title: Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients.
abstract: Polymorphisms in the MBL2 gene, which affect the structure and influence on the serum concentration of mannose-binding lectin (MBL), are associated with inflammatory and infectious conditions. The importance of MBL2 polymorphisms on outcome in critical ill patients is unclear. Five hundred and thirty-two consecutive critically ill patients admitted to an intensive care unit (ICU) were included over a period of 18 months. Five hundred and thirty-three individuals served as controls. Vital status was obtained 15.5 months after the last patient was included. MBL2 polymorphisms were determined by a PCR-based assay. Homozygosity for MBL2 variant alleles (O/O) causing MBL structural defects was associated with the highest adjusted mortality rate followed by homozygosity for the normal MBL2 allele (A/A) encoding high MBL levels, whereas heterozygous A/O patients had the most favourable outcome (P = 0.015). MBL2 alleles were not associated with death in ICU (n = 166, P = 0.7), but the association appeared soon after discharge from ICU (n = 366): hazard ratio (HR) for O/O using A/A as reference was 1.33 (95% CI: 0.8-2.2) and for A/O it was 0.62 (95% CI: 0.4-0.8) respectively (P = 0.0045) at completion. No difference in MBL2 frequency was observed between patients and controls at baseline, and between patients classified as having sepsis or not. However, patients with the MBL2 O/O genotype had an increased frequency of Gram-positive bacterial infection (P = 0.01). Heterozygosity for MBL2 alleles confers a protective effect whereas homozygosity is associated with the worst outcome soon after discharge from ICU. This may be an example of heterosis.
authors.affiliation: Department of Anaesthesiology and Intensive Care, Herlev, Copenhagen University Hospital, Rigshospitalet, Denmark.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Hellemann
authors.forename: Anders
authors.initials: A
authors.lastname: Larsson
authors.forename: Hans O
authors.initials: HO
authors.lastname: Madsen
authors.forename: Jan
authors.initials: J
authors.lastname: Bonde
authors.forename: Jens Otto
authors.initials: JO
authors.lastname: Jarløv
authors.forename: Jørgen
authors.initials: J
authors.lastname: Wiis
authors.forename: Torsten
authors.initials: T
authors.lastname: Faber
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D016022:Case-Control Studies; D016638:Critical Illness / Q000401:mortality*; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D006823:Hybrid Vigor / Q000235:genetics / Q000502:physiology*; D007362:Intensive Care Units; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics*; D008875:Middle Aged; D010351:Patient Discharge; D011379:Prognosis; D018805:Sepsis / Q000235:genetics* / Q000401:mortality
chemical_list: C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin