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Clinical Implications of S100A12 and Resolvin D1 Serum Levels, and Related

Genes in Children with Familial Mediterranean Fever
Article in Journal of Child Science · April 2021
DOI: 10.1055/s-0041-1731303

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 THIEME
Original Article e163

Clinical Implications of S100A12 and Resolvin D1

Serum Levels, and Related Genes in Children
with Familial Mediterranean Fever
Zeinab Y. Abdallah1 Mona Ibrahim1 Manal M. Thomas2 Hisham Megahed2 Ghada Nour Eldeen3
Khaled Hamed2 Mohamed Fares4,5 Mahmoud ElHefnawi4 Hala T. El-Bassyouni2

1 Division of Human Genetics and Genome Research, Department of Address for correspondence Zeinab Y. Abdallah, PhD, Division of
Biochemical Genetics, National Research Centre, Cairo, Egypt Human Genetics and Genome Research, Department of Biochemical
2 Division of Human Genetics and Genome Research, Department of Genetics, National Research Centre, Cairo 12622, Egypt (e-mail:
Clinical Genetics, National Research Centre, Cairo, Egypt zeinabwakad@[Link]).

3 Division of Human Genetics and Genome Research,

Department of Molecular Genetics and Enzymology, National
Research Centre, Cairo, Egypt
4 Division of Engineering Research, Department of
Informatics and Systems, Biomedical Informatics and
Chemoinformatics Group, National Research Centre, Cairo, Egypt
5 Division of The Veterinary Medicine, National Research
Centre, Cairo, Egypt

J Child Sci 2021;11:e163–e169.

Abstract The aim of this article was to study the role of S100A12 and resolvin D1-related genes

and serum levels in the diagnosis and detection of subclinical inflammation in children
with familial Mediterranean fever (FMF) during the quiescent stage of the disease.
Seventy-eight children with FMF during the silent state and 60 healthy control were
studied. Serum S100A12 and resolvin D1 were quantitatively measured using enzyme-
linked immunosorbent assay. In addition, the levels of C-reactive protein, erythrocyte
sedimentation rate, and hemoglobin were determined. The clinical severity was
evaluated. The link between the Mediterranean fever (MEFV) gene and the genes
related to the two studied biomarkers was also assessed. Correlation between S100A12
and resolvin D1 and the clinical severity was assessed. The mean serum levels of
S100A12 and resolvin D1 were 847.4 and 793.3, respectively, which were highly
significantly increased (p ¼ 0.001) compared with the controls (324.3 and 235.1,
respectively). The receiver operating characteristic curve test showed that S100A12
Keywords had a sensitivity of 97.4% and specificity of 80% with cutoff value of 529.5, while
► familial resolvin D1 showed a sensitivity of 100% and specificity of 50% with cutoff value of
Mediterranean fever 231.2. A correlation was detected between the clinical severity and S100A12 and
► inflammation resolvin D1. This study delineated that S100A12 and resolvin D1 are sensitive
► MEFV gene biomarkers to detect the degree of inflammation in children with FMF during the
► S100A12 protein silent period. Consequently, we recommend adjusting the colchicine dose to amelio-
► resolvin D1 rate the disease’s symptoms and to improve the quality of life in these patients.

received DOI [Link] © 2021. The Author(s).

February 6, 2021 10.1055/s-0041-1731303. This is an open access article published by Thieme under the terms of the
accepted after revision ISSN 2474-5871. Creative Commons Attribution License, permitting unrestricted use,
April 18, 2021 distribution, and reproduction so long as the original work is properly cited.
([Link]
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart,
Germany
e164 Clinical Implications of S100a12, Resolvin D1, and Related Genes in FMF Abdallah et al.

14
Introduction established according to the Tel-Hashomer criteria. A quiescent
disease state was considered with clearance of all the signs and
Familial Mediterranean fever (FMF) is the most common monogenic symptoms of an FMF attack for at least two consequent weeks. All
autoinflammatory disease in the world; its prev-alence is very high the patients were on colchicine treat-ment when the samples were
among people from the eastern Mediter-ranean such as Jews, Turks, drawn.
1
Armenians, and Arabs. Although it is known to be inherited The FMF patients were recruited from the Clinical Genet-ics
autosomal recessively, a substan-tial number of heterozygotes are Department outpatient clinic at the Medical Center of Excellence,
2 National Research Centre. The participants did not have other
presently expressing the phenotypic characteristics. The disease is
characterized by recurrent fever episodes, which may be systemic diseases (diabetes mellitus, chronic renal failure,
accompanied by serositis, arthritis, vasculitis, dermal manifestations, malignancy and ischemic heart disease) or performed heavy
3
and long-term complications, mainly renal. The episodes are self- exercises. Other exclusion criteria were smoking, trauma, or
limiting lasting 12 to 72 hours, and the interval between the episodes administration of drugs other than colchicine. This study was
4 approved by the Research Ethics Committee of the NRC according
is extremely variable from weeks to years. The most common
genetic mutations encoded from exon ten and exon 2 are responsible to the World Association Declaration of Helsinki, and written
5 informed consent was obtained from all patients’ legal guardians.
for more than 85% of FMF cases in the Mediterranean basin. The
Mediterranean fever (MEFV) gene encodes for protein pyrin
(marenostrin), mostly in neutro-phils and macrophages and has a Patients were subjected to detailed medical history, includ-ing
crucial role in apoptosis and inflammatory pathways. M694V is the demographic data, age at the onset, consanguinity, simi-larly
most common muta-tion in Turk, Armenian, and Jewish populations, affected family members with three-generation pedigree
6
while M694I is mostly seen in the Arabic population. construction, meticulous clinical evaluation, and disease se-verity
15,16
assessment using the scoring systems. The eryth-
rocyte sedimentation rate, SAA, and CRP were assessed.
There has been an increasing interest in the function of S100A12 The blood samples from patients and controls were immediately
protein and its role as an indicator of inflammation. S100A12 was centrifuged within 20 minutes at 3,000 g for 10 minutes and stored at
shown to be associated with active FMF. It is involved in the –20°C for subsequent assay. Serum S100A12 and resolvin D1
pathogenesis of this disease, and its release is independently
concentrations were evaluated using enzyme-linked immunosorbent
7
regulated from inflammasome activation. It shows an excellent assay kits (Human S100 Calcium Binding Protein A12, Human
relation to disease activity, and serum levels are higher in patients Resolvin D1, Bioneovan Co., Ltd; Beijing, China) according to the
8
with unstable disease state under colchicine treatment. manu-facturer’s instructions.

Bioactive derivatives of omega-3 fatty acids, mainly eico-

sapentaenoic acid and docosahexaenoic acid, are essential for the DNA Extraction
innate immune system and have natural anti-inflamma-tory, pro- All cases were diagnosed by molecular analysis of MEFV gene
9 mutation. Genomic DNA was extracted from venous blood,
resolving properties. Resolvin mainly switches in-flammation to the
17 18,19
resolution phase by inhibition of endothelial migration and according to Miller et al. Both MEFV exon 2 and 10 were
infiltration of leukocytes and promotion of clearance of apoptotic individually amplified by PCR using two pairs of primers: Exon
polymorphonuclear leukocytes. The efficacy of endogenous resolvin 2: F: 5′- GCCTGAAGACTCCAGACCACCCCG-3′, R: 5′- AGGCC-
D1 has been tested for anti-inflammatory actions in several in vivo CTCCGAGGCCTTCTCTCTG-3′ Exon10: F: 5′GAGGTGGAGGTT-
10
experimental mod-els. The serum levels of resolvin D1 increase in GGAGACAA-3′,R:5′-TGACCACCCACTGGACAGAT-3′
both the attack and silent periods of FMF and correlate with classical Bidirectional direct sequencing of purified PCR products was
biomark-ers of inflammation such as highly sensitive C-reactive performed using the Big Dye Terminator V1.1 Cycle Sequencing kit
11 (ABI prism, Foster City, California, United States) and an Applied
protein (CRP) and serum amyloid A (SAA).
Biosystems 3500DX Genetic analyzer.
Colchicine is the mainstay of FMF treatment and should be Analysis of MEFV gene functional association and interac-tion
started once a clinical diagnosis is established. Its regular use with our biomarkers and their associated genes was performed using
prevents attacks and suppresses chronic subclinical inflam-mation. 20
the Gene MANIA prediction server. The genes involved in the
Anti-interleukin-1 drugs emerged as promising resolvin D1 biosynthesis pathway (Alox5) and S100A12 protein
treatment options in patients who fail to respond or tolerate production were queried against the MEFV gene. Association links
12,13 screening param-eters included protein and genetic interactions,
colchicines. This work aimed to study the role of
S100A12 and resolvin D1 in the diagnosis and detection of pathways, coexpression, and protein domain similarity.
subclinical inflammation in children with FMF during the quiescent
stage of the disease. Variation influence on the final protein structure and stability was
21
modeled using Site-Directed Mutate web-server. A three-
Patients and Methods dimensional structure for wild-type pro-tein was used as a reference
with pdb id: 2WL1. Mutations M694I, V726A, A744S, and M680I
Seventy-eight Egyptian FMF children during the quiescent disease were covered by the reference protein structure, and hence their
state and 60 age and sex-matched healthy controls were enrolled in influence was evaluated.
this study. The diagnosis of FMF was

Journal of Child Science Vol. 11 No. 1/2021 © 2021. The Author(s).

 Clinical Implications of S100a12, Resolvin D1, and Related Genes in FMF Abdallah et al. e165

Statistical Analysis Table 1 Characteristics of patients with FMF

The variables were expressed as mean and standard devia-tion or as
frequencies and percentage. Mann–Whitney U test was used for the Variables FMF patients
comparison of the two groups. Spearman’s correlation was used to Mean SD (range) or n (%) (n ¼ 78)
assess the correlation between S100A12 and resolvin D and between Age (y) 5 3.4 (3–13)
S100A12, resolvin D, CRP, and serum amyloid A. In addition, it Gender (male/female) 32/46
was used to analyze the correlation between the disease phenotypes Disease duration (y) 4.56 2.21 (5–10)
and S100A12 and resolvin D biomarkers. The receiver operating
Consanguinity 22 (28)
characteristic (ROC) curve was used to evaluate the sensitiv-ity and
specificity of S100A12 and resolvin D1 to estimate the efficacy of Laboratory ESR (mm/1st h) 29.5 24.9
these biomarkers in detecting the degree of inflammation. A Elevated ESR 56 (71.8)
significance level of p < 0.05 was used in all tests. All statistical CRP (mg/dL) 22.2 17.2
procedures were performed using SPSS version 20 for Windows Positive CRP 50 (64.1)
(SPSS Inc, Chicago, Illinois, United States).
Anemia 34 (43.6)
Serum amyloid A 70 (89.7)
Elevated liver function 4(5.1)
tests
Results
Colchicine dose (mg/d) (0.5–3) 1.8 0.74
The patients’ mean age was 5 3.4 years (3–13 years); there were 32 Echo Patent foramen oval 4 (5.1)
males and 46 females with a M: F ratio of 1:1.4. Their mean disease and MVP
duration was 4.56 2.21 years. Consanguinity was present in 22 Mitral regurgitation 4 (5.1)
(28%) cases. The number of attacks ranged from 2 to 3 times/week
Subcortical 1 (1.3)
to 3 to 4 times/month. All patients were on colchicine treatment
epileptogenic activity
ranging from 0.5 to 3 mg/day. Twelve patients (15.4%) met the
Abd. US Mesenteric 8 (10.3)
definition of refractory FMF.
lymphadenitis

The 60 controls were of matched age 5.96 2.25 years (4–14 Epididymitis, 1 (1.3)
hydrocele and orchitis
years) and gender (21 males and 39 female) (M: F
1:1.8) (p ¼ 0.06 and p ¼ 0.47, respectively). Lymphadenopathy, 1 (1.3)
splenomegaly, and
The characteristics of the patients are presented
hernia
in ►Table 1. The mutational distribution is presented in ►Table 2.
Fatty liver 1 (1.3)
This is a leading study on the link between the MEFV and relevant
genes to the studied biomarkers to the best of our knowledge. The Abbreviations: Abd. US, abdominal ultrasounds; CRP, C-reactive
gene interaction network analysis using the GeneMANIA web tool protein; Echo, echocardiogram; ESR, erythrocyte sedimentation rate;
showed that the MEFV gene possesses direct and indirect co- FMF, familial Mediterranean fever; MVP, major vault protein; SD,
expression link evidence with genes responsible for producing standard deviation.

biomarker S100A12, S100A8, and S100A9 (►Fig. 1).

►Table 3 showed the mutated protein structure stability. The

Table 2 Mutational distribution among the FMF patients
available protein reference structure did not cover the residue
location E148Q, while the remaining four mutations were subjected Gene mutations n (%) FMF patients
to the evaluation. The analysis revealed that three out of these four (n ¼ 78)
mutations resulted in increased structure stability (M694I, V726A, MEFV 78
and M680I). Only A744S mutation caused reduced stability with a
Heterozygous
predicted ΔG difference from the wild type of negative 0.14 value.
M694I 60 (76.9)
Howev-er, the M694I mutation, the most common mutation ob-
served, caused increased residue solvent accessibility compared with M6801 8 (10.2)
the wild type and caused the loss of side-chain-sidechain hydrogen A744S 2 (2.6)
bond formation at the respective residue location suggesting marked E148Q 2 (2.6)
structure conformation-al change at the mutation location. The V726A 2 (2.6)
mutation caused a positive increase in ΔΔG by 0.72, leading to a
Homozygous
more stable structure than the wild type. M680I mutation shows the
E148Q 2 (2.6)
slightest difference in ΔΔG in all studied mutations with only 0.03
ΔΔG change due to the variation with no marked protein structural M694I 2 (2.6)
property change. Abbreviations: FMF, familial Mediterranean fever; MEFV,
Mediterranean fever.

Journal of Child Science Vol. 11 No. 1/2021 © 2021. The Author(s).

e166 Clinical Implications of S100a12, Resolvin D1, and Related Genes in FMF Abdallah et al.

Fig. 1 Interaction network analysis among Mediterranean fever (MEFV) gene and genes associated with the production of S100A12 and resolvin
D1. Interaction analysis showed a set of intermediate genes including (ALOX5AP, S100AB, S100A9, PYCARD, COTL1, PSTPIP1) sharing
coexpression, protein-domain similarity and pathway interaction links connecting all MEFV, ALOX5, and S100A12 genes.

Table 3 Mutated protein structural stability analysis in FMF patients

Mutation Mutated protein structural stability analysis in FMF patients (n ¼ 78)

Residue RSA (%) Depth (Å) OSP SS SN SO ΔΔG Stability
M694I Wild type 40.3 4 0.32 T F F 0.72 Increased
Mutation 54.6 3.8 0.28 F F F
V726A Wild type 56.3 3.5 0.21 F F F 0.12 Increased
Mutation 54.1 3.2 0.23 F F F
A744S Wild type 67.9 3.2 0.24 F F F 0.14 Reduced
Mutation 71.6 3.3 0.23 F F F
M680I Wild type 52.7 3.7 0.17 F F F 0.03 Increased
Mutation 37.9 3.7 0.26 F F F

Abbreviations: F, false; FMF, familial Mediterranean fever; OSP, occluded surface packing; RSA, relative solvent accessibility; SN, sidechain-main
chain amide hydrogen bond; SO, sidechain-main chain carbonyl hydrogen bond; SS, sidechain-sidechain hydrogen bond; SSE, main chain
conformational class; T, true.

The serum levels of S100A12 and resolvin D1 were significantly although there was a highly significant correlation between S100A12
increased in the FMF patients during colchicine treatment compared and resolvin D1 among controls with rs ¼ 0.627 and p ¼ 0.003.
with the control (mean: 847.4 553 pg/mL, median: 726.5 and 793.3
622 pg/mL, 700 vs. 324.3 201.7 pg/mL, median: 272.5 and 235.1 On comparing the serum levels between those with heterozygous
154.7 pg/mL, 261.5; p ¼ 0.001). Spearman’s correlation test showed mutation of M694I gene and those with other mutations, the levels
no significant correlation between S100A12 and resolvin D1 among were 842.4 611 pg/mL, median 723.5 and 710.7 487.8 pg/mL, 572.5
cases with rs ¼ 0.014 and p ¼ 0.943, vs. 864 314.8 pg/mL 726.5 and 958.4 841.9 pg/mL, 810; p ¼ 0.516
and 0.607 (►Fig. 2).

Journal of Child Science Vol. 11 No. 1/2021 © 2021. The Author(s).

 Clinical Implications of S100a12, Resolvin D1, and Related Genes in FMF Abdallah et al. e167

Discussion
FMF is the most common autoinflammatory disease prevalent in the
Middle East. There is increasing demand for new biomarkers to
estimate inflammation and treatment follow-up in FMF patients. In
this study, the role of S100A12 and resolvin D1 was evaluated in the
quiescent period to estimate the degree of inflammation. This may
assist in further studies to adjust the doses of colchicine to
ameliorate disease symptoms. The present study confirmed that the
level of S100A12 was significant-ly increased in the quiescent
period of FMF patients during

colchicine treatment compared with controls. This coin-cides with

10,22,23
previous studies. Therefore, S100A12 can
be used to detect subclinical inflammation during the attack-free
Fig. 2 Levels of S100A12 and resolvin D1 between familial Medi- period.
terranean fever patients and controls (left) and between those with According to the current study, the most common muta-tion was
M694I mutation versus other mutations (right). heterozygous M694I (76.9%), heterozygous M680I (G/C) (10.2%),
followed by E148Q, V726A, and A744S with lower frequencies.
Table 4 Spearman’s correlation between S100A12 and The M694V mutation could not be iden-tified in this study in
resolvin D versus serum amyloid A and C-reactive protein 18
agreement with the results reported in previous work. Moreover,
S100A12 (pg/mL) Serum C-reactive there was no significant differ-ence in S100A12 levels between cases
with heterozygous M694I mutation and those with other types of
amyloid A protein
mutations. This may be due to the small number of FMF patients in
rs a a
0.907 0.857 the subgroups.
p-Value 0.001 0.001
Significant HS HS The current study showed S100A12 to be a reliable biomarker of
Resolvin rs a a inflammation during the quiescent period of FMF patients by the
0.983 0.925
D (pg/mL) ROC test with high sensitivity, specifici-ty, and highly significant p-
p-Value 0.001 0.0001
value. Therefore, determining the level of S100A12 can help gauge
Significant HS HS the effectiveness of treat-ment by the detection of the degree of
a
inflammation during the quiescent period of FMF. Resolvin
Spearman’s rho.
regulates the pro-inflammatory state, and it actively promotes
resolution via monocyte/macrophage uptake of debris and apoptotic
The Spearman’s correlations revealed a significant value with p 23,24 25
polymorphonuclear neutrophils. Serhan elucidated that
¼ 0.001 between the studied biomarkers and the classical resolvin was an important molecular player involved in the active
inflammation markers (SAA and the C-reactive protein) (►Table 4) termination of inflammation specialized pro-resolving mediators.
and between the disease phenotypes and both S100A12 and resolvin When this active process fails, chronic inflammation may proceed to
D1 biomarkers. different disorders like rheu-matoid arthritis, inflammatory bowel
The sensitivity, specificity, and area under the curve (AUC) of disease, and other autoimmune diseases. FMF is an
S100A12 and resolvin D1 for the diagnosis of the inflammation autoinflammatory disease
degree in cases were 97.44%, 80%, AUC 0.96 and 100%, 50%,
that primarily affects the leucocytes of the innate immune
AUC 0.82, respectively, with p ¼ 0.001 (►Fig. 3). 26,27
system. In the present study, the level of resolvin was
significantly higher in the cases compared with the controls. This is
12
in agreement with the study of Taylan et al. Addi-tionally, no
significant correlation was found in relation to the types of
mutations.
The ROC curve enlightened that resolvin is a good diag-nostic
biomarker for the degree of inflammation in the quiescent period of
FMF patients, besides its role in the resolution of inflammation and
may point to the presence of subclinical inflammation.

The levels of S100A12 and resolvin D correlated signifi-cantly (p

< 0.001) with the classical inflammatory bio-markers as 70 (89.7%)
Fig. 3 The ROC curve of S100A12 and resolvin D1 was at a cutoff
patients had high serum amyloid levels, which agree with Lofty et al
point of 529.5 pg/mL and 231 pg/mL respectively, their sensitivity was
97.4 and 100%, specificity 80 and 50% respectively and the areas
28 29 24
and Duzova et al. Similarly, Ben-Zvi and Livneh affirmed
under the curve (AUC) was 0.958 and 0.82 respectively. that although the

Journal of Child Science Vol. 11 No. 1/2021 © 2021. The Author(s).

e168 Clinical Implications of S100a12, Resolvin D1, and Related Genes in FMF Abdallah et al.

patients are under treatment, both CRP and SAA increased in 30 to 3 Ozen S, Batu ED, Demir S. Familial Mediterranean Fever: recent
90% of their patients during the episode-free period. On the other developments in pathogenesis and new recommendations for management.
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28,29,32 6 Aksentijevich I, Centola M, Deng Z, et al; The International FMF
the findings of others studies. The number of Consortium. Ancient missense mutations in a new member of the RoRet
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