| 1. |
- Wessel, Jennifer, et al.
(författare)
-
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
|
|
| 2. |
- Holm, Elena, et al.
(författare)
-
Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network.
- 2015
-
Ingår i: Blood Coagulation and Fibrinolysis. - 1473-5733. ; 26:4, s. 383-388
-
Tidskriftsartikel (refereegranskat)abstract
- Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P < 0.0001), gastrointestinal bleeding (P = 0.0003), joint bleeding (P < 0.0001), and menorrhagia (P = 0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD.
|
|
| 3. |
- Pipe, Steven W., et al.
(författare)
-
Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B
- 2023
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 388:8, s. 706-718
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. Methods: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. Results: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. Conclusions: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile.
|
|
| 4. |
- Warrier, Indira, et al.
(författare)
-
Factor IX inhibitors and anaphylaxis in hemophilia B
- 1997
-
Ingår i: Journal of Pediatric Hematology/Oncology. - : Ovid Technologies (Wolters Kluwer Health). - 1077-4114 .- 0192-8562. ; 19:1, s. 23-27
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: We present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B. Patients and Methods: Twelve hemophilia centers from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes. Results: All 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor liters were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children. Conclusion: Physicians treating young children with hemophilia B should be aware of the potentially life- threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients.
|
|
