Predictors of Chronic Obstructive Pulmonary Disease Exacerbations

Takeo Ishii; Kozui Kida

Disclosures

Curr Opin Pulm Med. 2014;20(2):138-145. 

In This Article

New Viewpoints From a SIGLEC-14 Study: Copy Number Variants, Evolution, and Ethnic Differences

A null variant of SIGLEC14 could be considered as a CNV (Fig. 2b). Compared to single nucleotide polymorphisms, CNVs can powerfully influence a person's susceptibility to disease,[46] including COPD exacerbations. For example, a CNV of β-defensin, an antibacterial peptide, was associated with COPD, which led to the hypothesis that β-defensin was involved in the pathogenesis of COPD through modification of exacerbation susceptibility.[47]

The expression of sialic acids by NTHi likely represents an evolutionary process that has the advantage of mimicking sialic acid-based 'self-associated molecular patterns', which are normally recognized by inhibitory Siglecs such as Siglec-5. The cross-recognition by Siglec-14 (activating counterpart) probably represents a host evolutionary response to this bacterial evolutionary development. However, such a host response may also generate unwanted inflammation, which is detrimental to a host with a chronic disease such as COPD (Fig. 2a),[29] as human life expectancy at birth has doubled to tripled during the last 200 years because of industrialization.[48]

East/southeast Asia is considered to be the epicenter of cross-species transmission of influenza viruses from migratory birds (natural host) to humans. An influenza infection frequently leads to a secondary NTHi infection that often results in more fulminant symptoms and increased mortality, likely because of 'cytokine storm'. A lack of Siglec-14 might mitigate the cytokine storm that is triggered by a secondary NTHi infection. This may explain why the null allele frequency of SIGLEC14 is high in Asia, despite the potential risk of attenuated immune control from other bacterial pathogens that display sialic acids (T Angata 2013, personal communication). In industrialized countries, the frequency of exacerbations is higher in whites[49,50] as compared to that of Japanese populations.[20,51] This difference regarding exacerbation frequency between societies could be partially explained by ethnic differences in the null allele frequency of SIGLEC14.[30] As differences in allele frequency of various genetic variances that are related to a frequent-exacerbation phenotype could induce differences in exacerbation frequency among social groups, ethnic differences are a new and critical viewpoint for determining the genetic factors related to a frequent-exacerbation phenotype.

Macroscopic evolutionary changes are also important. Descent of the larynx from chimpanzees to humans has caused the emergence of sleep apnea and gastroesophageal reflux,[52,53] and these two diseases are related to exacerbation risk.[7,54] Thus, further study is necessary regarding the genetic factors related to anatomical issues.

Although humans acquired the SIGLEC14 gene during evolution, mice do not have this gene.[55] Studies using gene-knockout mice have had much impact on COPD research. However, we must be careful as human have genes that mice do not, such as Siglec-14, which could be a cause of COPD as well as its exacerbations from an evolutionary point of view.

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