J Hum Genet (2008) 53:1016–1021
DOI 10.1007/s10038-008-0337-4

SHORT COMMUNICATION

Molecular basis of complement factor I (CFI) polymorphism:
one of two polymorphic suballeles responsible for CFI A
is Japanese-specificIsao Yuasa Æ Mayumi Nakagawa Æ Kazuo Umetsu Æ Shinji Harihara Æ Aya Matsusue Æ
Hiroaki Nishimukai Æ Yasuo Fukumori Æ Naruya Saitou Æ Kyung Sook Park ÆFeng Jin Æ Gérard Lucotte Æ Prasanta K. Chattopadhyay Æ Lotte Henke Æ Jürgen Henke

Received: 7 July 2008 / Accepted: 1 September 2008 / Published online: 30 September 2008
Ó The Japan Society of Human Genetics and Springer 2008

Abstract Isoelectric focusing has revealed that human
complement factor I (CFI) is controlled by two polymorphic alleles, CFI*A and CFI*B, and a few rare variant
alleles. In this study the molecular basis of the CFI polymorphism was investigated in 174 Japanese. The CFI*A
was divided into two suballeles, CFI*As (R201S) andCFI*Ah (R406H). CFI*Aj, a rare variant allele originating

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10038-008-0337-4) contains supplementarymaterial, which is available to authorized users.
I. Yuasa (&)
Division of Legal Medicine, Faculty of Medicine,
Tottori University, Yonago 683-8503, Japane-mail: yuasai@med.tottori-u.ac.jp
M. Nakagawa
Department of Pathobiological Science and Technology,
Faculty of Medicine, Tottori University, Yonago, JapanK. Umetsu
Department of Experimental and Forensic Pathology,
Faculty of Medicine, Yamagata University,
Yamagata, Japan
S. Harihara
Department of Biological Sciences,
Graduate School of Science, University of Tokyo,
Tokyo, Japan
A. Matsusue
Department of Forensic Medicine,
Fukuoka University School of Medicine,
Fukuoka, Japan
H. Nishimukai
Division of Legal Medicine,
Ehime University School of Medicine,
Ehime, Japan

123

from CFI*Ah, had an additional mutation (R502L). The
distribution of these three mutations and two registered
SNPs was investigated in a total of 2,471 individuals in 20
populations from various areas, and six haplotypes wereobserved. Haplotype H3, which is characterized by
CFI*As, was found only in Far East populations: the frequencies were about 0.03 in the main island of Japan andlower than 0.01 in Okinawa and Korea. Haplotype H5,characterized by CFI*Ah, prevailed almost exclusively in
East Asians and was observed at the highest frequencies insouthern Chinese Han and Thais. CFI*Ah must have arisen
Y. Fukumori
Osaka Red Cross Blood Center, Osaka, Japan
N. Saitou
Division of Population Genetics,
National Institute of Genetics, Mishima, JapanK. S. Park
Department of Biology, Sungshin Women’s University,
Seoul, South Korea
F. JinInstitute of Genetics and Developmental Biology,
Chinese Academy of Sciences, Beijing, China
G. LucotteCenter of Molecular Neurogenetics, Paris, France
P. K. Chattopadhyay
Amity Institute of Forensic Sciences, Defence Colony,
New Delhi, India
L. Henke  J. Henke
Institut für Blutgruppenforschung, Cologne, Germany

J Hum Genet (2008) 53:1016–1021

in a southeastern part of Asia and thereafter have spread toneighboring populations.
Keywords Complement factor I  Molecular basis 
Mutation  Polymorphism  Population study

Introduction
Complement factor I (CFI), or C3b/C4b inactivator, is aregulatory serine protease of the complement cascade andis responsible for cleaving the alpha-chains of C4b and C3bin the presence of the cofactors C4-binding protein
and factor H, respectively (Nagasawa and Stroud 1977;
Pangburn et al. 1977). The human CFI gene (GenBank
GeneID: 3426; accession numbers: NM_000204.2 andNT_000004.10) spans 63 kb on chromosome 4q25 andconsists of 13 exons, encoding a 583-amino acid polypeptide as an unprocessed precursor with a signal peptide
consisting of 18 amino acids (Catterall et al. 1987; Goldberger et al. 1987; Shiang et al. 1989; Vyse et al. 1994).
The protein is synthesized predominantly in the liver. Prior
to secretion, the CFI proprotein is cleaved to be the mature
protein, which is a heterodimeric glycoprotein composed ofheavy and light chains (Mr 50,000 and 38,000) linked bydisulfide bonds. It circulates in plasma at a concentration of
35 lg/ml (Pangburn et al. 1977; Goldberger et al. 1984).
CFI deficiency is associated with a propensity to pyrogenic
infections and an increased incidence of immune complex
diseases due to impaired complement-mediated functions(Vyse et al. 1996; Baracho et al. 2003). Some nonsynonymous mutations result in atypical hemolytic uremic
syndrome (aHUS), which is characterized by acute renal
failure, microangiopathic hemolytic anemia, and thrombocytopenia (Fremeaux-Bacchi et al. 2004; Kavanagh et al.
2008). The genetic polymorphism of CFI was first discovered by isoelectric focusing of desialyzed plasma
samples followed by immunoblotting (Nakamura and Abe1985). The CFI polymorphism is controlled by two major
alleles, CFI*A and CFI*B, and a few rare variant alleles(Nakamura et al. 1990). CFI*A was rare in Europeans, but
was observed at frequencies of more than 0.10 in East
Asians, suggesting that this allele is Asian-specific (Yuasa
et al. 1988). In this study, we elucidated the molecularbasis of the CFI polymorphism and investigated the distribution of haplotypes in more than 2,400 people from 20
African and Eurasian populations.

1017

extracted from unrelated individuals living in various areasof Eurasia were used for a population study. Most of thesesamples were from the same set as those in a previous study(Yuasa et al. 2007). This study was approved by the EthicalCommittee at the Faculty of Medicine, Tottori University.
CFI phenotyping of desialylated serum samples was performed by isoelectric focusing and immunoblotting asreported previously (Yuasa et al. 1988). Mutations wereidentified by direct sequencing of products for 13 exons,obtained by the polymerase chain reaction (PCR) withprimers designed by Kavanagh et al. (2005). Nucleotide andamino acid numbering begin from the ATG initiation codon
and includes the 18-residue signal peptide. PCR products forexons 4 and 11 were digested with MboII and TaiI (Fermentas, Glen Burnie, MD), respectively, according to the
supplier’s instructions. For the population study, threemutations found in this study and two known single nucleotide polymorphisms (SNPs), rs2298749 (c.804G[A,S268S), and rs11098044 (c.898G[A, A300T), were simultaneously typed by pentaplex PCR based on the amplified
product length polymorphism (APLP) method. This method
requires three primers for the amplification of DNA fragments at a locus: two allele-specific primers differing inlength and one common primer on the opposite DNA chain.
Noncomplementary nucleotides were introduced into
primers to give a difference in length between two PCR
products, to enhance the specificity of primers, and to
optimize annealing temperature of primers (Watanabe et al.
1997; Yuasa et al. 2007). The nucleotide sequence andamount of each primer are shown in the online Table S1. The
PCR cocktail consisted of 100 ll of Multiple PCR MasterMix from a Multiplex PCR Kit (Qiagen, Hilden, Germany),
18 ll of 15 primers with a concentration of 100 pmol/ll, and82 ll of water. PCR was performed in a volume of 8 ll
containing 7.5 ll of the PCR cocktail and 0.5 ll of a solution containing about 20 ng of genomic DNA. The cycle
conditions were 95°C for 15 min, then 30 cycles of 94°C for
10 s, 56°C for 10 s, 72°C for 10 s, and a final extension stepof 15 min at 72°C. The products were separated using apolyacrylamide gel (9%T, 5%C), then visualized by ethidium bromide staining. Allele and haplotype frequencies
were estimated, and the Hardy-Weinberg equilibrium wastested using Arlequin program version 3.11 (Excoffier et al.
2005). Clustal W and TreeView were used to investigate thephylogenetic relationships of the haplotypes.

Results and discussion
Subjects and methods
Both DNA and serum were obtained from 174 unrelated
Japanese individuals living in Tottori. DNA samples

Figure 1 shows the banding patterns of CFI after isoelectric
focusing of the serum samples. Three common phenotypes
and one anodal variant were observed in 174 Japaneseindividuals. Judging from the data reported previously

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1018

J Hum Genet (2008) 53:1016–1021(Nakamura et al. 1990), the variant band seemed to be very
similar in isoelectric point to the CFI A1 band, but to bedifferent in intensity from the CFI A1 band, which wasmuch less intense than the CFI A and B bands. A directcomparison of these two variants was not carried out,
because the CFI A1 sample was unavailable. The variant
found in this study was designated CFI Aj tentatively. CFI
A phenotype was found in 4 samples, CFI AB in 38
samples, CFI B in 131 samples, and CFI AjB in 1 sample.
The allele frequencies for CFI*A, CFI*B, and CFI*Aj were
calculated to be 0.1322, 0.8649, and 0.0029, respectively.
The observed distribution was in good agreement with the
Hardy-Weinberg law (P = 0.58). These allele frequencies
were consistent with the previous data on western Japan(Yuasa et al. 1988).
To elucidate the molecular basis of CFI*A, wesequenced all 13 exons in individuals with the CFI AB
phenotype. CFI*A arose from a G-to-A transition at
nucleotide position 1217 in exon 11 (Fig. 2b), resulting inthe substitution of histidine (CAT) for arginine (CGT) at
amino acid position 406. This substitution was previously
identified as two heterozygotes in 100 healthy French
control samples for a study of aHUS and was shown not tobe responsible for aHUS (Fremeaux-Bacchi et al. 2004).
The frequency was comparable to that (0.006) in a French

+
Av
A
B

1

2

3

4

5

6

7

8

Fig. 1 Banding patterns of desialylated complement factor I (CFI)
obtained by isoelectric focusing and immunoblotting. Anode at top.
Lanes 1, 2, 4, 7 CFI B phenotype, 3, 8 CFI AB, 5 CFI A, 6 CFI AjB

a

R201S

c.603A>Cb

R406H

c.1217G>A

Fig. 2 Automated DNA sequence electropherograms of CFI genemutations. Sequence analysis demonstrating the presence of themutation in exon 4 from an individual with CFI AB phenotype (a),123

population (Montpellier) obtained by an isoelectric focusing study (Yuasa et al. 1988).
This G-to-A transition brought about the loss of a TaiI
restriction site. In some samples the results from therestriction fragment length polymorphism (RFLP) analysis
were inconsistent with those from the isoelectric focusing.
The frequency of this allele, designated CFI*Ah, wasestimated to be 0.1034. When the CFI AB samples without
the loss of restriction site were sequenced, an additional
substitution was found: an A-to-C transversion at nucleotide position 603 in exon 4 (Fig. 2a), leading to a change
from arginine (AGA) to serine (AGC) at amino acidposition 201. This transversion brought about the loss of an
MboII restriction site. RFLP analysis showed a consistency
with the data from the isoelectric focusing. The frequencyof this new additional allele, designated CFI*As, was calculated to be 0.0316. Thus, CFI*A was divided into two
suballeles, CFI*Ah and CFI*As, which could not be subdivided by isoelectric focusing. Desialyzed CFI bands haveisoelectric points near 7. Generally, the resolution power ofisoelectric focusing is diminished in the higher pH range.
Sequencing of the CFI AjB sample revealed a G-to-T
transversion at nucleotide position 1505 in exon 12(Fig. 2c), resulting in the replacement from arginine (CGT)
to leucine (CTT) at amino acid position 502 in addition to
the c.1217G[A. The isoelectric point of the CFI Aj band
indicated that these two mutations were linked to eachother on a chromosome. We have identified three mutations: one in exon 4 occurred in the scavenger receptor
cystein-rich (SRCR) domain and the others in exons 11 and
12, in the serine protease (SP) domain (Vyse et al. 1994;
Kavanagh et al. 2005). The three mutations identified here
were not registered in the Entrez SNP database.
Figure 3 shows the band patterns of products obtainedby pentaplex PCR. The nucleotide substitutions wereclearly and unambiguously detected as PCR products withdifferent sizes (Fig. 3). The sizes ranged from 60 bp in
c.603C to 100 bp in c.898A.
Haplotypes were constructed on the basis of the genotype
data from 2,471 individuals by the EM algorithm, withphase-unknown samples, and six haplotypes were observed
c

R502L

c.1505G>T

exon 11 from another individual with CFI AB phenotype (b), andexon 12 from an individual with CFI AjB phenotype (c)J Hum Genet (2008) 53:1016–1021

1019

bp
125
A
G c.898

100

A
G
T
G
A
G
A
C

75

50

M

1

2

3

4

5

6

7

8

c.1217c.1505
c.804
c.603

9

Fig. 3 Simultaneous genotyping of the five SNPs by pentaplex PCR
based on the APLP method. Lanes M 25-bp ladder, 1 haplotypes H1/
H4, 2 H1/H6, 3 H1/H3, 4 H3/H5, 5 H5, 6 H2/H3, 7 H2, 8 H1, 9 H1/
H2. Six haplotypes, H1–H6 estimated from the five SNPs are shownin Fig. 4
c.603A>Cac.804G>A
c.898G>A12bc.1217G>A
c.1505G>T

3

4 56

7

8

910 11

H1

A

G

G

G

G

H2

A

A

G

G

G

H3

C

A

G

G

G

H4

A

G

A

G

G

H5

A

G

G

A

G

H6

A

G

G

A

T

12 13

c

Fig. 4 Five SNPs in the CFI gene and phylogenetic relationships of
estimated haplotypes. a Gene map and five SNPs in the CFI gene on
chromosome 4q25. Coding exons are marked by blue blocks and 50 and 30 -UTR by white blocks. The first base of transcription start site isdenoted as ?1. b Phylogenetic relationships of six haplotypes (c)investigated using Clustal W and TreeView programs. c Six
haplotypes estimated from the five SNPs using Arlequin program(Fig. 4), indicating that no recombination occurred. Thisregion forms a haploblock according to the data of theInternational HapMap Project. The distribution of haplotypes is shown in Table 1. Two main haplotypes, H1 and H2,classified by c.804G[A, were observed in every population.
The frequencies of this mutation in African, European,
Chinese, and Japanese were similar to the data of the four
populations in the HapMap data. Haplotype H1 was deduced
to be ancestral, because chimpanzee has the same haplotype(GeneID: 471271; accession number: XM_526653). The
other haplotypes were derived from these two haplotypes.

Haplotype H4 was characteristic of the African population including Nigerians and Ghanaians. The CFI*300T
frequency was very similar to that in Yoruba of the HapMap data (0.15).
Haplotype H3, which is characterized by CFI*As, wasrestricted to Japanese and Koreans. The frequency waspolymorphic only in Japanese from the main island ofJapan, whereas it was rare in Okinawa and Korea. Koreans
and Japanese from the main island of Japan and Okinawa
have high genetic affinity with each other (Tokunaga et al.
1996; Omoto and Saitou 1997). They share common alleles,
e.g., haplogroups O-SRY465 and O-47z on Y chromosome(Hammer et al. 2006). HLA haplotype B44-BFF-C4A3C4B1-DR13 is shared by Koreans and main island Japanese, but is low or rare in Okinawa and other parts of East
Asia (Tokunaga et al. 1996). Y-haplogroups C-M8 and DM55* and mtDNA-haplogroup M7a are observed at highfrequencies in Japanese, whereas at rare and lower frequencies in Koreans (Hammer et al. 2006; Tanaka et al.
2004). These distributions could be explained by a dual
structure model (Hanihara 1991). Modern Japanese are theresult of an intermixture between the upper Paleolithic
native population of Japan (Jomon people) and migrants
from northeast Asia through the Korean peninsula during
the Neolithic Yayoi period (300 BC-300 AD). Yayoi people
made less contribution to Japanese in Okinawa. However,
haplotype H3 is ubiquitous only in the main island Japanese. Haplotype H3 must have occurred in the main islandof Japan rather than be a remnant of the Jomon people. The
fusion gene (sefus) at the ABO-secretor locus (FUT2) was
found in the Japanese populations with a relatively highfrequency of 0.057, but in the Korean population at a rarefrequency of 0.006 (Liu et al 1999). AHSG*5 in the alpha2HS-glycoprotein gene is polymorphic in Okinawa with afrequency of 0.026, whereas it is quite rare or absent inother populations (Yuasa et al. 1985; Tamaki 1998). These
two variant alleles are characteristic of the Japanese in themain island of Japan and in Okinawa. Haplotype 3(CFI*As) is also specific for the main island Japanese. This
restricted distribution suggested that all CFI*As detected byisoelecric focusing were inferred to correspond to CFI*Ahin populations other than Far-East Asian populations.
Haplotype H5, characterized by CFI*Ah, prevails mainlyin East Asian populations. The highest frequencies wereobserved in Han Chinese from Changsha and the second
highest in Thais. An isoelectric focusing study showed that
Chengdu had the highest frequency for CFI*A (0.153)
among the data obtained to date (Zhang et al. 1999). This
haplotype flowed into Japan and Korea with fairly highfrequencies. According to an HLA study (Tokunaga et al.
1996), there are multiple migration and dispersal routes in
East Asia. This haplotype may have dispersed to Japan like
HLA haplotypes B46-DR9 and B54-DR4. Khalha and

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1020

J Hum Genet (2008) 53:1016–1021

Table 1 Distribution of CFI haplotypes in various populations
No.

Population

Collection place

n

H1

H2

H3

H4

H5

H6

1

AfricanWest Germany

68

0.44120.4044–0.1544––

2

FrenchRheims98

0.72450.2704–0.0051––

3

GermanWest Germany

192

0.75000.2500

–

–

–

–

4

Turk

West Germany

200

0.64750.3400–0.00250.0100–5

IndianDelhi

1070.75230.1963––0.0514–

6

BuryatEastern Mongolia

146

0.56510.4212––0.0137–

7

KhalhaUlaan Baator

173

0.62140.3555––0.0231–8

KoreanSeoul

140

0.65710.2607––0.0821–9

KoreanKwangju

145

0.63450.28620.0069–0.0724–

10

Japanese

Yamagata

154

0.55190.33120.0292–0.0877–

11
12

JapaneseJapanese

Tottori
Okinawa

174
88

0.51440.40340.3506
0.4716

0.03160.0057––0.10060.11930.0029–13

Han Chinese

Shenyang

68

0.66180.2647––0.0735–

14

Han Chinese

Beijing

40

0.68750.2625––0.0500–15

Han Chinese

Xi’an

109

0.54130.3624––

0.0963–

16

Han Chinese

Wuxi

119

0.60500.2815––0.1134–17

Han Chinese

Changsha107

0.63080.2196––0.1495–18

Han Chinese

Putien118

0.64830.2627––0.0890–19

Han Chinese

Huizhou

111

0.55410.3108––0.1351

–

20

Thai

Bankok1140.50000.3596––0.1404–

Buryat in Mongolia showed low frequencies among East
Asian populations. The frequencies of haplotype H5 werehigher in the southern part of East Asia than in the northern
part. There was a significant correlation between allele
frequencies and the degree of latitude in 15 East Asian
populations (r = -0.872, P \ 0.001), showing a southnorth downward geographical gradient. The Indian population investigated here belongs to the Gujars, who are an
important population of northern India. The frequency in
the Gujars was similar to that (0.058) in the Newars from
Nepal (Yuasa et al. 1988). It is noteworthy that haplotype
H5 occurred at fairly high frequencies in the northern part ofSouth Asia. The distribution of haplotype H5 reflects the
migration of ancient southeastern Asians. Haplotype H6
was observed only in a Japanese individual.
In conclusion, this study has presented molecular evidence of the CFI polymorphism. Haplotypes characterized
by CFI*As and CFI*Ah are unique in their distribution. It
would be interesting to scrutinize whether there are differences in frequency of haplotype H3 among Japaneseliving in various areas, including the Kyushu and the
Nansei islands. East Asians are divided into northern andsouthern populations (Tokunaga et al. 1996; Xue et al.
2006). Haplotype H5 is characteristic of the southern
populations. However, this allele was also detected inSouth Asians. There may be some populations with higher
frequencies in Tibet and the western part of China.

123

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