Effect of genetic and environmental factors on protein biomarkers for common non-communicable disease and use of personally normalized plasma protein profiles (PNPPP)

Abstract

Objective: To study the impact of genetic and lifestyle factors on protein biomarkers and develop personally normalized plasma protein profiles (PNPPP) controlling for non-disease-related variance.

Materials and methods: Proximity extension assays were used to measure 145 proteins in 632 controls and 344 cases with non-communicable diseases.

Results: Genetic and lifestyle factors explained 20–88% of the variation in healthy controls. Adjusting for these factors reduced the number of candidate biomarkers by 63%.

Conclusion: PNPPP efficiently controls for non-disease-related variance, allowing both for efficient discovery of novel biomarkers and for covariate-independent linear cut-offs suitable for clinical use.

• Non-communicable diseases
• normalization
• plasma protein biomarkers
• proximity extension assay

Acknowledgements

We are grateful for the contribution of district nurse Svea Hennix for data collection and Inger Jonasson for logistics and coordination of the health survey. We would also like to thank all the participants from the community for their interest and willingness to contribute to this study. Illumina genotyping was performed by the SNP&SEQ Technology Platform in Uppsala, Sweden. Whole Exome Sequencing was performed by the Uppsala Genome Center Facility in Uppsala, Sweden. PEA measurements were carried out by the Clinical Biomarker facility in Uppsala, Sweden. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under projects b2011203 and p2013140.

Declaration of interest

Ulf Gyllensten and Stefan Enroth are authors on a patent application entitled “Determination and analysis of Biomarkers in clinical samples”; United Kingdom Patent Application No. 1414913.2 (2014, Pending). The remaining authors declare no competing financial interests. The Northern Swedish Population Health Study (NSPHS) was funded by the Swedish Medical Research Council (Project Number K2007-66X-20270-01-3, and 2011-2354), the Foundation for Strategic Research (SSF). NSPHS as part of EUROSPAN (European Special Populations Research Network) was also supported by European Commission FP6 STRP grant number 01947 (LSHG-CT-2006-01947). This work has also been supported by the Swedish Society for Medical Research (SSMF).

Supplementary material available online.