Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction

Tobacco consumption has become a major public health issue, which has motivated studies to identify and understand the biological processes involved in the smoking behavior for prevention and smoking cessation treatments. CYP2A6 has been identified as the main gene that codifies the enzyme that metabolizes nicotine. Many alleles have been identified after the discovery of CYP2A6, suggesting a wide interethnic variability and a diverse smoking behavior of the allele carrying individuals. The main purpose of this review is to update and highlight the effects of the CYP2A6 gene variability related to tobacco consumption reported from diverse human populations. The review further aims to consider CYP2A6 in future studies as a possible genetic marker for the prevention and treatment of nicotine addiction. Therefore, we analyzed several population studies and their importance at addressing and characterizing a population using specific parameters. Our efforts may contribute to a personalized system for detecting, preventing and treating populations at a higher risk of smoking to avoid diseases related to tobacco consumption

The IL1B-511 Polymorphism (rs16944 AA Genotype) Is Increased in Aspirin-Exacerbated Respiratory Disease in Mexican Population

Aspirin exacerbated respiratory disease (AERD) is characterized by chronic hyperplastic rhinosinusitis, nasal polyposis, asthma, and aspirin sensitivity. The mechanisms which produce these manifestations of intolerance are not fully defined, current research focuses on cyclooxygenase 1 (COX-1) inhibition, metabolism of arachidonic acid, and the COX pathway to the lipoxygenase (LO) route, inducing increased synthesis of leukotrienes (LT). The biological plausibility of this model has led to the search for polymorphisms in genes responsible for proinflammatory cytokines synthesis, such as IL1B and IL8. We performed a genetic association study between IL8-251 (rs4073) and IL1B-511 (rs16944) polymorphisms in AERD, aspirin-tolerant asthma (ATA), and healthy control subjects. Using allelic discrimination by real-time PCR, we found statistically nonsignificant associations between AERD, ATA, and healthy control subjects for the GG and GA genotypes of IL1B (rs16944). Interestingly, the AA genotype showed an increased frequency in the AERD patients versus the ATA group (GF = 0.19 versus 0.07, p = 0.018, OR 2.98, and 95% CI 1.17–7.82). This is the first observation that IL1B polymorphisms are involved in AERD. Thus, future studies must investigate whether interleukin-1β is released in the airways of AERD patients and whether it relates to genetic polymorphisms in the IL1B gene

MS4A2-rs573790 Is Associated With Aspirin-Exacerbated Respiratory Disease: Replicative Study Using a Candidate Gene Strategy

Aspirin exacerbated respiratory disease (AERD) is a set of diseases of the unified airway, and its physiopathology is related to disruption of the metabolism of arachidonic acid (AA). Genetic association studies in AERD had explored single nucleotide polymorphism (SNPs) in several genes related to many mechanisms (AA metabolism, inflammation, drug metabolism, etc.) but most lack validation stages in second populations. Our aim is to evaluated whether contribution to susceptibility of SNPs reported in other populations are associated with AERD in Mexican Mestizo patients. We developed a replicative study in two stages. In the first, 381 SNPs selected by fine mapping of associated genes, (previously reported in the literature), were integrated into a microarray and tested in three groups (AERD, asthma and healthy controls -HC-) using the GoldenGate array. Results associated to risk based on genetic models [comparing: AERD vs. HC (comparison 1, C1), AERD vs. asthma (C2), and asthma vs. HC (C3)] were validated in the second stage in other population groups using qPCR. In the first stage, we identified 11 SNPs associated with risk in C1.The top SNPs were ACE-rs4309C (p = 0.0001) and MS4A2-rs573790C (p = 0.0002). In C2, we detected 14 SNPs, including ACE-rs4309C (p = 0.0001). In C3, we found MS4A2-rs573790C (p = 0.001). Using genetic models, C1 MS4A2-rs57370 CC (p = 0.001), and ACE-rs4309 CC (p = 0.002) had associations. In C2 ACE-rs4309 CC (p = 0.0001) and C3 MS4A2-rs573790 CC (p = 0.001) were also associate with risk. In the second stage, only MS4A2-rs573790 CC had significance in C1 and C3 (p = 0.008 and p = 0.03). We concluded that rs573790 in the MS4A2 gene is the only SNP that supports an association with AERD in Mexican Mestizo patients in both stages of the study

IFNAR2 relevance in the clinical outcome of individuals with severe COVID-19

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19

Mediators of inflammatory response in asthma and its association with obesity

There is an increase in the prevalence of asthma and obesity, constituting a public health problem at national and global levels. The association between the two pathologies has not been clearly determined; however, a certain synergy has been proposed, which leads to more severe bronchospasms, longer recovery time, and more prolonged use of medications in obese asthmatic patients. The discovery of leptin, an adipokine that is directly related to the amount of total body fat and the production of proinflammatory cytokines, has generated greater interest in white adipose tissue. Our objective was to describe the possible mechanisms involved and the association between obesity and asthma. A bibliographic search was conducted in the scientific literature using the National Biotechnology Information Center (NCBI) database of the USA as a search tool; keywords used were: asthma, leptin, obesity and inflammation. There are numerous clinical and experimental studies that explore the role of obesity as an inflammatory entity in asthma, some of which have evaluated the role of “shared” genetic polymorphisms in both pathologies. Apparently, the interaction between asthma and obesity is complex, there are mechanisms that link both pathologies, these can influence the improvement or exacerbation of symptoms

HLA Class II Alleles in the Otomi Population of the Mezquital Valley: A Genetic Approach to the History of Interethnic Migrations in the Mexican Central Plateau

From a historical and genetic point of view, the Otomi of the Mezquital Valley are a frontier people that have played an important role in the population dynamics of the Mexican Central Plateau. Due to the antiquity of their presence in the area, the Otomi may be bearers of ancient genetic variability, shared mainly today with other groups belonging to the Otomanguean linguistic family and with the Nahua. In this study we analyzed the HLA class II allele frequencies reported in Mexican indigenous populations, in order to provide an intraregional-level historical perspective of the genetic relationships between the Otomi of the Mezquital Valley and indigenous populations from other regions of Mexico. We examined genetic variation in HLA-DRB1 and -DQB1 loci in 66 nonrelated individuals belonging to seven indigenous communities from the Ixmiquilpan municipality in the Mezquital Valley, in the State of Hidalgo, Mexico. The variability of the HLA-DRB1 gene among the Otomi of the Mezquital Valley was mainly concentrated in five alleles: -DRB1*08:02 (31.06%), -DRB1*04:07 (25.77%), -DRB1*14:06 (7.55%), -DRB1*14:02 (6.06%), and -DRB1*16:02 (4.55%); these alleles have been previously described in other indigenous populations. The most frequent alleles at the HLA-DQB1 locus were -DQB1*03:02 (34.09%), -DQB1*04:02 (31.03%), and -DQB1*03:01 (19.7%). Furthermore, the HLA-DQB1*02:02 allele was found in the Otomi group with a frequency of 2.27%; this allele has not been reported in Mexican indigenous populations. In conclusion, the genetic constitution of the Otomi population is intermediate to the northern groups and the genetic variability shared by the peoples of the central regions of Mexico. Furthermore, HLA-DRB1 and -DQB1 allelic variability among the Otomi provides insight into the historical processes implied in the biological admixture with European, Asian, and African populations as well as in the admixture with the population of Mexico City associated with long-standing migratory processes

La variabilidad genética en las poblaciones indígenas mexicanas a partir del Complejo Principal de Histocompatibilidad (MHC)

Resumen. El presente artículo revisa la distribución alélica de los genes HLA-A, -B, -DRB1 y -DQB1, previamente reportados en diez poblaciones indígenas mexicanas, con elpropósito de analizar la variabilidad genética a nivel regional y compararla con losresultados obtenidos en otras poblaciones del continente americano. Tomando en cuenta losalelos de clase I y clase II, se apunta que la variabilidad genética de las poblacionesindígenas americanas es reducida y ésta se concentra en unos cuantos alelos -exceptuando las poblaciones que presentan un elevado aporte de genes no amerindios en suacervo genético-. Las diferencias detectadas a nivel intra-continental se pueden explicar porla acción del flujo y la deriva genética. Respecto al locus HLA-A, la variación se agrupafundamentalmente en cinco alelos: HLA-A*02:02; HLA-A*02:06; HLA-A*24:02; HLA-A*31:01y HLA-A*68:01. La diversidad del HLA-B se concentra en sólo siete alelos: HLA-B*15:01;HLA-B*35:01; HLA-B*35:12; HLA-B*39; HLA-B*40:02; HLA-B*51 y HLA-B*61. Por otraparte, las frecuencias más altas del locus HLA-DRB1 se presentan entre los subtipos HLADRB1*04:03/*04:04/*04:07/*04:10, HLA-DRB1*08:02 y HLA-DRB1*14:02/*14:06. Encuanto al locus HLA-DQB1, los alelos más frecuentes entre los grupos estudiados son elHLA-DQB1*03:01/*03:02 y el HLA-DQB1*04:02. De los 30 haplotipos comunesmundialmente, trece son compartidos por las poblaciones indígenas americanas; mientrasque se reportan 27 haplotipos exclusivos de las poblaciones indígenas mexicanas.Genetic Variation of the Major Histocompatibility Complex (MHC) inMexican Indigenous PopulationsAbstract. The following article analyzes the allelic distribution of HLA-A, -B, -DRB1 and-DQB1 genes reported in ten Mexican indigenous populations in order to compare it withdata from other populations of the American continent. By considering the variability ofClass I and Class II genes it can be noted that the distribution of genetic variability ofindigenous peoples of the Americas is reduced, since it is concentrated in a few alleles,except in those populations with high frequency of non-Amerindian genes. Differencesobserved at intra-continental level can be explained as result of the isolated and combinedaction between genetic flow and genetic drift. Locus HLA-A variations are distributed in fivealleles: HLA-A*02:02; HLA-A*02:06; HLA-A*24:02; HLA-A*31:01 y HLA-A*68:01; the diversityof HLA-B is concentrated in only seven alleles: HLA-B*15:01; HLA-B*35:01; HLA-B*35:12;HLA-B*39; HLA-B*40:02; HLA-B*51 y HLA-B*61 while the highest frequencies of HLA-DRB1alleles are subtypes HLA–DRB1 *04:03/ *04:04/*04:07/ *04:10, HLA-DRB1*0:802 and HLADRB1*14:02/*14:06. In relation to locus HLA-DQB1, the most frequent alleles reported areHLA-DQB1*03:0