Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein‐coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain‐of‐function to loss‐of‐function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein‐coding variants (i.e., the residuals were reduced), and approximately one‐third of these individuals (12/39) were re‐assigned from normal to slow metabolizer status. Rare coding variants can alter an individual’s CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Common CYP2A6 variants (minor allele frequency >1%) explain 30–35% of the variation in CYP2A6 activity, despite high heritability estimates (60–80%) in the CYP2A6 activity biomarker measure. One hypothesis is that rare coding variants (minor allele frequency <1%) may explain a portion of the missing heritability from pharmacogenes, including CYP2A6.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the relative contribution of rare coding variants in explaining variation in CYP2A6 activity? How necessary is the incorporation of rare coding variants in predicting individual metabolic status, and consequent tailoring of treatment?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Rare coding variants may explain only a small fraction of the variation on a population level; however, their role may be important on an individual level, altering the predicted metabolic status in a third of the individuals with these rare coding variants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Evaluating rare coding variants in pharmacogenes, such as CYP2A6, will be valuable in enhancing the investigation of CYP2A6’s influence on tobacco addiction and disease pathogenesis, by providing a more accurate reflection of the phenotypic metabolic status through improved genetic assessments.     

Nutritional Therapy in Persons Suffering from Psoriasis

Psoriasis is a chronic inflammatory skin disease. Immunological, genetic, and environmental factors, including diet, play a part in the pathogenesis of psoriasis. Metabolic syndrome or its components are frequent co-morbidities in persons with psoriasis. A change of eating habits can improve the quality of life of patients by relieving skin lesions and by reducing the risk of other diseases. A low-energy diet is recommended for patients with excess body weight. Persons suffering from psoriasis should limit the intake of saturated fatty acids and replace them with polyunsaturated fatty acids from the omega-3 family, which have an anti-inflammatory effect. In diet therapy for persons with psoriasis, the introduction of antioxidants such as vitamin A, vitamin C, vitamin E, carotenoids, flavonoids, and selenium is extremely important. Vitamin D supplementation is also recommended. Some authors suggest that alternative diets have a positive effect on the course of psoriasis. These diets include: a gluten-free diet, a vegetarian diet, and a Mediterranean diet. Diet therapy for patients with psoriasis should also be tailored to pharmacological treatment. For instance, folic acid supplementation is introduced in persons taking methotrexate. The purpose of this paper is to discuss in detail the nutritional recommendations for persons with psoriasis.     

Evaluation of Selected Properties of Sodium Alginate-Based Hydrogel Material—Mechanical Strength, μDIC Analysis and Degradation

The search for ideal solutions for the treatment of urethral stenosis continues. This includes developing the material, design, while maintaining its optimal and desired properties. This paper presents the results of the research conducted on sodium alginate-based hydrogel material (AHM), which may be used as a material for stents dedicated to the treatment of pathologies occurring in the genitourinary system. In order to determine the selected parameters of the AHM samples, strength and degradation tests, as well as analysis of the micro changes occurring on the surface of the material using a digital image correlation (µDIC) system, were performed. This study shows that the material possessed good mechanical strength parameters, the knowledge of which is particularly important from the point of view of the stent-tissue interaction. The degradation analysis performed showed that the AHM samples degrade in an artificial urine environment, and that the degradation time mainly depends on the chemical composition of the material. The novel µDIC method performed allowed us to characterize the homogeneity of the material structure depending on the cross-linking agent used.     

A preliminary observation: Male pattern hair loss among hospitalized COVID‐19 patients in Spain – A potential clue to the role of androgens in COVID‐19 severity

A preliminary observation of high frequency of male pattern hair loss among admitted COVID‐19 patients and suggest that androgen expression might be a clue to COVID‐19 severity.     

Dietary supplementation by older adults in southern China: a hospital outpatient clinic study

Background  

There has been little knowledge about dietary supplementation by the Chinese elderly. The aim of this cross-sectional study was to investigate the usage of dietary supplements by older adults in southern China.