Modern Rheumatology

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MEFV E148Q variant is more associated with

familial Mediterranean fever when combined
with other non-exon 10 MEFV variants in Japanese
patients with recurrent fever

Kyoko Fujimoto, Yukiko Hidaka, Takuma Koga, Shinjiro Kaieda, Satoshi

Yamasaki, Munetoshi Nakashima, Tomoaki Hoshino, Ken Yamamoto, Ryuta
Nishikomori & Hiroaki Ida

To cite this article: Kyoko Fujimoto, Yukiko Hidaka, Takuma Koga, Shinjiro Kaieda, Satoshi
Yamasaki, Munetoshi Nakashima, Tomoaki Hoshino, Ken Yamamoto, Ryuta Nishikomori & Hiroaki
Ida (2021): MEFV E148Q variant is more associated with familial Mediterranean fever when
combined with other non-exon 10 MEFV variants in Japanese patients with recurrent fever, Modern
Rheumatology, DOI: 10.1080/14397595.2021.1880534

To link to this article: https://doi.org/10.1080/14397595.2021.1880534

Published online: 16 Mar 2021.

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MODERN RHEUMATOLOGY
https://doi.org/10.1080/14397595.2021.1880534

ORIGINAL ARTICLE

MEFV E148Q variant is more associated with familial Mediterranean fever when
combined with other non-exon 10 MEFV variants in Japanese patients with
recurrent fever
Kyoko Fujimotoa, Yukiko Hidakaa, Takuma Kogaa, Shinjiro Kaiedaa, Satoshi Yamasakib, Munetoshi Nakashimab,
Tomoaki Hoshinoa, Ken Yamamotoc, Ryuta Nishikomorid and Hiroaki Idaa
a
Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan;
b
Center for Rheumatic Diseases, Kurume University Medical Center, Kurume, Japan; cDepartment of Medical Biochemistry, Kurume
University School of Medicine, Kurume, Japan; dDepartment of Pediatrics, Kurume University School of Medicine, Kurume, Japan

ABSTRACT ARTICLE HISTORY

Objective: To investigate the genetic characteristics of one of the MEFV gene variants, p.Glu148Gln Received 29 September 2020
(E148Q), in patients with familial Mediterranean fever (FMF) and examine its significance in Japanese Accepted 20 January 2021
patients with recurrent fever.
KEYWORDS
Methods: The clinical phenotype and genomic variants of systemic autoinflammatory diseases (SAIDs),
E148Q; familial
including MEFV, were analyzed in 211 Japanese patients with recurrent fever. Genetic analysis was per- Mediterranean fever; MEFV;
formed via next-generation sequencing of exons, including exon-intron boundaries. recurrent fever
Results: Twelve patients met the diagnostic criteria for SAIDs other than FMF. Considering 199
patients with recurrent fever, 137 cases (68.8%) were clinically diagnosed with FMF. Although
Bonferroni-adjusted p-value did not reach significance level, the group containing heterozygous
E148Q and other variants tended to be at higher risk of developing the FMF phenotype (nominal
p ¼ .036) than the group with heterozygous E148Q only. Comparison between the group with hetero-
zygous E148Q and other variants and the heterozygous group containing non-E148Q showed no stat-
istically significant difference in FMF phenotype expression (nominal p ¼ 1.00).
Conclusion: Patients with heterozygous E148Q and other variants exhibited higher expression of FMF
phenotype than those with heterozygous E148Q only, and suggested that other variants than E148Q
as well as exon 10 variants might contribute to the FMF phenotype.

1. Introduction In this study, we investigated the genetic characteristics

Familial Mediterranean fever (FMF) is the most frequent
hereditary autoinflammatory syndrome [1] and is diagnosed
according to the Tel-Hashomer criteria [2] in Japan. From a
genetic point of view, the location of variants in the disease
gene MEFV differs greatly between the Mediterranean
region, where many FMF patients are present, and Japan
[3,4]. The MEFV variants in FMF patients in Japan have
overwhelmingly few exon 10 variants with established diag-
nostic value compared to the Mediterranean region, and
MEFV polymorphisms, mainly in exon 2, are frequently pre-
sent in healthy individuals [5,6]. In particular, the E148Q
variant is a polymorphic gene present in >20% of the
healthy Japanese population [1]. There has been much
debate about how the E148Q variant contributes to the
diagnosis of FMF not only in Japan but also in the
Mediterranean region [7–10]. In Japan, it has been reported
that the E148Q variant affects the phenotype of FMF
patients, and it is considered that the E148Q variant may
act as a disease modifier [1]; however, this has not been
statistically evaluated properly to date.
of the E148Q variant in Japanese FMF patients and exam-
ined its significance in Japan, where more than 20% of
healthy individuals have the E148Q variant.
2. Materials and methods
2.1. Patients
In total, 211 patients with recurrent fever (three or more
episodes with 37.5  C) treated between March 2011 and
March 2020 at 61 Japanese hospitals, including Kurume
University Hospital, were enrolled in this study after obtain-
ing informed consent (Figure 1). Patients suffering from
infection, collagen diseases, and malignant diseases were
excluded from the study. Twelve patients met the diagnostic
criteria for SAIDs [11], including 10 cases of tumor necrosis
factor receptor-associated periodic syndrome (TRAPS), one
case of cryopyrin-associated periodic syndromes (CAPS),
and one case of pyrin-associated autoinflammation with
neutrophilic dermatosis (PAAND) [12] (Figure 1).

CONTACT Hiroaki Ida ida@med.kurume-u.ac.jp Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School
of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
ß 2021 Japan College of Rheumatology
2 K. FUJIMOTO ET AL.

Japanese patients with recurrent fever

(n = 211)

Excluded (n = 12)

TRAPS, n = 10
CAPS, n = 1
PAAND, n = 1

Included in the study

(n = 199)

Tel-Hashomer criteria

FMF (n = 137) Non-FMF (n = 62)

Figure 1. Flow diagram of patient enrollment.

TRAPS: tumor necrosis factor receptor-associated periodic syndrome; CAPS: cryopyrin-associated periodic syndromes; PAAND: pyrin-associated autoinflammation
with neutrophilic dermatosis; FMF: familial Mediterranean fever.

FMF was diagnosed if the patient met 1 or more major
criteria, or 2 or more minor criteria of the modified Tel-
Hashomer criteria [2]. Typical fever means temperature of
38  C or more, with a duration of 12 h to 3 d. On that basis,
we divided the patients into 2 groups, typical FMF and atyp-
ical FMF. Patients with typical FMF had the typical episode
of peritonitis, pleuritis, monoarthritis, or fever alone, as speci-
fied in the criteria. Patients with atypical FMF had an
‘incomplete’ attack. An attack was considered incomplete if it
differed from a typical attack in only 1 or 2 of the following
features: temperature less than 38  C; attack duration longer
or shorter than the specified period (12 h to 3 d), though not
shorter than 6 h or longer than a week; no sign of peritonitis
during an abdominal attack, or localized signs, if any; and
atypical distribution of arthritis. According to the Tel-
Hashomer criteria [2], 137 and 62 patients were classified
into FMF and non-FMF groups, respectively (Table 1).
The study was conducted in accordance with the
Declaration of Helsinki and was approved by the Ethics
Committee of Kurume University (No. 337).
2.2. Genetic analysis
Blood from patients with unexplained fever was collected in
EDTA-containing tubes, and DNA was extracted using the
QIAamp DNA Blood Midi Kit according to the manufac-
turer’s instructions (Qiagen, Waltham, USA). Three genes
related to SAIDs, namely MEFV, TNFRSF1A, and NLRP3
were investigated. Target sequencing of these genes was per-
formed on an Illumina MiSeq or NextSeq500 platform
(Illumina, Inc., San Diego, USA) via amplicon sequencing
[13,14] or hybridization-capture sequencing with prede-
signed capture probes for these genes (Integrated DNA
Technologies, Inc., Coralville, USA) [15] at the Kazusa DNA
Research Institute (Kisarazu, Japan).
Allele frequencies of the detected missense variants in East
Asia were searched using the Exome Aggregation
Consortium (ExAC) Browser (http://exac.broadinstitute.org/)
and reported variants from INFEVERS, the registry for FMF
and hereditary inflammatory disorders mutations (http://fmf.
igh.cnrs.fr/ISSAID/infevers/). The missense variants in <1%
of healthy individuals were classified as rare variants and
those not described in the database as novel variants.
2.3. Group classification on the basis of MEFV
genotypes
As there has been a constant debate over whether the
E148Q variant is associated with clinical conditions of FMF,
we focused on the E148Q variant in this study. To investi-
gate the role of E148Q, patients with MEFV variants were
grouped as follows. The cases with exon 10 variants were
classified as group 1. Homozygous E148Q cases, cases with
heterozygous E148Q and other variants in which E148Q
heterozygous variants were combined with other variants,
and heterozygous E148Q cases were classified as groups 2,
3, and 4, respectively. In addition, variants other than
E148Q were called non-E148Q variants. Homozygous non-
E148Q variant cases and non-E148Q variant plus other
non-E148Q variants were classified as group 5, and hetero-
zygous non-E148Q cases were classified as group 6. The
number and proportion of each group in the FMF and non-
FMF groups are presented in Tables 1 and 2. The cases
without MEFV variants were classified as group 7.
2.4. Statistical analyses
Data were analyzed using JMP version 11 (SAS Institute
Inc., Cary, NC, USA). Results were expressed as the mean-
± standard deviation for continuous variables. For
 MODERN RHEUMATOLOGY 3

Table 1. Group classification on the basis of MEFV genotypes.

No
Exon10 variants E148Q variants Non-E148Q variants variants
　 Total
　 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7
　 E148Q/ E148Q/ E148Q/ Non-E148Q/ Non-E148Q/
E148Q others normal non-E148Q or normal
Non-E148Q/
others

FMF n 11 5 27 19 11 21 43 137
(Typical FMF) (11) (5) (19) (16) (10) (16) (37) (114)

% 8.0 3.6 19.7 13.9 8.0 15.3 31.4 100.0

(Typical FMF/FMF) (100.0) (100.0) (70.3) (84.2) (90.9) (76.1) (86.0) (83.2)

Non-FMF n 0 5 9 18 3 7 20 62
% 0.0 8.1 14.5 29.0 4.8 11.3 32.3 100.0

quantitative data, the Wilcoxon rank sum test compared
two independent groups. Categorical variables were com-
pared using the chi-square test (or Fisher’s exact test when
appropriate). All tests were two-sided. Nominal P values
were corrected for the number of tests using the Bonferroni
method, and significance was determined at cor-
rected p < .05.
3. Results
3.1. Comparisons of MEFV genotype groups
When 137 FMF cases were divided into typical FMF and
atypical FMF, 114 cases were typical FMF and 23 cases were
atypical FMF as shown in Table 1. In the comparison of the
ratio of typical FMF, all cases of group 1 (exon 10 variants)
and group 2 (E148Q homozygote) were typical FMF, and
the lowest frequency of typical FMF (70.3%) was the group
3 (heterozygous E148Q and other variants). The frequency
of typical FMF was not significantly different between group
3 and group 4 (nominal p ¼ .27).
In a comparison of allelic frequencies between the FMF
group and the Non-FMF group, the pathogenic allele M694I
was the only allele with statistically significant difference
(nominal p ¼ .023), so the contribution of M694I to FMF
development was examined. Comparing the M694I/E148Q
(n ¼ 10) cases with the E148Q hetero group (group 4) or
the heterozygous E148Q and other variants group (group 3),
the M694I/E148Q cases significantly contributed to FMF
development compared to the E148Q hetero group (group
4) (nominal p ¼ .005), but there was no significant differ-
ence in the comparison of the heterozygous E148Q and
other variants group (group 3) (nominal p ¼ .077).
Next, in order to examine whether the presence or
absence of the E148Q variant affects the development of
FMF, the groups with the E148Q variant (groups 2, 3, and
4) and the groups with the non-E148Q variants (groups 5
and 6) were examined. Results showed no significant differ-
ence in the developmental contribution of FMF between the
groups (nominal p ¼ .099). Additionally, we examined
whether there was a significant difference between the three
groups with E148Q variants (groups 2, 3, and 4) (Table 3).
Although Bonferroni-adjusted p-value did not reach signifi-
cance level, the group containing heterozygous E148Q and
other variants (group 3) tended to be at higher risk of devel-
oping the FMF phenotype (2.84 times higher; nominal
p ¼ .036), than the group with heterozygous E148Q (group
4) (Table 3). In contrast, comparison between the group
with heterozygous E148Q and other variants (group 3) and
the heterozygous group containing non-E148Q (group 6)
showed no statistically significant difference in FMF pheno-
type expression (OR ¼ 1, nominal p ¼ 1.00), suggesting that
the E148Q may not act as a diseases-modifier for the non-
E148Q and non-M694I variants.
The L110P variant was included in 48.1% of the patients
in the group with heterozygous E148Q and other variants
(group 3: 13 out of 27 cases). Since the L110P variant was
always associated with the E148Q variant in our study, the
L110P variant seems to be a cis allele of the E148Q variant.
We examined which genes in the cases with heterozygous
E148Q and other variants contributed to FMF development
in collaboration with E148Q. In group 3, we examined
L110P, P369S, and R408Q, which are often combined with
E148Q. Among these three variants, there were no variants
that significantly contributed to FMF development (data
not shown).
3.2. Comparisons of clinical features in groups 3 and 4
In FMF patients, the clinical features of the group with het-
erozygous E148Q and other variants (group 3) and the het-
erozygous E148Q group (group 4), which were significantly
different, were compared (Table 4). The frequency of
abdominal pain (55.6% vs. 26.3%, nominal p ¼ .048) and
arthralgia (51.9% vs. 21.1%, nominal p ¼ .035) were signifi-
cantly higher in group 3 than in group 4.
4. Discussion
In this study, we investigated the significance of the E148Q
variant, which is common in Japanese patients clinically
diagnosed with FMF. It was found that cases with
4 K. FUJIMOTO ET AL.

Table 2. MEFV Genotypes in FMF and non-FMF patients.

Group classification 　 　 FMF 　 　 non-FMF 　
　 　 Number % 　 Number %
exon10 variants Group 1 M694I/normal 1 0.7 　 0 0.0
　 　 M694I/E148Q 10 7.3 　 0 0.0
E148Q variants Group 2 L110P/L110P/E148Q/E148Q 1 0.7 　 0 0.0
　 L110P/E148Q/E148Q 2 1.5 　 3 4.8
　 L110P/E148Q/E148Q/P369S/R408Q 0 0.0 　 1 1.6
E148Q/E148Q 2 1.5 　 1 1.6
Group 3 L110P/E148Q 12 8.8 　 2 3.2
　 L110P/E148Q/P369S 1 0.7 　 0 0.0
　 E148Q/R202Q 0 0.0 　 1 1.6
　 E148Q/R202Q/P369S 1 0.7 　 0 0.0
　 E148Q/P369S 2 1.5 　 0 0.0
　 E148Q/P369S/R408Q 10 7.3 　 5 8.1
　 E148Q/P369S/R408Q/S503C 0 0.0 　 1 1.6
　 E148Q/P369S/P369S/R408Q/R408Q 1 0.7 　 0 0.0
Group 4 E148Q/normal 19 13.9 　 18 29.0
Non-E148Q variants Group 5 E84K/R410H 0 0.0 　 1 1.6
　 R202Q/P369S/R408Q 1 0.7 　 0 0.0
　 R202Q/S503C 1 0.7 　 1 1.6
　 P257L/P257L 1 0.7 　 0 0.0
　 G304R/G304R 1 0.7 　 0 0.0
　 P369S/R408Q 7 5.1 　 1 1.6
Group 6 E84K/normal 2 1.5 　 1 1.6
　 R202Q/normal 8 5.8 　 2 3.2
　 G304R/normal 6 4.4 　 1 1.6
　 A317T/normal 1 0.7 　 0 0.0
　 S503C/normal 3 2.2 　 3 4.8
　 I591M/normal 1 0.7 　 0 0.0
No variants Group 7 43 31.4 　 20 32.3
FMF: familial Mediterranean fever.

Table 3. Comparisons of MEFV genotypes classified into groups. were 2.84 times more likely to be diagnosed with FMF than
　 Group 2 Group 3 those with heterozygous E148Q alone. In contrast, compari-
　 E148Q/E148Q E148Q/others Total nominal P OR [CI 95%] son between the group with heterozygous E148Q and other
FMF
n 5 27 32 0.12 3.00[0.70, 12.80] variants and the heterozygous group containing non-E148Q
% 15.6 84.4 100.0 showed no significant difference in FMF phenotype expres-
Non-FMF
n 5 9 14
sion, suggesting that the E148Q may not act as a dis-
% 35.7 64.3 100.0 eases-modifier.
　 Group 2 Group 4 Many patients in Japan have been reported with atypical
　 E148Q/E148Q E148Q/normal Total nominal P OR [CI 95%] FMF compared to Mediterranean patients [1]. This could be
FMF
n 5 19 24 0.93 1.05[0.26, 4.26]
attributed to the fact that Japanese patients with FMF have
% 20.8 79.2 100.0 a large number of exon 2 variants, which are often genetic
Non-FMF polymorphisms found in healthy individuals, in addition to
n 5 18 23
% 21.7 78.3 100.0 that in exon 10. In this study, the group with heterozygous
　 Group 3 Group 4 E148Q and other variants had more atypical FMF and all
　 E148Q/others E148Q/normal Total nominal P OR [CI 95%] atypical cases (8 cases) in this group were atypical fever
FMF attacks with abdominal pain. However, there was no signifi-
n 27 19 46 0.036 2.84[1.05, 7.66]
% 58.7 41.3 100.0 cant difference between the group with heterozygous E148Q
Non-FMF and other variants and the heterozygous E148Q only group
n 9 18 27 in the frequency of typical and atypical FMF.
% 33.3 66.7 100.0
There has been much debate about the significance of
　 Group 3 Group 6
　 E148Q/others Non-E148Q/normal Total nominal P OR [CI 95%] the E148Q variant [16,17]. Table 5 shows a list of litera-
FMF ture-derived population-based studies, family studies
n 27 21 48 1.00 1[0.31, 3.12] through pedigree analysis, and case reports describing the
% 56.3 43.8 100.0
Non-FMF role of E148Q. The E148Q variant has been reported as a
n 9 7 16 benign polymorphic gene because after examining the fre-
% 56.3 43.8 100.0
quency of compound heterozygosity between the exon 10
FMF: familial Mediterranean fever.
and E148Q variants in an area with a higher frequency of
exon 10 variants than in Japan, there was no difference
heterozygous E148Q and other variants in which another between FMF patients and healthy subjects [8]. Other
variant was associated with the heterozygous E148Q variant studies have reported that the disease activity of FMF
 MODERN RHEUMATOLOGY 5

Table 4. Comparisons of clinical features in group 3 and group 4 among FMF patients.
　 Group 3 Group 4
　 E148Q/others E148Q/normal
　 n ¼ 27 % n ¼ 19 % nominal P
Male/female 5/22 8/11 0.080
Age at onset (means ± SD) 32.2 ± 17.7 38.5 ± 24.0 0.30
Family history of periodic fever 1 3.7 4 21.1 0.062
Fever
A Temperature (38  C) 24 88.9 18 94.7 0.48
B Duration (12 h to 3 d) 21 77.8 16 84.2 0.58
Typical fever (A and B) 19 70.3 16 84.2 0.27
Abdominal pain 15 55.6 5 26.3 0.048
Thoracic pain 8 29.6 3 15.8 0.27
Arthralgia (hip, knee, and ankle) 14 51.9 4 21.1 0.035
Myalgia 3 11.1 3 15.8 0.64
Exanthema 7 25.9 5 26.3 0.97
Colchicine administration 16 59.3 10 52.6 0.65
Good response (% of administered patients) 11 68.8 8 80.0 0.52
FMF: familial Mediterranean fever.

Table 5. Literature-derived population-based studies, pedigree analysis, and case reports describing the role of E148Q in FMF.
Author MEFV allele Role of E148Q Ref. No. (Year)
Population-based studies
1. Tchernitchko M694V/E148Q: FMF Pt vs. Healthy relatives benign polymorphism 8 (2003)
2. Topaloglu E148Q/others vs. E148Q/E148Q higher frequency of 9 (2005)
(comp. hetero) (homo) symptoms in comp. hetero
3. Marek-Yagel E148Q-V726A/E148Q-V726A vs. V726A/V726A severe phenotype 21 (2009)
E148Q-V726A/V726A vs. V726A/V726A
4. Ece M694V/M694V, M694V/others, or M694V/- vs. mild disease course in 18 (2014)
E148Q/E148Q, E148Q/others, or E148Q/- E148Q group
5. Topaloglu M694V/E148Q vs. E148Q/E148Q milder disease activity 19 (2018)
in homo
6. Aydin M694V/M694V vs. E148Q/E148Q, E148Q/- milder disease activity in 20 (2019)
M694V/M694V vs. E148Q/exon 10 E148Q/E148Q, E148Q/-
7. Eyal M694V/E148Q vs. M694V/- higher disease penetrance 22 (2020)
Pedigree analysis in families
1. Ben-Chetrit M694V/E148Q onset 7 (2000)
2. Tchernitchko M694V/E148Q benign polymorphism 10 (2006)
Case reports
1. Umeda S632S/E148Q onset 23 (2017)
2. Kiyota S242R/E148Q onset 15 (2020)
FMF: familial Mediterranean fever; comp. hetero: compound heterozygote; homo: homozygote; hetero: heterozygote.

patients with E148Q variant is milder than that of FMF
patients with exon 10 variants [18–20]. In contrast, it has
been reported that compound heterozygotes with E148Q
show a severe phenotype [21] and that compound hetero-
zygous E148Q has a higher disease penetrance [22], sug-
gesting that E148Q plays a role as a modifier of other
risk alleles. Moreover, a pedigree of a family in a study
[7] as well as two case reports [15,23] showed that indi-
viduals did not develop diseases (FMF and PAAND) due
to the presence of the pathogenic heterozygous variant
alone; when the heterozygous E148Q variant was added,
they developed diseases, suggesting that the E148Q variant
may be involved in disease development. The E148Q vari-
ant is globally regarded as a genetic polymorphism,
although there are regional differences in frequency, par-
ticularly in Japan where more than 20% of healthy indi-
viduals harbor this variant [1]. This study may be
meaningful in that the cases with heterozygous E148Q
and other variants and those with E148Q heterozygote
only were directly compared, and E148Q did not modify
non-E148Q and non-M694I alleles in Japanese patients.
Moreover, the group with heterozygous E148Q and other
variants had a significantly higher frequency of abdominal
pain and arthralgia than the group with heterozygous
E148Q only, suggesting that FMF patients with heterozy-
gous E148Q and other variants were clinically more
severe than those with heterozygous E148Q alone.
Recently, the activation mechanism of pyrin inflamma-
somes, which are involved in the MEFV-encoded protein
pyrin, has been elucidated [24]. The exon 10 variant in the
MEFV disease gene of FMF is considered to act as a loss-of-
function variant in the B30.2 domain, which is an important
functional site of the pyrin protein. However, the MEFV
variant has been shown to act as a gain-of-function variant
to confer a gene dosage effect in the exon 10 variant [25].
Moreover, MEFV variants arise from hypermorphic variants
that specifically decrease the activation threshold of the
pyrin inflammasome [25]. If E148Q is a hypermorphic vari-
ant, it may have some role in the development or aggrava-
tion of FMF.
6 K. FUJIMOTO ET AL.
We recently reported the first case of a PAAND patient
in Japan [15]. In PAAND patient, the S242R variant in exon
2 produced IL-1b and caused inflammasome activation due
to lack of 14-3-3 protein binding site, exhibiting a pheno-
type (PAAND) different from FMF [26,27]. In our case, the
patient had a compound heterozygous variant for S242R
and E148Q, while his mother who only had the heterozy-
gous S242R variant was asymptomatic. Assuming that the
E148Q variant modifies inflammasome activation, it is con-
ceivable that the patient developed PAAND due to the for-
mation of a compound heterozygous variant between S242R
and E148Q (Table 5) [15].
We previously performed a gene search for SAID in 176
cases of unexplained fever, and 43 of these cases (24.4%)
were diagnosed with FMF [28]. In this study, we focused on
patients with recurrent fever (three or more episodes of
37.5  C), who were more likely to have SAID. Therefore,
137 cases (68.8%) out of 199 cases were clinically diagnosed
with FMF. Thus, it can be suggested that patients presenting
with recurrent fever have a higher chance of being diag-
nosed with FMF than patients with unexplained fever.
Moreover, 31.4% of FMF patients met the diagnostic criteria
for FMF without MEFV variants identified by NGS. This
frequency was higher than reported in Japanese epidemio-
logical survey [29]; however, some previous reports have
exceeded 30% [30,31], which suggested that it was likely due
to differences in the populations studied.
The Tel Hashomer criteria are based on clinical symp-
toms that have been observed in people from the
Mediterranean area [2] and have been used in Japan for a
long time. In East Asian countries like Japan where many
non-exon 10 variants are prevalent, it might be necessary to
establish new criteria that can be applied to Japanese FMF
patients instead of the Tel Hashomer criteria.
From now on, in order to clarify the significant role of
the E148Q variant, it will be necessary to improve the
accuracy of genetic research and to carry out a further
large-scale clinical validation in Japan. Eventually, we need
to conduct multifaceted cellular and molecular level studies
using induced pluripotent stem cells derived from patients
harboring the E148Q variant.
5. Conclusion
In this study, patients who were heterozygous for E148Q
along with other non-exon 10 MEFV alleles demonstrated a
higher risk of expressing the FMF phenotype compared
with those with heterozygous E148Q alone. Further verifica-
tion is required to examine the increased number of
FMF cases.
Acknowledgments
The authors would like to thank Dr. Manabu Nakayama and Dr.
Osamu Ohara for performing the genetic analysis and Ms. Yurina
Iwanaga for analyzing the clinical data.
Conflict of interest
None.
Funding
This work was supported by the “Research on Measures for Intractable
Diseases” grant from the Japanese Ministry of Health, Labour and
Welfare [H31-Nanchi-Ippan-020] to RN and HI and JSPS KAKENHI
[Grant Number 19K08899] to HI.
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