration
ratios of A-SAA to C-reactive protein (CRP) were
significantly higher in the population carrying the
SAA1.5 genotype than in either the SAA1.1 or
SAA1.3 genotype population. The data from our
luciferase reporter gene assay seem inconsistent
with Yamada’s results. However, an increased
transcriptional activity does not necessarily result
in an elevated serum protein concentration as
many factors, such as mRNA stability, A-SAA
protein degradation and transfer to extra vascular
regions, may influence the serum concentration of
the A-SAA protein. The serum concentration of
the A-SAA protein may depend upon the rate of
protein production and metabolism. Therefore,
even if the SAA1.1 or SAA1.3 protein can be
produced more readily than the SAA1.5 protein, it
may be cleared more rapidly so that the serum
concentration might settle at lower levels, as were
found in Yamada’s report. In fact, Yamada’s latest
paper showed that recombinant human SAA1.5
disappeared from plasma more slowly than the
other isotypes, SAA1.1 and SAA1.3 [22]. If faster
clearance of SAA correlates with higher production
of amyloid A fibrils, individuals with the SAA1.5
allele should be less susceptible to AA-amyloidosis
than those with other alleles. Therefore, our results
from the luciferase reporter gene assays and
Yamada’s results would support a hypothesis that
greater production and faster clearance of SAA1
are associated with the susceptibility to AA-
amyloidosis.
We previously demonstrated a significant negative
correlation between the number of SAA1.3 (SAA1g)alleles and the duration of RA, prior to a diagnosis of
AA-amyloidosis. Conversely, a significant positive
correlation was found between the number of
SAA1.3 alleles and the mean CRP level before a
diagnosis of AA-amyloidosis [15]. In addition, we
found that the SAA1.3 allele was associated with the
clinical severity of AA-amyloidosis, including symp-
toms of hypoalbuminemia and massive proteinuria
compared to other SAA1 alleles [17]. These clinical
findings indicated that the SAA1.3 allele possibly
results in enhanced inflammatory responses in
patients with AA-amyloidosis. As most of the
SAA1.3 genotypes carry the 7 13T SNP at the
SAA1 promoter region (Table I), the 7 13T SNP
possibly accelerates response of many cytokines
through an increase in transcriptional activity and
production of A-SAA. In fact, previous studies have
provided data indicating that A-SAA has cytokine-
like abilities, such as induction of synthesis of matrix
metalloproteinases [23], IL-1b [24,25], IL-1 recep-
tor antagonist, soluble TNF-a type II receptor [24],
TNF-a [25] and IL-8 [25,26]. Recently, He et al.
showed that A-SAA stimulates NF-kB activation,
phosphorylation of ERK1/2 and p38, and transcrip-
tion of the IL-8 gene through a G protein-coupled
receptor, FPRL1/LXA4R [26]. It is possible that the
SAA1 promoter having the7 13T SNP increases the
production of A-SAA in an autocrine manner by
NF-kB activation, through the FPRL1/LXA4R
signaling pathway. Although the difference in the
transcriptional activity between the 7 13T and
7 13C promoters, especially 7 13T versus
7 13C1, seems small, an accumulative effect on the
long-standing inflammation of RA may result in a
large difference in amyloidogenicity.
30 M. Moriguchi et al.
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In conclusion, we suggest that the susceptibility to
AA-amyloidosis may be modulated by the 7 13T
SNP of the SAA1 promoter as a result of the
increased transcriptional activity of the SAA1 gene.
So far, we cannot deny the possibility that the SNPs
in the coding region of SAA1 may correlate with the
amyloidogenicity through a different property of the
SAA1 isotypes. Further studies are necessary to
determine which are the predominant SNPs, coding
or non-coding, associated with the susceptibility to
AA-amyloidosis.
Acknowledgments
This work was supported by grants from the Ministry
of Education, Science, and Culture of Japan
(No.13670479 and 15591066).
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