Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

TY - JOUR

T1 - Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

AU - Munthe-fog, L

AU - Hummelshoj, T

AU - Honoré, C

AU - Moller, M E

AU - Skjoedt, M O

AU - Palsgaard, I

AU - Borregaard, N

AU - Madsen, H O

AU - Garred, P

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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.

U2 - 10.1038/gene.2012.27

DO - 10.1038/gene.2012.27

M3 - Journal article

SN - 1466-4879

VL - 13

SP - 515

EP - 522

JO - Genes and Immunity

JF - Genes and Immunity

IS - 7

ER -