Study Reveals Causal Link Between Apolipoprotein A-I, COPD

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A new study supports a causal link between apolipoprotein A-I (apoA-I) and chronic obstructive pulmonary disease (COPD).¹

Preliminary research has identified a potential link between COPD and lipid metabolism. Cigarette smoke extract disrupts lipid metabolism in human bronchial epithelial cells, promoting lipid accumulation via the sphingolipid pathway. From there, phospholipid peroxide buildup in lung epithelial cells triggers ferroptosis, and the disrupted iron homeostasis elevates oxidative stress in COPD, worsening lung tissue damage.²

The involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis suggests the link between COPD and lipid metabolism. It also suggests that abnormal blood lipid levels are related to inflammation, oxidative stress, and lung function.

Investigators, led by Ping Huang, from the department of rehabilitation medicine at the General Hospital of Central Theater Command in the People’s Republic of China, sought to examine the potential causal connection between blood lipids and COPD.¹ The team conducted a genome-wide association study with 112,582 European participants from the MRC-IEU and collected data on blood lipid profiles from the UK Biobank among European participants with low-density lipoprotein cholesterol (LDL-C) (n = 440,545), high-density lipoprotein cholesterol (HDL-C) (n = 403,943), triglycerides (n = 441,016), total cholesterol (n = 187,365), apoA-I (n = 393,193), and apolipoprotein B (apoB) (n = 439,214).

“Identifying disease-related exposure factors is crucial in the prevention and treatment of diseases, as it can reduce the incidence rate, delay the onset, alleviate patient suffering, and minimize economic burdens,” investigators wrote.

Investigators performed MR analyses for both lipids and COPD., including the following number of single nucleotide polymorphisms: 22 for total cholesterol, 372 for triglycerides, 80 for LDL-C, 80 for HDL-C, 160 for apoA-I, and 91 for apoB.

MR analyses indicated a causal link between COPD and LDL-C (odds ratio [OR], 0.994; 95% confidence interval [CI], 0.989 – 0.999; P = .019), triglycerides (OR, 1.005; 95% CI, 1.002 – 1.009; P = .006), and apoA-I (OR, 0.995; 95% CI, 0.992 – 0.999; P = .008). Particularly, COPD appeared to have an inverse relationship with LDL-C, a negative correlation with ApoA-I, and a positive correlation with triglycerides. The analysis showed no causal link between COPD, HDL-C, total cholesterol, and apoB (P > .05).

After conducting a multivariate MR and multiple testing correction, LDL-C (OR, 0.997; 95% CI, 0.992 – 1.003; P = .357) and triglycerides (OR, 0.997; 95% CI, 0.992 – 1.002; P = .233) no longer had a causal effect on COPD. Only apoA-I stayed a protective factor for the risk of COPD (OR, 0.994; 95% CI, 0.990 – 0.999; P = .008).

Sensitivity analyses, such as the MR-Egger regression analysis for apoA-I (P = .470), triglycerides (P = .4808), and LDL-C (P = .361), showed a lack of pleiotropy between single nucleotide polymorphisms and outcomes, showing the robustness of the MR analysis.

Investigators highlighted several limitations, including the focus on Europeans which overlooks dietary and regional variations, and the MR analysis assumes a linear relationship, potentially missing non-linear effects. Additionally, different stages of outcomes complicate establishing a clear causal link between blood lipid levels and COPD progression.

“In the treatment of COPD, besides focusing on issues such as pulmonary inflammation and airway obstruction, attention should also be paid to correcting lipid metabolism disorder to reduce its impact on COPD,” investigators concluded. “Additionally, for individuals with lipid metabolism disorder and high risk of COPD, early intervention and prevention measures should be taken to lower the incidence and severity of COPD.”

References

1. ^{Huang P, Zhao Y, Wei H, Wu W, Guo Z, Ma S, Xu M, Wang Q, Jia C, Xiang T, Li H. Causal Relationships Between Blood Lipid Levels and Chronic Obstructive Pulmonary Disease: A Mendelian Randomization Analysis. Int J Chron Obstruct Pulmon Dis. 2025 Jan 8;20:83-93. doi: 10.2147/COPD.S476833. PMID: 39802042; PMCID: PMC11725246.}
2. ^{Yoshida M, Minagawa S, Araya J, Sakamoto T, Hara H, Tsubouchi K, Hosaka Y, Ichikawa A, Saito N, Kadota T, Sato N, Kurita Y, Kobayashi K, Ito S, Utsumi H, Wakui H, Numata T, Kaneko Y, Mori S, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Iwamoto T, Imai H, Kuwano K. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nat Commun. 2019 Jul 17;10(1):3145. doi: 10.1038/s41467-019-10991-7. PMID: 31316058; PMCID: PMC6637122.}