Juan M. Reséndiz-Hernández

Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD)

Aspirin exacerbated respiratory disease (AERD) is a distinct clinical entity characterized by eosinophilic rhinosinusitis, asthma and often nasal polyposis. Exposure to aspirin or other nonsteroid anti-inflammatory drugs (NSAIDs) exacerbates bronchospasms with asthma and rhinitis. Disease progression suggests a skewing towards TH2 type cellular response along with moderate to severe eosinophil and mast cell infiltration. Alterations in upper and lower airway cellular milieu with abnormalities in eicosanoid metabolism and altered eicosanoid receptor expression are the key features underlying AERD pathogenesis. Dysregulation of arachidonic acid (AA) metabolism, notably reduced prostaglandin E2 (PGE2) synthesis compared to their aspirin tolerant counterpart and relatively increased PGD2 production, a TH2/eosinophil chemoattractant are reported in AERD. Underproduced PGE2 is metabolized by overexpression of 15 prostaglandin dehydrogenase (15-PGDH) to inactive products further reducing PGE2 at real time. This relives the inhibitory effect of PGE2 on 5-lipoxygenase (5-LOX) resulting in overproduction of cysteinyl leukotrienes (CysLTs). Diminished formation of CysLT antagonists called lipoxins (LXs) also augments CysLTs responsiveness. Occasional intake of NSAIDs favors even more 5-LOX product formation, further narrowing the bronchoconstrictive bottle neck, resulting in acute asthmatic exacerbations along with increased mucus production. This review focuses on abnormalities in biochemical and molecular mechanisms in eicosanoid biosynthesis, eicosanoid receptor dysregulation and associated polymorphisms with special reference to arachidonic acid metabolism in AERD.

Prevalencia de variantes de alto riesgo de alfa-1 antitripsina en población mestiza mexicana y su relación con los valores de la función pulmonar

INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by restricted airflow. The best-documented genetic factor is alpha-1 antitrypsin (AAT). AAT is encoded by the SERPINA1 gene. The PiZ (rs28929474) and PiS (rs17580) variants are believed to cause severe AAT deficiency and are linked to a high risk of developing COPD. This study sought to identify whether genetic polymorphisms rs28929474 and rs17580 are associated with COPD susceptibility and lung function values in a Mexican mestizo population. METHODS In this study, 558 smokers were included, of whom 279 had COPD and 279 did not (smokers without COPD - SWC). The PiS and PiZ variants were genotyped by allelic discrimination. Independent populations and lung function values were compared using the Kruskal-Wallis test. A bivariate logistic regression analysis was also conducted. RESULTS Stage I and iv COPD patients showed significant differences in the frequencies of both heterozygous genotypes compared to SWC. For PiS, individuals with the heterozygous genotype AT demonstrated a decreased FEV1/FVC ratio compared to subjects with the homozygous genotype AA (P=0.037). A significant association was found between the FEV1/FVC ratio and genotype AA for PiS (OR=0.982, β coefficient=-0.019, 95% CI=0.966-0.997). CONCLUSIONS COPD-causing AAT deficiency risk alleles exist at a very low frequency among Mexican mestizo population. Although they are not directly linked in our study population with disease susceptibility, these risk alleles are associated with poorer lung function measurements. It is important to characterize how often these genetic risk variants occur in other Latin American populations.

Identification of genetic variants in the TNF promoter associated with COPD secondary to tobacco smoking and its severity.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of “contig” alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.

TNF promoter polymorphisms are associated with genetic susceptibility in COPD secondary to tobacco smoking and biomass burning

Background Smoking and smoke from biomass burning (BB) are the main environmental risk factors for COPD. Clinical differences have been described between COPD related to smoking and related to wood smoke, but no studies have shown genetic differences between patients exposed to these two risk factors. Methods To investigate a possible association of tumor necrosis factor (TNF) promoter polymorphisms, we conducted a case–control study. A total of 1,322 subjects were included in four groups: patients with a diagnosis of COPD secondary to smoking (COPD-S, n=384), patients with COPD secondary to biomass burning (COPD-BB, n=168), smokers without COPD (SWOC, n=674), and biomass burning-exposed subjects (BBES n=96). Additionally, a group of 950 Mexican mestizos (MMs) was included as a population control. Three single nucleotide polymorphisms (SNPs) were selected in the TNF gene (rs1800629, rs361525, and rs1800750) and one SNP in the lymphotoxin alpha gene (rs909253). Results Statistically significant differences were found with genotype GA of the rs1800629: COPD-S vs SWOC, (p<0.001, odds ratio [OR] =2.55, 95% CI=1.53–4.27); COPD-S vs COPD-BB (p,0.01). When performing the comparison of the less severe (G1: I + II) and the more severe (G2: III + IV) levels, differences were identified in G1 (p<0.05, OR=1.94, 95% CI=1.04–3.63) and G2 (p<0.001, OR=3.68, 95% CI=1.94–3.07) compared with SWOC. Regarding genotype GA of rs361525, it has been associated when comparing COPD-BB vs BBES (p=0.0079, OR=5.99, 95% CI=1.38–53.98). Conclusion The heterozygous genotype GA of polymorphisms rs1800629 and rs361525 in the TNF promoter are associated with the risk of COPD.

Influence of proinflammatory cytokine gene polymorphisms on the risk of COPD and the levels of plasma protein

Introduction Chronic obstructive pulmonary disease (COPD) is a complex and multifactorial disease involving systemic inflammation. Although certain genetic components have been implicated in the development and progression of this disease, few studies have examined the participation of polymorphisms in proinflammatory genes and the extent to which polymorphisms are related to plasma levels of cytokines involved in the inflammatory process. Methods Of the 1125 smokers participating in the study, 438 had COPD, and 687 did not. We determined the genotype of 5 SNPs distributed in the genes: IL6, CXL8, CSF2, CCL1 and IL1B. The plasma protein expression of these genes was also evaluated and categorized according to genotype and the severity of COPD (GOLD grade). Results An analysis using the codominant model showed an association between rs1818879 in IL6 and susceptibility to COPD (GA OR = 1.1, AA OR = 1.77; p < 0.01), as well as an association between rs25882 in CSF2 and a greater severity of the disease (TC OR = 1.84, CC OR = 3.62; p < 0.01). No association was found between the presence of certain alleles in the SNPs and the plasma levels of the corresponding proteins. Conclusions There are genetic polymorphisms related to susceptibility to COPD (rs1818879/A in IL6), as well as to the risk of greater severity of the disease (rs25882/T in CSF2). The presence of the alleles of interest did not significantly affect plasma levels of the codified proteins. Highlightsrs1818879/AA in IL6 is associated to an increased risk of COPD.rs25882/T in CSF2 is associated to severe forms of the disease.No difference between the genotypes and the plasma levels.There were difference between G1 vs. G2 INF‐&ggr;, IL‐10 and IL‐6 plasma levels.

An Increased Frequency in HLA Class I Alleles and Haplotypes Suggests Genetic Susceptibility to Influenza A (H1N1) 2009 Pandemic: A Case-Control Study

Background The influenza A H1N1/09 pandemic infected a small number of exposed individuals, which suggests the involvement of genetic factors. There are scarce data available on classical HLA class I association with the influenza A H1N1/09 pandemic. Methods We analyzed the frequency of classical HLA class I alleles and haplotypes in A H1N1/09 influenza in a case-control study including 138 influenza patients (INF-P) and 225 asymptomatic healthy contacts (INF-C) simultaneously recruited. HLA class I typing was performed by high-resolution sequence-based typing method. Results Our analysis revealed higher frequency of C∗07:02:01, B∗39:06:02, C∗03:02:01, B∗44:03:01, B∗51:01:05, and B∗73:01 (p < 0.05; OR = 1.84–9.98) and of two haplotypes—A∗68:01:02-C∗07:02:01 (p = 1.05E − 05; OR = 23.99) and B∗35:01:01-C∗07:02.01 (p = 4.15E − 04, OR = 2.15)—in A H1N1/09 influenza subjects. A∗68:01:01 was exclusively present only in the INF-P group (5/138). A decrease in the frequency of C∗03:03:01, A∗11:01:01, B∗39:01:01, A∗24:02:01, C∗03:04:01, B∗51:01:01, and C∗07:01:01 (p < 0.05; OR = 0.12–0.52) and of haplotypes A∗02:01:01-B∗35:01:01-C∗04:01:01, A∗24:02:01-B∗35:01:01, B∗39:01:01-C∗07:02:01, and B∗40:02:01-C∗03:04:01 (p < 0.05; OR = 0.08–0.22) were observed in INF-P group. Conclusion Selective classical HLA class I allele and haplotype combinations predispose individuals towards susceptibility or protection against the influenza A H1N1/09 pandemic. This work has significant implications for accessing population transmission risk for A H1N1/09 or a similar strain breakout in the future.

Genetic polymorphisms and their involvement in the regulation of the inflammatory response in asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are widely documented diseases with an inflammatory component. Asthma is a heterogeneous disorder of the airways that involves chronic inflammation, decline of the airway function and tissue remodeling. Chronic obstructive pulmonary disease is a preventable and treatable disease, which is characterized by persistent limited airflow, and is usually progressive with an increased inflammatory response in the airways. The inflammatory response is evoked by the stimulus of noxious particles and gases. Inflammation is a natural process in response to injury, but in asthma and COPD patients it occurs as an abnormal immune response to pathogenic stimuli which induce chronic inflammation, a key process in the pathogenesis of both diseases. However, the inflammatory process is different in both diseases, and is involved in several release patterns of inflammation mediators. It is not entirely clear whether these proteins are simply markers of the inflammatory process that accompanies a chronic disease or if they play a major role in the pathogenesis of the disease. The main proteins which have been described in these illnesses are: IL-4, IL-6, IL-8, and TNF-α. In addition, polymorphisms have been described in genes encoding these proteins that alter the transcription and susceptibility associated with these diseases. In this review, we will focus on asthma and COPD, and the involvement of these proteins and their genetic polymorphisms.