Mitochondrial and Nuclear Mitochondrial Variants in Allergic Diseases

Abstract

The mitochondrial genome encodes core catalytic peptides that affect major metabolic processes within a cell. Here, we investigated the association between mitochondrial DNA (mtDNA) variants and allergic diseases, including atopic dermatitis (AD) and asthma, alongside heteroplasmy within the mtDNA in subjects with allergic sensitization. We collected genotype data from 973 subjects with allergic sensitization, consisting of 632 children with AD, 498 children with asthma, and 481 healthy controls by extracting DNA from their blood samples. Fisher's exact test was used to investigate mtDNA and nuclear DNA variants related to mitochondrial function (MT-nDNA) to identify their association with allergic diseases. Among the 69 mtDNA variants, rs28357671 located on the MT-ND6 gene displayed statistically significant associations with allergic diseases (Bonferroni-corrected P < 7.25E-4), while 6, 4, and 2 genes were associated with allergic sensitization, AD, and asthma, respectively ( P < 0.0002), including NLRX1 , OCA2 , and CHCHD3 among the MT-nDNA genes. Heteroplasmy of mitochondrial DNA associated with allergic sensitization was evaluated in a separate cohort of patients consisting of 59 subjects with allergic sensitization and 52 controls. Heteroplasmy was verified when a patient carried both alleles of a mitochondrial single-nucleotide polymorphism (SNP) when clustered. One of the 134 mitochondrial SNPs showed heteroplasmy at a level of 0.4313 when clustering was applied. The probe sequence located at mitochondrial position 16217 and within the D-loop, which acts as a major control site for mtDNA expression. This is the first study to evaluate the association between mitochondrial DNA variants and allergic diseases. A harmonized effect of genes related to mitochondrial function may contribute to the risk of allergic diseases.

NLR in eXile: Emerging roles of NLRX1 in immunity and human disease

“…Further studies manipulating the in vitro expression of these are essential to understand the relative contribution of individual NLRs, including NLRX1, in a relevant disease setting. More recently, a study has uncovered a genetic association (rs4245191) between NLRX1 and both allergic sensitization and atopic dermatitis 94 . Intriguingly, when considering the interaction with mtDNAs such as mt‐ND6, the odds ratio associated with these NLRX1 variants increased, with the authors of this study suggesting a ROS‐based mechanism at play.…”

“…There has been a recent emergence of the role of NLRX1 in multiple autoimmune conditions. Aside from IBD as discussed above, NLRX1 has been implicated in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and, most recently, atopic dermatitis and allergic sensitization 9,93,94 . Given the innate immune function of NLRX1, this is hardly surprising, but the suggested mechanisms of NLRX1 in autoimmunity are intriguing.…”

Identification of OCA2 as a novel locus for the co‐morbidity of asthma‐plus‐eczema

“…38,39 Suggestive evidence of associations of OCA2 genetic variants with allergic sensitization, eczema and lung function phenotypes (FEV1/FVC ratio) have been also reported. 40,41 Moreover, a polymorphism, located within an intron of the HERC2 gene an adjacent neighbour of OCA2 which is involved in the regulation of OCA2 expression, was significantly associated with asthma response to diisiocyanate. 42 The OCA2 gene (Oculocutaneous Albinism II) codes for a melanosomal transmembrane protein which is involved in many biological processes as tyrosine transport.…”

“…25 Lastly, the SNP rs1402470 which showed suggestive evidence of association to asthma-plus-eczema, is an intronic variant located in the LRP1B gene (Low Density Lipoprotein Receptor-Related Protein 1B). Suggestive evidence of association was shown between LRP1B genetic variants and post-bronchodilator FEV1, 39 Diisocyanateinduced asthma 40 and childhood-onset asthma. 53 Besides that, a LRP1B mutation was shown to be a predictive marker for the presence of chronic obstruction pulmonary disease in patients with lung adenocarcinoma.…”

Impact of intracellular innate immune receptors on immunometabolism

“…NLRX1 has been linked to the regulation of the host innate immune response in the context of pathogen sensing, inflammation, ROS production, ER stress, and autophagy [ 121 , 124 – 134 ]. One consistency is that many studies have shown that NLRX1 attenuates diseases, including chronic obstructive pulmonary disease (COPD) [ 135 ], autoimmune diseases [ 136 – 139 ], and cancer [ 140 – 144 ]. In cancer, NLRX1 has been shown to downregulate key cytokines that are important in cancer progression, such as tumor necrosis factor (TNF) and interleukin (IL)-6.…”