C Menzaghi

H Osawa

H. Makino

H. Onuma

H. Osawa

J. Ohashi

JP Ioannidis

K Azuma

MF Hivert

R. Kawamura

S Smith

Y Cho

Y. Tabara

English

PubMed

Osawa, H

Tabara, Y

Ohashi, J

Kawamura, R

Onuma, H

Makino, H

University of Melbourne Institutional Repository

Diabetologia

Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population?

Springer - Publisher Connector

LETTER
Is rs34861192 or rs1862513 a more promising variant
for determining plasma resistin in an aged Japanese population?
H. Osawa & Y. Tabara & J. Ohashi & R. Kawamura &
H. Onuma & H. Makino
Received: 21 September 2009 /Accepted: 7 December 2009 /Published online: 4 February 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Keywords Gene expression . Insulin resistance . Plasma .
Polymorphism . Protein . Resistin . Serum . SNP
Abbreviations
LD Linkage disequilibrium
SNP Single nucleotide polymorphism
To the Editor: In a recent paper, Asano et al. reported on an
analysis of single nucleotide polymorphisms (SNP) of the
human resistin gene (RETN) in an aged Japanese popula-
tion, and suggested that rs34861192 (SNP-638G>A) and
rs3745368 (3′ UTR) are significant determinants of plasma
resistin [1]. We wish to report that this statement may cause
readers to conclude erroneously that rs34861192, but not
rs1862513 (SNP-420C>G), is a causal variant determining
circulating resistin. If the functional data were to be taken
into account, the interpretation of the genetic data would be
different.
It appears to us that rs1862513 can still be considered to
be a promising candidate for a causal variant, as evidenced
from findings available to date, including their reported
results [1–5]. First, it should be noted that their conclusion
was drawn entirely from statistical analyses of genetic data.
These data should be interpreted with caution, since it is not
possible to assess the effect of A of rs34861192 indepen-
dent of G of rs1862513, due to the absence of individuals
having both the A/A genotype of rs34861192 and the C/C
genotype of rs1862513. Second, their conclusion was not
verified by functional analyses. Of rs34861192, rs1862513
and rs3219175 (SNP-358G>A, which is in complete
linkage disequilibrium [LD] with rs34861192), functional
roles have been proven only for rs1862513 in vitro [2–5].
Most crucially, when the data in Fig. 3 of Asano et al. [1]
are inspected carefully, all individuals with the A/A
genotype of rs34861192 also had the G/G genotype of
rs1862513. There were no individuals with both the A/A
genotype of rs34861192 and the C/C genotype of
rs1862513. Therefore, it is not possible to assess the effect
of A of rs34861192 independent of G of rs1862513.
Individuals with the A/A genotype of rs34861192 and the
C/C genotype of rs1862513 should have been included in
the analysis in order to determine which SNP is more
critical for determining circulating resistin levels. This does
not appear to be feasible due to the very low frequency of
H. Osawa (*) :R. Kawamura :H. Onuma :H. Makino
Department of Molecular and Genetic Medicine,
Ehime University Graduate School of Medicine,
Shitsukawa,
Toon, Ehime 791-0295, Japan
e-mail: harosawa@m.ehime-u.ac.jp
Y. Tabara
Department of Basic Medical Research and Education,
Ehime University Graduate School of Medicine,
Toon, Ehime, Japan
J. Ohashi
Doctoral Program in Life System Medical Sciences,
Graduate School of Comprehensive Human Sciences,
University of Tsukuba,
Tsukuba, Ibaraki, Japan
H. Osawa :Y. Tabara :H. Onuma
Ehime Proteo-Medicine Research Center, Ehime University,
Toon, Ehime, Japan
H. Makino
Institute of Diabetes Research Center, Takanoko Hospital,
Matsuyama, Ehime, Japan
Diabetologia (2010) 53:795–797
DOI 10.1007/s00125-010-1665-4
individuals with the combination of these two genotypes,
which may be due to limitations in genetic epidemiology
because of the available sample size. In addition,
rs34861192, rs1862513 and rs3219175 are all located in
the same LD block, and all of these three SNPs are strongly
associated with circulating resistin levels. Based on their
data, rs34861192 and rs1862513 are in moderate LD (r2=
0.47). When calculated from our previous data in 200 type
2 diabetic cases and in 200 controls [2], r2 was similar to
that of Asano et al. (r2=0.51 and 0.57, respectively),
whereas D′ was 1 in both groups. It should be pointed out
that it is difficult to identify a causal variant from highly
correlated SNPs by the exclusive use of statistical analyses
of genetic data, in the absence of other information [6].
From the functional point of view, four previously
published papers, including ours, have shown that RETN
promoter activity with G of rs1862513 is higher than that
with C (see Table 1 for summary) [2–5]. Of these papers,
two suggested that the effect of G of rs1862513 is
independent of A of rs34861192. Using SL2 cells, we
previously showed that Sp1 and Sp3 transcription factors
enhance RETN promoter activity with G of rs1862513 in
the absence of rs34861192 [2]. Smith et al. showed that
promoter activity with G of rs1862513 is ∼300% higher
than that with C of rs1862513 in 3T3-L1 adipocytes,
without rs34861192 [5]. In addition, we reported that Sp1
and Sp3 transcription factors specifically bind to DNA
sequences with G of rs1862513 [2]. In contrast, Azuma et
al. reported that the combination of risk alleles, A of
rs34861192 and G of rs1862513, showed a higher RETN
promoter activity than the other combinations of these
SNPs, suggesting that A of rs34861192 and G of rs1862513
may both be required for the highest activity. There have
been no reports on the clear function of rs34861192 and
rs3219175 to date.
It should be noted that one cannot conclude that
rs1862513 is more promising than rs34861192. First, the
association of plasma resistin with rs34861192 is much
stronger than that for rs1862513 (1×10−60 vs 1×10−24,
respectively) [1]. Given the moderate correlation between
the two SNPs (r2=0.47), it appears likely that this
association signal is driven by rs34861192. The effect of
rs1862513 appears to become more evident in the presence
of rs34861192, although functional data in support of this is
not available at this point. Second, the association between
rs1862513 and circulating resistin had been reported in
Japanese and Korean individuals [1, 2, 4], but not in white
individuals [7, 8]. Since rs34861192/rs3219175 are nearly
monophormic (very low frequencies of risk alleles) in white
individuals (dbSNP [www.ncbi.nlm.nih.gov/snp] and
dbHAPMAP [www.hapmap.org/index.html.en]), the risk
alleles of these SNPs, together with that of rs1862513,
may both be required for the highest circulating resistin
levels.
In summary, it should not be simply concluded that
rs34861192 is a stronger candidate for determining plasma
resistin concentration than rs1862513, based on the
exclusive use of statistical analyses of their genetic data
[1]. From the genetic point of view, it is difficult to
determine which is the most promising candidate, since
rs34861192, rs1862513, and rs3219175 are in the same LD
block and are strongly correlated with plasma resistin,
where the sample size used was limited. From the
functional data available to date, a significant function has
been proven only for rs1862513 [2–5]. Therefore, at this
point, it appears that rs1862513 can still be considered to be
a promising candidate for a causal variant, with the
possibility that a certain combination of these three SNPs,
including G of rs1862513, may have the strongest activity.
The function of these SNPs, including interactions between
Table 1 Comparison of human resistin gene promoter activities between G and C of rs1862513 in previous papers
Authors
[reference no.]
rs34861192
(−638G>A)
rs1862513
(−420C>G)
rs3219175
(−358G>A)
Promoter activity
(fold induction)
Cell type
Osawa et al. [2] – G G ×4 (Sp1), ×10(Sp3) SL2
Azuma et al. [3] A G G ×1.2 THP1, 3T3-L1 (fibroblast)
Cho et al. [4] N G N ×1.4 3T3-L1 (fibroblast)
Smith et al. [5] – G N ×4 373-L1 (adipocyte)
Fold induction of promoter activity with G of rs1862513 is compared with that with C of rs1862513, whereas the other SNPs are unchanged. A of
rs34861192, G of rs1862513 and A of rs3219175 are risk alleles for higher serum resistin in humans. It should be noted that Azuma et al. [3]
compared promoter activity with A of rs34861192 and G of rs1862513 (both risk alleles) with that with G of rs34861192 and C of rs1862513
(both non-risk alleles), but stated that the other two promoter reporters with risk/non-risk alleles combination had activities similar to that with the
both non-risk alleles. In all their reporter constructs, rs3219175 was G
N, a nucleotide of the SNP included in the promoter reporter constructs is not specified; –, the SNP is not included in the promoter reporter
constructs
796 Diabetologia (2010) 53:795–797
them, remains to be elucidated. Further experiments will be
required to clarify these points.
Duality of interest The authors declare that there is no duality of
interest associated with this manuscript.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
References
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2. Osawa H, Yamada K, Onuma H et al (2004) The G/G genotype of a
resistin single-nucleotide polymorphism at −420 increases type 2
diabetes mellitus susceptibility by inducing promoter activity
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3. Azuma K, Oguchi S, Matsubara Y et al (2004) Novel resistin
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Diabetologia (2010) 53:795–797 797


Crossref

A promoter genotype and oxidative stress potentially link resistin to human insulin resistance.

Association of variants in RETN with plasma resistin levels and diabetesrelated traits in the Framingham Offspring Study.

Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans.

Heritability of serum resistin and its genetic correlation with insulin resistancerelated features in nondiabetic Caucasians.

Novel resistin promoter polymorphisms: association with serum resistin level in Japanese obese individuals. Horm Metab Res 36:564–570

Onuma H et al (2004) The G/G genotype of a resistin single-nucleotide polymorphism at −420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3.

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Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population?

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