| 1. |
- Jonsson, Stefan, et al.
(författare)
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Identification of sequence variants influencing immunoglobulin levels
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 49:8, s. 1182-1191
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
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| 2. |
- Schou, Henning, et al.
(författare)
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Circulatory effects of hypoxia, acute normovolemic hemodilution, and their combination in anesthetized pigs
- 1996
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Ingår i: Anesthesiology. - 1528-1175. ; 84:6, s. 1443-1454
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Because hemodilution decreases the oxygen-carrying capacity of blood, it was hypothesized that severe hemodilution would decrease the tolerance to alveolar hypoxia. METHODS: Hemodynamics, oxygen transport, and blood lactate concentrations were compared in ten pigs with normal hematocrit (33 +/- 4%), and ten hemodiluted pigs (hematocrit 11 +/- 1%; mean +/- SD) anesthetized with ketamine-fentanyl-pancuronium during stepwise decreases in inspired oxygen fraction (FIO2; 1.0, 0.35, 0.21, 0.15, 0.10, 0.05). RESULTS: Median systemic oxygen delivery (DO2SY) became critical (the DO2SY value when arterial lactate exceeded 2.0 mmol.l-1) at 10.4 ml.kg-1.min-1 (range 6.9-16.1) in hemodiluted animals and at 11.8 ml.kg-1.min-1 (5.9-32.2) in animals with normal hematocrits (NS). The relationship between mixed venous oxygen saturation and arterial lactate values was less consistent and median critical mixed venous oxygen saturation was higher (P < 0.05) in the hemodiluted group (35%, range 21-64), than in animals with normal hematocrits (21%, 7-68%). In animals with normal hematocrit, decreasing FIO2 from 1.0 to 0.10 resulted in a decrease in DO2SY from 26.3 +/- 9.1 to 9.3 +/- 3.9 ml.kg-1.min-1 (P < 0.01). Cardiac output did not change, systemic oxygen extraction ratio increased from 0.23 +/- 0.08 to 0.68 +/- 0.13 (P < 0.01), and arterial lactate from 0.9 +/- 0.2 to 3.4 +/- 3.0 mmol.l-1 (P < 0.05). Cardiac venous blood flow, as measured by retrograde thermodilution, increased from 5.7 +/- 2.9 to 12.6 +/- 5.7 ml.kg-1.min-1 (P < 0.01). When FIO2 was reduced to 0.05, three animals became hypotensive and died. In the second group, hemodilution increased cardiac output and systemic oxygen extraction ratio (P < 0.01). Cardiac venous blood flow increased from 4.1 +/- 1.7 to 9.8 +/- 5.1 ml.kg-1.min-1 (P < 0.01), and cardiac venous oxygen saturation from 22 +/- 5 to 41 +/- 10% (P < 0.01). During the subsequent hypoxia, cardiac output and DO2SY were maintained until FIO2 = 0.15 (DO2SY = 10.1 +/- 3.3 ml.kg-1.min-1). Cardiac venous blood flow was then 18.5 +/- 10.7 ml.kg-1.min-1 (P < 0.01), but in spite of this, myocardial lactate production occurred. At FIO2 = 0.10 (DO2SY = 7.7 +/- 3.0 ml.kg-1.min-1), arterial lactate concentration increased to 8.5 +/- 2.3 mmol.l-1 (P < 0.01), and most animals became hypotensive. All hemodiluted animals died when FIO2 was decreased to 0.05 (P < 0.01 when compared to animals with normal hematocrit). CONCLUSIONS: Systemic and myocardial lactate production occurred at similar systemic oxygen delivery rates in hemodiluted and nonhemodiluted animals. Mixed venous oxygen saturation may be a less reliable indicator of inadequate oxygen delivery during hemodilution.
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| 3. |
- Swaminathan, Bhairavi, et al.
(författare)
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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).
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