Correlation analysis of gene polymorphisms and β-lactam allergy
J Zhejiang Univ-Sci B (Biomed & Biotechnol)
Correlation analysis of gene polymorphisms and ?-lactam allergy*
Jing LI 0
Xin-yue LIU 0
Lin-jing LI 0
Chong-ge YOU 0
Lei SHI 0
Shang-di ZHANG 0
Qian LIU 0
Jun WANG 0
Ze-jing LIU 0
Ting-hong LV 1
0 Centre of Laboratory Medicine, Lanzhou University Second Hospital , Lanzhou 730030, China) (
1 School of Basic Medical Science, Lanzhou University , Lanzhou 730030 , China)
2 Project supported by the Natural Science Foundation of Gansu Province , China (Nos. 3ZS061-A25-084 and 1208RJZA192) , the Key Laboratory of Digestive System Tumors of Gansu Province, and the Fundamental Research Funds for the Central Universities (No. lzujbky-2011-t03-15), China ORCID: Xin-yue LIU
A total of 64 patients with ?-lactam allergy and 30 control subjects were enrolled in a case-control study. This study is aimed to analyze the relationship between ?-lactam allergy and 10 single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10), IL-13, IL-4R?, high-affinity immunoglobulin E-receptor ? chain (Fc?RI?), interferon ? receptor 2 (IFNGR2), and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom MassARRAY? platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males (P=0.022; odds ratio (OR)=0.167, 95% confidence interval (CI): 0.032-0.867). Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with ?-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and ?-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls.
Allergy; ?-Lactam; Interleukin (IL); Pharmacogenomics; Single nucleotide polymorphism (SNP) doi; 10; 1631/jzus; B1400309 Document code; A CLC number; R394; 6
?-Lactams are widely used in clinical practice
worldwide. However, it is difficult to prevent adverse
reactions of the drug
(Prematta et al., 2012; Torres
et al., 2014)
. Penicillin G presented the most serious
allergic reactions with an incidence of 0.7%?10%,
and anaphylactic shock with an incidence of 0.004%?
0.018%, within which there was a 10%?20%
mortality rate. The incidence of skin rash as a result of using
ampicillin is greater than 10%. Urticaria,
angioneurotic edema, gastrointestinal reactions, and aplastic
anemia are the most common allergic symptoms,
which may lead to anaphylactic shock and death
(Bousquet et al., 2009; Comte et al., 2012; Lee, 2014)
However, the mechanism of ?-lactam antibiotics
inducing the allergic reactions remains unclear
(Comte et al., 2012).
The present study attempts to identify the
underlying genetic mechanisms involved in the allergic
reactions caused by ?-lactam antibiotics. The
correlation between ?-lactam allergy and the single
nucleotide polymorphisms (SNPs) of genes such as
interleukin-10 (IL-10) rs1800871, IL-10 rs1800872,
IL-10 rs1800896, IL-13 rs20541, IL-13 rs1881457,
IL-13 rs1800925, IL-4R? rs1801275, high-affinity
immunoglobulin E-receptor ? chain (Fc?RI?) rs569108,
interferon ? receptor 2 (IFNGR2) rs9808753, and
CYP3A4 rs2242480 was assessed within the Han
Chinese population of Northwest China by
performing multiplex polymerase chain reaction (PCR)
using iPLEX single-base extension technology from
Sequenom MassARRAY? (Bo?ao Biotechnology Co.,
Beijing, China) and matrix-assisted laser desorption/
ionization-time of flight (MALDI-TOF). The
relationship between the haplotype and ?-lactam allergy
was also further analyzed. This study provides data
concerning the genetic diagnosis for patients with
?-lactam allergy, and further clarifies the relationship
between pharmacogenomics and the efficacy and
safety of drugs. These findings also provide evidence
that several new genetic targets can be utilized in the
diagnosis and prevention of the adverse drug
reactions to antibiotics and that treatment can be provided
for a specific target gene with polymorphic variation.
2 Materials and methods
The subjects for this study were recruited from
the outpatient department of Lanzhou University
Second Hospital (Lanzhou, China) between Jan. 2010
and Apr. 2013. The allergic work-up was performed
according to the European Network for Drug Allergy
guidelines (Torres et al., 2002; 2003). The case group
had to have a history compatible with an immediate
reaction to ?-lactam and with a positive result of skin
tests. Skin tests were made with major and minor
determinants of benzyl penicillin (penicilloyl-polylysine
and minor determinant mixture (MDM) containing
benzyl-penicillin, sodium benzyl-penicilloate, and
benzyl-penicilloic acid at a final concentration of
1.5 mmol/L) (Torres et al., 2003;
Gu?ant et al., 2015
The control group included the patients who
presented negative skin test to ?-lactam and had no
history of allergic, dermatologic, or respiratory diseases,
or autoimmune diseases such as asthma, eczema,
allergic rhinitis, and urticaria. All the subjects were
selected from the Han Chinese population of
Northwest China and matched for age, race, and gender. Of
the 94 patients enrolled, 64 (33 males and 31 females)
were included in the case group (mean age:
(42.04?14.4) years) and 30 (15 males and 15 females)
were included in the control group (mean age:
(41.73?6.06) years). There was no significant
differences in the average age or gender between the two
The study protocol and medical informed
consent were approved by the ethical committee of
Lanzhou University Second Hospital (Lanzhou,
China). In accordance with the medical informed
consent, 3 ml of whole blood was drawn in ethylene
diamine tetraacetic acid (EDTA) tubes from all subjects,
and was stored at ?20 ?C whilst awaiting analysis.
2.2 Genomic DNA extraction
Genomic DNA was extracted from 200 ?l of
venous blood anticoagulated with EDTA using the
QuickGene DNA whole blood kit (Shenggong,
Shanghai, China) as per the manufacturer?s
instructions. All DNA samples were tested using the
NanoDrop 2000 spectrophotometer (Thermo
Scientific, USA) for evaluation of template quality and
quantity, and then adjusted to a concentration of
20 ng/?l and stored at ?40 ?C.
2.3 Gene polymorphism analysis of the SNPs
The following 10 SNPs of six genes that might
increase the susceptibility to ?-lactam allergy were
selected: IL-10 rs1800871, IL-10 rs1800872, IL-10
rs1800896, IL-13 rs20541, IL-13 rs1881457, IL-13
rs1800925, IL-4R? rs1801275, Fc?RI? rs569108,
IFNGR2 rs9808753, and CYP3A4 rs2242480. The
primers were synthesized by Invitrogen Co.
(Shanghai, China; Table 1). The iPLEX? Gold Reagent kit
(SEQUENOM Co., USA) was used for SNP genotyping.
MassARRAY Nanodispenser RS1000 (SEQUENOM
Co., USA) was used for chip spotting. MassARRAY
Analyzer Compact (SEQUENOM Co., USA) was
used for mass spectrometry detection and analysis.
2.4 Plex PCR
Plex PCR was performed with a total volume of
5 ?l, and the reaction mixture contained 10 ng DNA,
0.5 U Hotstar Taq, 0.5 pmol of each primer, and 0.1 ?l
of 25 mmol/L dNTP. The PCR reaction conditions
were as follows: 94 ?C for 4 min; 45 cycles of 94 ?C
for 20 s, 56 ?C for 30 s, and 72 ?C for 1 min; final
3 min extension at 72 ?C, and then kept at 4 ?C.
2.5 Purification of the PCR product
Firstly, the remanent dNTP was removed by
adding 0.5 U shrimp alkaline phosphatase (SAP) into
the PCR product. The reaction mixture that contained
5 ?l PCR product and 2 ?l SAP buffer (0.5 U SAP,
0.17 ?l buffer) was incubated at 37 ?C for 20 min and
85 ?C for 5 min and then kept at 4 ?C.
2.6 Single-base extension and resin purification
In total, 7 ?l SAP-treated PCR product, 0.804 ?l
primer mixture, 0.041 ?l iPLEX, and 0.2 ?l extension
mixture were combined in an Eppendorf tube. The
reaction conditions were as follows: 94 ?C for 30 s; 40
cycles of 94 ?C for 5 s, 52 ?C for 5 s, 80 ?C for 5 s, and
94 ?C for 5 s; and final 3 min extension at 72 ?C. Each
extension product was purified using 6 mg Clean
Resin (SEQUENOM Co., USA).
2.7 Chip spotting and mass spectrometric examination
The purified product was examined by Spectro
CHIP (SEQUENOM Co., USA). SpectroCHIP was
analyzed by MALDI-TOF, and the results were
exported using TYPER Version 4.0 (SEQUENOM Co.,
2.8 Statistical analysis
All data were analyzed using statistical software
SPSS 17.0. The relationships between the nine SNPs
and ?-lactam allergy susceptibility were assessed
using chi-square test for estimation of the odds ratio
(OR) and 95% confidence interval (CI) for each SNP
genotype. Hardy-Weinberg equilibriums of each SNP
in the control group were tested using chi-square test.
All the statistics were inspected using bilateral
probability, and statistical significance was
determined as being below the conventional level of
P=0.05. Moreover, the online SHEsis software
was used to analyze the linkage
disequilibrium (LD) and haplotype construction. D' and r2
were calculated for LD analysis.
3.1 SNPs associated with ?-lactam allergy
In order to increase statistical power,
homozygous mutant genotypes were merged into
heterozygous genotypes to conduct statistical analysis. For
gender and age, no significant statistical difference
was found between the trial group and the control
group. The results showed that the nine SNPs such as
rs1800871, rs1800872, rs1800896, rs20541, rs1881457,
rs1800925, rs1801275, rs569108, and rs9808753
were not significantly correlated with ?-lactam
allergy in the Han Chinese population of Northwest
China between the case and control groups (P>0.05;
Table 2). The rs2242480/CT genotype of CYP3A4
gene was significantly correlated with ?-lactam
allergy in the male patients (P=0.022, OR=0.167, 95%
CI: 0.032?0.867; Table 3).
3.2 LD analysis
Three SNPs of IL-10 such as rs1800871,
rs1800872, and rs1800896 were located at the
promoter region of IL-10 (separation distance <100 bp).
The LD analysis was performed to study the
relationships between these three SNPs and ?-lactam
allergy. For patients with ?-lactam allergy in the Han
Chinese population of Northwest China, rs1800872
and rs1800871 showed complete linkage; rs1800896
and rs1800872, rs1800896 and rs1800871,
respectively, showed strong linkage (Table 4).
The LD analysis on three SNPs of IL-13 showed
that rs1881457 and rs1800925 had strong linkage,
rs1800925 and rs20541 had strong linkage. However,
rs1881457 and rs20541 did not show LD (Table 5).
Three SNPs of IL-10 and IL-13 exhibited LD. The haplotype was constructed to analyze the effect of the LD on ?-lactam allergy in the Chinese Han population of Northwest China.
The SNPs such as rs1800871, rs1800872, and
rs1800896 showed complete linkage. Three
haplotypes were found in the three SNPs of IL-10 gene:
CCA, CCG, and TAA, respectively. These haplotypes
were observed in the case and control groups
(F=0.895, 0.905, and 0.851, respectively). None of
the three haplotypes correlated with ?-lactam allergy
in the Han Chinese population of Northwest China
Six haplotypes were observed in rs20541,
rs1881457, and rs1800925 of IL-13. Four of them
were observed in the case and control groups that
included CAC, CCC, TAC, and TCT (F=0.069, 0.500,
0.928, and 0.238, respectively). Hence, these four
haplotypes were not correlated with the ?-lactam
allergy in the Han Chinese population of Northwest
China. Among these six haplotypes, CCT was only
observed in the control group (F=0.026). The F-value
of CAC was a marginal value of 0.069 (Table 6).
4.1 Relationship between genetic polymorphisms of T cell-related cytokine and ?-lactam allergy
T cells play an important role in ?-lactam allergy.
They are reported to be involved in various types of
(Kim et al., 2005; Rubio et al., 2010)
T helper (Th) 1 and Th2 cells are the two types of T
cells. Th2 cells can be involved in immunoglobulin E
(IgE)-mediated immediate hypersensitivity as they
promote the secretion of cytokines such as IL-4, IL-5,
IL-6, IL-10, and IL-13 (Palomares, 2013).
IL-10 can inhibit the clonal expansion of Th0,
Thl, and Th2 cells
, and it plays an
important role in the occurrence and development of
allergy. This study selected rs1800871, rs1800872,
and rs1800896, which directly affected the expression
Apter et al. (2008)
reported that there was
no significant correlation between IL-10 genetic
polymorphism and ?-lactam allergy.
Guglielmi et al.
suggested that IL-10 promoter and IL-4R?
genetic polymorphisms were related to immediate
?-lactam allergy in female patients. The results of
present study show that rs1800872 of IL-10 was not
correlated with ?-lactam allergy in the Han Chinese
population of Northwest China. Additionally, three
types of haplotype, CCA, CCG, and TAA of IL-10,
were not found to be correlated with ?-lactam allergy
in the Han Chinese population. The study data were
consistent with the findings of
Apter et al. (2008)
however, it was not consistent with that of
et al. (2006)
. The reason might be that because our
SNP chip is based on Sequenom MassARRAY?
technology which is used to perform high-throughput
sequencing. The chip presented high sensitivity and
specificity, so the results are more reliable. The
researchers have utilized different technologies
including classic sequencing and high-sensitive PCR.
The threshold for the detection of gene expression
might be further explored using such procedures.
Guglielmi et al. (2006)
Apter et al. (2008)
proved that other important factors, such as race,
region, and environmental conditions, can also
influence the distribution of genotype.
The IL-4R? gene was located on chromosome
16p11?16p12. It is a subunit that plays a key role in
allergic disease by promoting the IgE production (Wu
and Scheerens, 2014). The present study showed that
the distribution frequency of rs1801275 of IL-4R?
was not significantly different between the groups
(P>0.05), and the same results were obtained when
the patients were stratified by gender (P>0.05).
IL-13 was mainly involved in the allergic
reactions through inducing the B lymphocytes to secrete
(Ford et al., 2001)
. IL-13 and IL-4
were isogenous, because of their chromosomal
localization and the molecular composition of proteins.
Additionally, the sharing receptor structure presented
the same signal pathway, and it also demonstrated
similar physiological functions. IL-13 can indirectly
play a role in eosinophils by upregulating the
expression of eotaxin, and the effect of IL-13 was
greater than that of IL-4
(Levine and Wenzel, 2010)
The present study results showed that the distribution
frequencies of three SNPs of IL-13 gene such as
rs20541, rs1881457, and rs1800925 were not
significantly different between the case and control groups
(P>0.05). The same results were obtained when the
patients were stratified by gender (P>0.05). Six
haplotypes were constructed on these three SNPs of IL-13
gene, in which CCT was only one observed in the
control group (F=0.026) but not in the case group.
The F-value of CAC was 0.069. Therefore, the
relationship between these two haplotypes and ?-lactam
allergy in the Han Chinese population of Northwest
China requires further study.
4.2 Relationship between ?-lactam allergy and other genetic polymorphisms
The study of SNPs of Fc?RI? and IFNGR2
mainly focused on their relationships with allergic
diseases such as asthma
(Kim and Park, 2006; Sanak
et al., 2007)
and allergic rhinitis (Nagata et al., 2001),
and was used to treat malignant tumors such as
(Purdue et al., 2007; Chen
et al., 2011)
and gastric cancer (Hou et al., 2007).
IFNGR1 was reported to correlate with ?-lactam
allergy, however, the relationship between SNP of
IFNGR2 and ?-lactam allergy was not clear. The
study showed that the SNPs of both Fc?RI? and
IFNGR2 were not correlated with ?-lactam allergy.
4.3 Relationship between CYP3A4 gene polymorphism and ?-lactam allergy
Cytochrome P450 is widely distributed across all
living organisms including vertebrates, invertebrates,
plants, fungi, and bacteria. It was one of the most
widely distributed enzymes of phase I drug
metabolism, and it presented the richest natural content and
the broadest substrate spectrum. Furthermore, CYP is
distributed in various organs and tissues of the human
body. CYP3A subfamily was one of the major
ratelimiting enzymes in drug metabolism
(Gellner et al.,
. Four genotypes were involved in drug
metabolism in humans including CYP3A4, CYP3A5,
CYP3A7, and CYP3A43
(Gibson et al., 2002)
The correlation between the SNPs of CYP3A4
and ?-lactam allergy was not reported in the past, and
we found that the rs2242480 of CYP3A4 gene was
correlated to ?-lactam allergy in male patients. The
frequency of genotype CT was significantly different
between the case and control groups when compared
with the wild-type gene CC (P=0.022; OR=0.167,
95% CI: 0.032?0.867).
The study provides evidence about the genetic diagnosis for patients with ?-lactam allergy in the Han Chinese population of Northwest China. CYP3A4
polymorphism was found to correlate with ?-lactam
allergy in male patients. The relationships between
?-lactam allergy and haplotypes CCT and CAC from
rs20541, rs1881457, and rs1800925 of IL-13 need to
be further studied using a larger sample. The roles of
these sites in the pathogenesis of ?-lactam allergy
require further clarification.
We appreciate the valuable comments from other
members of our laboratories.
Compliance with ethics guidelines
Jing LI, Xin-yue LIU, Lin-jing LI, Chong-ge YOU, Lei
SHI, Shang-di ZHANG, Qian LIU, Jun WANG, Ze-jing LIU,
and Ting-hong LV declare that they have no conflict of interest.
All procedures followed were in accordance with the
ethical standards of the responsible committee on human
experimentation (institutional and national) and with the
Helsinki Declaration of 1975, as revised in 2008 (5). Informed
consent was obtained from all patients for being included in the
study. Additional informed consent was obtained from all
patients for whom identifying information is included in this
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