Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10⁻¹¹). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10⁻⁴³), alkaline phosphatase (-0.025 SD, 1.2*10⁻³⁷), total cholesterol (-0.030 SD, p = 1.9*10⁻³⁶) and LDL cholesterol (-0.027 SD, p = 5.1*10⁻³⁰) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis. Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease.

A major trend in biomedical engineering is the development of reliable, self-contained point-of-care (POC) devices for diagnostics and in-field assays. The new generation of such platforms increasingly addresses the clinical and environmental needs. Moreover, they are becoming more and more integrated with everyday objects, such as smartphones, and their spread among unskilled common people, has the power to improve the quality of life, both in the developed world and in low-resource settings. The future success of these tools will depend on the integration of the relevant key enabling technologies on an industrial scale (microfluidics with microelectronics, highly sensitive detection methods and low-cost materials for easy-to-use tools). Here, recent advances and perspectives will be reviewed across the large spectrum of their applications.

Background: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene ( LDLR ) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia. Methods: To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls. Results: Rare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene ( NOS3 ), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80–3.26; P =5.50×10 ⁻⁹ ). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86–4.65]; P =5.00×10 ⁻⁶ ) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14–1.51]; P =2.00×10 ⁻⁴ ) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk. Conclusions: Beyond LDLR , we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.

Alexithymia has been considered both to predispose to depression and to worsen cardiac prognosis after an acute coronary syndrome. Nonetheless, no studies have evaluated its role as a risk factor for incident depression, in patients with acute coronary syndrome. In 251 consecutive patients, the presence of a first-ever depressive episode was evaluated with the Primary Care Evaluation of Mental Disorders at baseline and 1, 2, 4, 6, 9, 12 and 24 months after their first acute coronary syndrome. At baseline, patients completed the Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale. Out of 251 subjects (80.9% males), a first-ever depressive episode was diagnosed in 66 patients. Depressed and never-depressed patients differed in female gender, living status, alexithymic scores at TAS-20 and depressive symptoms. Nonetheless, nor the TAS-20 factors nor its total score were predictive of developing a depressive episode in a Cox regression. Moreover, baseline differences in TAS-20 scores between the two groups, disappeared after controlling for anhedonic symptoms. Our results do not support the hypothesis that alexithymia at TAS-20 is a risk factor for incident depression after acute coronary syndrome.