HLA-DQA1 as a Target for Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD) is a life-threatening respiratory condition caused by airway obstruction. It ranks among the top global causes of death,¹ with over 200 million cases and 3 million deaths reported in 2019.²

Symptoms include breathing difficulties, persistent coughing, wheezing, and unexplained weight loss. COPD is influenced by genetic factors, external influences, with smoking as the leading risk factor. Individuals with pre-existing conditions, such as asthma and respiratory infections face an elevated risk.

Although treatments exist to manage symptoms and slow disease progression, there is no definitive cure for COPD. By gaining a deeper understanding of the biological targets implicated in COPD, researchers can develop therapies which target the underlying mechanisms of the disease. Target identification holds tremendous potential for advancing scientific knowledge and augmenting treatment options to help alleviate the economic and societal impact of COPD.

Over the years, numerous specific targets for COPD have been document in scientific literature. According to Causaly, almost 5000 targets for COPD have been reported, some of which are already being investigated in clinical trials for other respiratory diseases, including asthma.

One effective strategy to expand and prioritize potential targets is the identification of specific genes or genetic regions associated with the disease. Around 750 targets for COPD have been reported in the GWAS catalogue, according to Causaly. Notably, to date, the COPD target with the highest number of articles reported in the last 5 years was HLA-DQA1.

The HLA-DQA1 gene is a member of the Human Leukocyte Antigen (HLA) family, specifically encoding the α-subunit of the DQ heterodimer of MHC class II protein family.³ The protein product of HLA-DQA1 combines with the protein product of HLA-DQAB to form a heterodimeric complex. This complex plays a crucial role in antigen presentation to the immune system which initiates an immune response, signaling to T cells that a foreign substance is present.

While much remains to be discovered in COPD pathogenesis, the involvement of immune cells such as CD4+ and CD8+ T lymphocytes, in the pathogenesis of COPD is widely reported.⁴ In the context, HLA-DQA1, a key player in immune response, may be of interest. A study involving HLA-genotyping in patients with chronic obstructive lung disease reported a negative association between a specific HLA-DQA1 allele and COPD.⁵ This finding suggests the presence of this allele could be linked to a reduced risk of developing COPD, underscoring the intricate interplay between our genetic makeup and immune response in complex diseases like COPD.

Targeting the HLA-DQA1 gene holds potential for modulating immune responses, reducing inflammation, promoting tissue repair, and mitigating COPD progression. Its association with both asthma and COPD, along with shared genetic factors and immunological pathways, makes HLA-DQA1 an appealing target for multiple respiratory disorders. However, further research is needed to fully understand its therapeutic potential in the context of COPD. This highlights the importance of rapid target identification and comprehensive knowledge of the disease for effective drug discovery.

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