Biomarkers of Micronutrients in Regular Follow-Up for Tyrosinemia Type 1 and Phenylketonuria Patients

Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal-Wallis, Fisher's exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized

Common variants in WFS1 confer risk of type 2 diabetes

We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Public injecting and willingness to use a drug consumption room among needle exchange programme attendees in the UK.

This study examines the prevalence of public injecting and willingness to use drug consumption rooms (DCRs) among UK needle exchange programme (NEP) attendees. Three hundred and one injecting drug users (IDUs) were surveyed using a brief questionnaire across five NEPs in London and Leeds between April and June 2005. Injection in a public place in the past week was reported by 55% of the sample and 84% reported willingness to use a DCR if it was available. Public injecting was positively associated with insecure housing (AOR=2.1, CI 1.2-3.5, p=0.009), unsafe needle and syringe disposal in the past month (AOR=3.6, CI 1.9-6.9, p<0.001) and willingness to use DCR (AOR=2.7, CI 1.3-5.4, p=0.006). Public injecting was negatively associated with being aged more than 30 years (AOR=0.4, CI 0.3-0.7, p=0.003) and living in close proximity (within 0.5 miles/0.8 km) of the usual place of drug purchase (AOR=0.6, CI 0.3-0.9, p=0.02). Our findings suggest that recent public injecting is prevalent among UK NEP attendees and the majority would be willing to use DCRs if available. It is also probable that if such services were located close to key drug markets they would engage vulnerable IDU sub-populations such as young people and the insecurely housed and reduce their levels of public injecting and unsafe needle/syringe disposal. Targeted pilot implementation of DCRs in the UK is recommended

A False-Negative Newborn Screen for Tyrosinemia Type 1-Need for Re-Evaluation of Newborn Screening with Succinylacetone

Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Elevated succinylacetone (SA) is pathognomonic for TT1 and therefore often used as marker for TT1 newborn screening (NBS). While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen. A nine-year-old boy presented with HCC in a cirrhotic liver. Additional tests for the underlying cause unexpectedly revealed TT1. Nine years prior, the patient was screened for TT1 via SA NBS with a negative result: SA 1.08 µmol/L, NBS cut-off 1.20 µmol/L. To our knowledge, this report is the first to describe a false-negative result from the TT1 NBS using SA. False-negative TT1 NBS results may be caused by milder TT1 variants with lower SA excretion. Such patients are more likely to be missed in NBS programs and can be asymptomatic for years. Based on our case, we advise TT1 to be considered in patients with otherwise unexplained liver pathology, including fibrosis, cirrhosis and HCC, despite a previous negative TT1 NBS status. Moreover, because the NBS SA concentration of this patient fell below the Dutch cut-off value (1.20 µmol/L at that time), as well as below the range of cut-off values used in other countries (1.29-10 µmol/L), it is likely that false-negative screening results for TT1 may also be occurring internationally. This underscores the need to re-evaluate TT1 SA NBS programs.</p

The FTO gene is associated with an atherogenic lipid profile and myocardial infarction in patients with type 2 diabetes:A genetics of diabetes audit and research study in Tayside Scotland (Go-DARTS) study

BACKGROUND: Common variation in the Fat Mass and Obesity related (FTO) gene is associated with increased body fat and susceptibility to type 2 diabetes (T2D). We hypothesized that this would also associate with metabolic phenotypes of insulin resistance, and increased risk of cardiovascular morbidity and mortality. METHODS AND RESULTS: FTO rs9939609 genotype was determined in 4897 patients with T2D in the prospective Genetics of Diabetes Audit and Research Study in Tayside Scotland (Go-DARTS) study. The A allele was associated with lower plasma HDL cholesterol (mean difference 0.03 mmol/L, p=0.008), higher triglycerides (0.1 mmol/L, p=0.007), higher atherogenic index of plasma (0.03, p=0.003) and, as expected, increased BMI (0.77 kg/m(2), p=8.8×10(−6)). During a mean follow up of 3.6 years the A allele was also associated with increased risk (HR 2.36, CI 1.49-3.74, p=0.0002) of fatal and non fatal myocardial infarction (total 324 events) in a model including baseline age, gender, prevalent myocardial infarction, smoking status, statin and insulin use. This association diminished but remained significant when obesity related traits such as BMI, glycated haemoglobin and lipid parameters were also included (HR 2.01 CI 1.18-3.45, p=0.011). There was a strong interaction of FTO genotype and statin use and cardiovascular outcome (p=0.001) such that cardiovascular morbidity and mortality was completely abrogated in individuals prescribed statins. CONCLUSION: The increased fat mass in carriers of the A allele of rs9939609 of FTO is associated not only with increased risk of T2D, but also with an increase in atherogenic lipid profile, and myocardial infarction in these patients. This variant may therefore in future contribute to more effective targeting of specific preventative therapy