Ingrid W Moen1, Helle K M Bergholdt1,2, Thomas Mandrup-Poulsen1,3, Børge G Nordestgaard1,4,5,6, Christina Ellervik7,2,8,9. 1. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2. Department of Clinical Biochemistry and The Danish General Suburban Population Study, Naestved Hospital, Naestved, Denmark. 3. Immuno-endocrinology Laboratory, Section for Endocrinological Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. 5. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. 6. The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark. 7. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; christina@ellervik.dk cel@regionsjaelland.dk. 8. Department of Production, Research, and Innovation, Region Zealand, Sorø, Denmark; and. 9. Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Abstract
BACKGROUND: It is unknown why increased plasma ferritin concentration predicts all-cause mortality. As low-grade inflammation and increased plasma ferritin concentration are associated with all-cause mortality, we hypothesized that increased plasma ferritin concentration is genetically associated with low-grade inflammation. METHODS: We investigated whether increased plasma ferritin concentration is associated with low-grade inflammation [i.e., increased concentrations of C-reactive protein (CRP) and complement component 3 (C3)] in 62537 individuals from the Danish general population. We also applied a Mendelian randomization approach, using the hemochromatosis genotype C282Y/C282Y as an instrument for increased plasma ferritin concentration, to assess causality. RESULTS: For a doubling in plasma ferritin concentration, the odds ratio (95% CI) for CRP ≥2 vs <2 mg/L was 1.12 (1.09-1.16), with a corresponding genetic estimate for C282Y/C282Y of 1.03 (1.01-1.06). For a doubling in plasma ferritin concentration, odds ratio (95% CI) for complement C3 >1.04 vs ≤1.04 g/L was 1.28 (1.21-1.35), and the corresponding genetic estimate for C282Y/C282Y was 1.06 (1.03-1.12). Mediation analyses showed that 74% (95% CI, 24-123) of the association of C282Y/C282Y with risk of increased CRP and 56% (17%-96%) of the association of C282Y/C282Y with risk of increased complement C3 were mediated through plasma ferritin concentration. CONCLUSIONS: Increased plasma ferritin concentration as a marker of increased iron concentration is associated observationally and genetically with low-grade inflammation, possibly indicating a causal relationship from increased ferritin to inflammation. However, as HFE may also play an immunological role indicating pleiotropy and as incomplete penetrance of C282Y/C282Y indicates buffering mechanisms, these weaknesses in the study design could bias the genetic estimates.
RCT Entities:
BACKGROUND: It is unknown why increased plasma ferritin concentration predicts all-cause mortality. As low-grade inflammation and increased plasma ferritin concentration are associated with all-cause mortality, we hypothesized that increased plasma ferritin concentration is genetically associated with low-grade inflammation. METHODS: We investigated whether increased plasma ferritin concentration is associated with low-grade inflammation [i.e., increased concentrations of C-reactive protein (CRP) and complement component 3 (C3)] in 62537 individuals from the Danish general population. We also applied a Mendelian randomization approach, using the hemochromatosis genotype C282Y/C282Y as an instrument for increased plasma ferritin concentration, to assess causality. RESULTS: For a doubling in plasma ferritin concentration, the odds ratio (95% CI) for CRP ≥2 vs <2 mg/L was 1.12 (1.09-1.16), with a corresponding genetic estimate for C282Y/C282Y of 1.03 (1.01-1.06). For a doubling in plasma ferritin concentration, odds ratio (95% CI) for complement C3 >1.04 vs ≤1.04 g/L was 1.28 (1.21-1.35), and the corresponding genetic estimate for C282Y/C282Y was 1.06 (1.03-1.12). Mediation analyses showed that 74% (95% CI, 24-123) of the association of C282Y/C282Y with risk of increased CRP and 56% (17%-96%) of the association of C282Y/C282Y with risk of increased complement C3 were mediated through plasma ferritin concentration. CONCLUSIONS: Increased plasma ferritin concentration as a marker of increased iron concentration is associated observationally and genetically with low-grade inflammation, possibly indicating a causal relationship from increased ferritin to inflammation. However, as HFE may also play an immunological role indicating pleiotropy and as incomplete penetrance of C282Y/C282Y indicates buffering mechanisms, these weaknesses in the study design could bias the genetic estimates.
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