Multi-Lipid Profiling and COPD

To learn more about the study and its wider implications, we spoke to Björn Titz, Computational Biologist at Philip Morris International.

AM: Can you tell us about the aims of your study?

BT: The study was designed to identify a lipidomic biomarker, or panel of biomarkers, suitable for the clinical classification of four groups:¹

• Cigarette smokers with mild to moderate COPD.
• Cigarette smokers who are asymptomatic of COPD.
• Individuals who have never smoked (who we call ‘never smokers’).
• Individuals who previously smoked, but who have quit for a year or more (‘former smokers’).

While it is known that smoke exposure and COPD are associated with changes in the lipidome, compared with the effects on other molecular endpoints, such as the transcriptome, the information on lipid alterations has previously been relatively sparse. To address this gap, we used a combination of four mass spectrometry based platforms, in combination with computational network biology, to analyse a total of 26 different lipid classes in a group of men and women aged between 41 and 70 years.

BT: Multi-lipid profiling effectively complements the other available biomarker identification methods, especially those targeting different molecule classes such as proteins, mRNAs, and microRNAs. All diseases affect the biology on many different levels simultaneously. It is therefore crucial to cover the affected biology as comprehensively as possible when we set out to identify the most robust biomarker set for a disease. However, it is only recently that mass-spectrometry based profiling methods have become available that allow for the precise analysis of large numbers of different lipids. Considering these recent technological developments and the known, but sparse, association of COPD with lipid changes, multi-lipid profiling is an especially well-suited complementary method to identify biological effects of smoking and COPD in blood samples. I envision that, in the future, multi-lipid profiling will become a common component of biomarker identification studies, with the huge potential to identify the intricate lipid footprints of diseases. However, what we will probably need, in the end, are multi-class biomarker panels that, for example, integrate lipid, protein, and microRNA profiling to robustly and specifically identify disease states.

AM: What lipidomic differences were noted between smokers and non-smokers?

BT: We identified three main lipidomic trends between smokers and non-smokers:

• A general increase in glycerophospholipids. These are the main component of all biological membranes, including cell membranes.
• Changes in fatty acid desaturation, involving a decrease in poly-unsaturated fatty acids and an increase in mono-unsaturated fatty acids.
• An imbalance in eicosanoids. These are signaling molecules that exert complex control over many bodily systems.

These effects often appeared amplified and more significant in the group of smokers with COPD, as compared to smokers asymptomatic of COPD.

Having established these differences, we also looked at the extent to which these trends could be used to identify which of the four study groups individuals belonged to (ie, the extent to which they constitute biomarkers for clinical classification). The lipidomic profiles clearly supported separation of the two smoking groups from the two non-smoking groups, with improved separation of smokers with COPD from non-smokers. Separation of smokers with COPD from asymptomatic smokers was not achieved, nor was separation of never smokers from former smokers.

AM: Can you tell us about the implications of these results, and potential avenues for future research?

BT: The study has yielded new insights into the complex interplay between cigarette smoke exposure, alterations in lipid profiles and COPD. It therefore provides relevant information for scientists working in COPD from the point of view of diagnostics, drug discovery, and, possibly, personalized medicine. For Philip Morris International (PMI), it also supports the development and assessment of Reduced-Risk Products (RRPs), products with the potential to reduce individual risk and population harm in comparison to cigarettes. Through technological innovation and rigorous scientific assessment, PMI is developing a range of RRPs, and is leading a full-scale effort to ensure that they ultimately replace cigarettes.²

It’s important to note that while the lipidomic characteristics we identified in smokers were most pronounced in smokers with COPD (as compared to asymptomatic smokers), the COPD group was also associated with higher cumulative cigarette smoke exposure than the asymptomatic smoking group. This means that we cannot necessarily be sure which of these lipidomic characteristics are more closely linked to COPD itself, rather than just being the result of more extensive smoking. In terms of future research therefore, and the ultimate goal of one day identifying a robust biomarker for COPD, it may be useful to look at former smokers who have COPD, to help identify effects that are specifically related to COPD rather than cigarette smoking.