Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation.
Ficolin-1 is a recognition molecule of the lectin complement pathway. The ficolin-1 gene FCN1 is polymorphic, but the functional and clinical consequences are unknown.The concentration of ficolin-1 in plasma and FCN1 polymorphisms in positions -1981 (rs2989727), -791 (rs28909068), -542 (rs10120023), -271 (rs28909976), -144 (rs10117466) and +7918 (rs1071583) were determined in 100 healthy individuals. FCN1 expression by isolated monocytes and granulocytes and ficolin-1 levels in monocyte culture supernatants were assessed in 21 FCN1-genotyped individuals. FCN1 polymorphisms were determined in a cohort of 251 patients with systemic inflammation. High ficolin-1 plasma levels were significantly associated with the minor alleles in position -542 and -144. These alleles were also significantly associated with high FCN1 mRNA expression. The level of ficolin-1 in culture supernatants was significantly higher in individuals homozygous for the minor alleles at positions -542 and -144. Homozygosity for these alleles was significantly associated with fatal outcome in patients with systemic inflammation. None of the other investigated polymorphisms were associated with FCN1 and ficolin-1 expression, concentration or disease outcome. Functional polymorphic sites in the promoter region of FCN1 regulate both the expression and synthesis of ficolin-1 and are associated with outcome in severe inflammation.
Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
L
L
Munthe-Fog
T
T
Hummelshoj
C
C
Honoré
M E
ME
Moller
M O
MO
Skjoedt
I
I
Palsgaard
N
N
Borregaard
H O
HO
Madsen
P
P
Garred
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D006720:Homozygote; D006801:Humans; D037102:Lectins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics* / Q000401:mortality; D000097604:Ficolins
D037102:Lectins; D012333:RNA, Messenger; D000097604:Ficolins