I n an extended twin study we estimated the heritability of fasting HbA1c and blood glucose levels. Blood glucose was assessed in different settings (at home and in the clinic). We tested whether the genetic factors influencing fasting blood glucose levels overlapped with those influencing HbA1c and whether the same genetic factors were expressed across different settings. Fasting blood glucose was measured at home and during two visits to the clinic in 77 healthy families with same-sex twins and siblings, aged 20 to 45 years. HbA1c was measured during the first clinic visit. A 4-variate genetic structural equation model was used that estimated the heritability of each trait and the genetic correlations among traits. Heritability explained 75% of the variance in HbA1c. The heritability of fasting blood glucose was estimated at 66% at home and lower in the clinic (57% and 38%). Fasting blood glucose levels were significantly correlated across settings (0.34 < r < 0.54), mostly due to a common set of genes that explained between 53% and 95% of these correlations. Correlations between HbA1c and fasting blood glucoses were low (0.11 < r < 0.23) and genetic factors influencing HbA1c and fasting glucose were uncorrelated. These results suggest that in healthy adults the genes influencing HbA1c and fasting blood glucose reflect different aspects of the glucose metabolism. As a consequence these two glycemic parameters can not be used interchangeably in diagnostic procedures or in studies attempting to find genes for diabetes. Both contribute unique (genetic) information.

Background: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 (ACVR1), is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. Methods: LUMINA-1 (NCT03188666) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period 1), followed by an open-label period (Period 2). After Period 2, patients were allowed to stay on garetosmab in an open-label extension. For Period 1, primary endpoints were HO total lesion activity (HO-TLA) by 18F-sodium fluoride positron emission tomography (18F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period 2 primary endpoint compared the number of new lesions in Period 2 versus Period 1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. Findings: Patients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P=0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18F-NaF PET, post-hoc P=0.009; 90% relative reduction by CT, post-hoc P=0.017); flare-ups were significantly reduced (P=0.0005). For placebo patients transitioning to garetosmab in Period 2, no patients developed new HO lesions (0% in Period 2 versus 40.9% in Period_1; P=0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients' ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period 2 or the open-label extension. The deaths were associated with baseline disease severity in some, pre-existing comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Interpretation: Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab.

Backgtound Deep venous thrombosis is a common disease, with genetic and acquired nsk factors Many patients have a history of minor events (short penods of iramobihsaüon such äs prolonged travel, short illness. ramor surgery or injunes) before onset of venous thrombosis However. the role of these mmor events has received httle formal study Also, we do not know how mmor events might mteract with the presence of genetic prothrombotic defects (factor V Leiden mutation factor II mutation, protein C S and antithrombin deficiency) Patients and Methods On the basis of case-control data from a thrombosis Service m the Netherlands we added a follow-up penod for a casecross-over analysis of minor events äs nsk factors, and a case only analysis toi the mteraction with factor V Leiden A total of 187 patients with first. objectively diagnosed venous thrombosis of the legs, aged 15-70, without underlymg malignanues and without major acquired nsk factors entered the study Tor the analy sis of minor events in the case-cross-over analysis we used a matched odds ratio, m the case only analysis we used the multiphcative s\nergy mdex Results In 32 6% ot the 187 patients with deep venous thrombosis who did not have major acquired nsk tactors, mmor events were the only external nsk factors Minor events mcreased the nsk of thrombosis about 3-fold äs estimated m the case-cross-over analysis (odds ratio 2 9, 95% confidence interval l 5-5 4) The synergy mdex between minor events and factor V Leiden mutation m the case-only analysis was 0 7 (95% confidence interval 03-15) Therefore, persons with factor V Leiden mutation who expenence a minor event will have an estimated nsk mcrease of about 17-fold. which exceeds the sum of the mdividual nsk factors Condusions Mmor events are hkelv to play an important role m the development of deep venous thrombosis, especially m the presence of genetic prothrombotic conditions

Fibrodysplasia ossificans progressiva (FOP), sometimes known as myositis ossificans progressiva, is an ultra-rare disease in which bone is formed in muscular tissue, tendons and ligaments. This is known as heterotopic ossification (HO). FOP is caused by a heterozygous mutation in the highly conserved ACVR1/ALK2 gene which affects about 1 in 1.5–2 million individuals. At birth, patients with the predominant R206H mutation only exhibit a bilateral hallux valgus. During childhood, heterotopic bone formation develops in a typical pattern, affecting the axial muscles first before appendicular body parts are involved. HO can start spontaneously but is often elicited by soft tissue trauma or medical procedures. After soft tissue injury, an inflammatory process called a flare-up can start, followed by the formation of HO. HO leads to a limited range of motion, culminating in complete ankylosis of nearly all joints. As a result of HO surrounding the thorax, patients often suffer from thoracic insufficiency syndrome (TIS). TIS is the most common cause of a limited life expectancy for FOP patients, with a median life expectancy of 56 years. Management is focused on preventing soft-tissue injury that can provoke flare-ups. This includes prevention of iatrogenic damage by biopsies, intramuscular injections and surgery. Anti-inflammatory medication is often started when a flare-up occurs but has a poor basis of evidence. Several forms of potential treatment for FOP are being researched in clinical trials. Progression of the disease is monitored using CT and 18F-NaF PET/CT combined with functional assessments. Patients are regularly evaluated for frequently occurring complications such as restrictive lung disease. Here, we review the current management, monitoring and treatment of FOP.