Whole blood gene expression and interleukin-6 levels

doi:10.1016/j.ygeno.2014.10.003

. 2014 Dec;104(6 Pt B):490-5.

doi: 10.1016/j.ygeno.2014.10.003. Epub 2014 Oct 13.

Whole blood gene expression and interleukin-6 levels

Affiliations

¹ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA. Electronic address: hhlin@bu.edu.
² National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
³ Epidemiology and Public Health, Medical School, University of Exeter, Exeter EX1 2 LU, UK.
⁴ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵ Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA.
⁶ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁷ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁸ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
⁹ Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA.
¹⁰ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: murabito@bu.edu.

PMID: 25311648
PMCID: PMC4262595
DOI: 10.1016/j.ygeno.2014.10.003

Whole blood gene expression and interleukin-6 levels

Honghuang Lin et al. Genomics. 2014 Dec.

. 2014 Dec;104(6 Pt B):490-5.

doi: 10.1016/j.ygeno.2014.10.003. Epub 2014 Oct 13.

Authors

Affiliations

¹ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA. Electronic address: hhlin@bu.edu.
² National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
³ Epidemiology and Public Health, Medical School, University of Exeter, Exeter EX1 2 LU, UK.
⁴ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵ Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA.
⁶ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁷ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁸ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
⁹ Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA.
¹⁰ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: murabito@bu.edu.

PMID: 25311648
PMCID: PMC4262595
DOI: 10.1016/j.ygeno.2014.10.003

Abstract

Background: Circulating interleukin-6 levels increase with advancing age and are a risk factor for various diseases and mortality. The characterization of gene expression profiles associated with interleukin-6 levels might suggest important molecular events underlying its regulation.

Methods and results: We studied the association of transcriptional profiles with interleukin-6 levels in 2422 participants from the Framingham Heart Study Offspring Cohort using Affymetrix Human Exon 1.0 ST Array. We identified 4139 genes that were significantly associated with interleukin-6 levels (FDR<0.05) after adjusting for age, sex and blood cell components. We then replicated 807 genes in the InCHIANTI study with 694 participants. Many of the top genes are involved in inflammation-related pathways or erythrocyte function, including JAK/Stat signaling pathway and interleukin-10 signaling pathway.

Conclusion: We identified and replicated 807 genes that were associated with circulating interleukin-6 levels. Future characterization of interleukin-6 regulation networks may facilitate the identification of additional potential targets for treating inflammation-related diseases.

Keywords: Epidemiology; Gene expression; Inflammation; Interleukin-6.

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Conflict of interest statement

Disclosures

The authors declare no commercial conflicts of interest.

Figures

**Figure 1. Study design**
Primary analyses were adjusted for age and sex. Secondary analyses were adjusted for age, sex, and additional clinical covariates. A total of 4139 genes were found significantly associated with interleukin-6 levels (FDR<0.05), which were then tested in the replication cohort. Eight hundred and ninety-seven of them were replicated (P<0.05).

**Figure 2. Volcano plot of association results from primary analyses**
Each dot represents one gene. The x-axis represents the beta estimation (β) of each gene, whereas the y-axis represents the log₁₀(P). Positive effects represent that the gene were positively associated with interleukin-6 levels, whereas negative effects represent that the genes were negatively associated with interleukin-6 levels. The red dash line indicates FDR<0.05.

**Figure 3. Comparison of T-statistics between primary analyses and secondary analyses**
The x-axis represents the T-statistics of log_e(interleukin-6) from the primary analysis and y-axis represents the T-statistics of log_e(interleukin-6) from the secondary analysis. Each point represents one gene. The results were highly correlated (R²=0.86).

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References

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[1] Kishimoto T. The biology of interleukin-6. Blood. 1989;74:1–10. - PubMed

[2] Kishimoto T. The biology of interleukin-6. Blood. 1989;74:1–10. - PubMed

[3] Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clinical chemistry. 2008;54:24–38. - PubMed

[4] Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clinical chemistry. 2008;54:24–38. - PubMed

[5] Raschke S, Eckel J. Adipo-myokines: two sides of the same coin--mediators of inflammation and mediators of exercise. Mediators of inflammation. 2013;2013:320724. - PMC - PubMed

[6] Raschke S, Eckel J. Adipo-myokines: two sides of the same coin--mediators of inflammation and mediators of exercise. Mediators of inflammation. 2013;2013:320724. - PMC - PubMed

[7] Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Frontiers in bioscience : a journal and virtual library. 1997;2:d12–d26. - PubMed

[8] Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Frontiers in bioscience : a journal and virtual library. 1997;2:d12–d26. - PubMed

[9] Abeywardena MY, Leifert WR, Warnes KE, Varghese JN, Head RJ. Cardiovascular biology of interleukin-6. Curr Pharm Des. 2009;15:1809–1821. - PubMed

[10] Abeywardena MY, Leifert WR, Warnes KE, Varghese JN, Head RJ. Cardiovascular biology of interleukin-6. Curr Pharm Des. 2009;15:1809–1821. - PubMed

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Whole blood gene expression and interleukin-6 levels

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Whole blood gene expression and interleukin-6 levels

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