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.

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.

Genetic susceptibility to multicase hypersensitivity pneumonitis is associated with the TNF-238 GG genotype of the promoter region and HLA-DRB1*04 bearing HLA haplotypes.

Hypersensitivity Pneumonitis (HP) is a lung inflammatory disorder caused by inhalation of organic particles by a susceptible host. Since only a small proportion of individuals exposed to HP-related antigens develop the disease, a genetic predisposition is largely suspected. However, studies regarding genetic susceptibility in this disease are scanty. We have previously found evidence supporting increased risk associated to the major histocompatibility complex (MHC) in sporadic HP. In the present study, we conducted a family-based research that includes nine multicase families with at least two related HP patients (RHP). We evaluated 19 RHP individuals, 25 additional healthy first-degree relatives (REA) and 246 healthy unrelated individuals (HUI). HLA class II typing (DRB1/3/4/5, DQA1, DQB1, DPA1, DPB1, DMA and DMB), and -863, -308 and -238 polymorphisms in the promoter region of TNF-α were performed by PCR based methods. We identified an increased frequency of HLA-DRB1*04:07, DRB1*04:05, DRB1*11:01 and DRB1*13:01 alleles in RHP individuals compared to healthy controls (p < 0.05). A significant higher frequency of DRB1*04:07-DQB1*03:02, DRB1*04:05-DQB1*03:02, and DRB1*04:03-DQB1*03:02 haplotypes was also detected in the group of patients. Likewise, TNF-238 GG genotype was more frequent in the RHP group as compared to REA (p = 0.01, OR = 7.2). Finally, the combination of HLA-DRB1*04 alleles and TNF-238 GG was significantly increased in the RHP group (p = 0.01, OR = 6.93). These findings indicate that genes located within the MHC region confer susceptibility to familial HP in Mexicans.

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.