Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis

Freitag, D., Butterworth, A.S., Willeit, P., Howson, J. M. M., Burgess, S., Kaptoge, S., Young, R., Ho, W. K., Wood, A. M., Sweeting, M., Spackman, S., Staley, J. R., Ramond, A., Harshfield, E., Nielsen, S. F., Grande, P., Lange, L. A., Bown, M. J., Jones, G. T., Scott, R. A., Bevan, S., Porcu, E., Thorleifsson, G., Zeng, L., Kessler, T., Nikpay, M., Do, R., Zhang, W., Hopewell, J. C., Kleber, M., Delgado, G. E., Nelson, C. P., Goel, A., Bis, J. C., Dehghan, A., Ligthart, S., Smith, A. V., Qu, L., van 't Hof, F. N. G., de Bakker, P. I. W., Baas, A. F., van Rij, A., Tromp, G., Kuivaniemi, H., Ritchie, M. D., Verma, S. S., Crawford, D. C., Malinowski, J., de Andrade, M., Kullo, I. J., Peissig, P. L., McCarty, C. A., Böttinger, E. P., Gottesman, O., Crosslin, D. R., Carrell, D. S., Rasmussen-Torvik, L. J., Pacheco, J. A., Huang, J., Timpson, N. J., Kettunen, J., Ala-Korpela, M., Mitchell, G. F., Parsa, A., Wilkinson, I. B., Gorski, M., Li, Y., Franceschini, N., Keller, M. F., Ganesh, S. K., Langefeld, C. D., Bruijn, L., Brown, M.A., Evans, D.M., Baltic, S., Ferreira, M. A., Baurecht, H., Weidinger, S., Franke, A., Lubitz, S. A., Müller-Nurasyid, M., Felix, J. F., Smith, N. L., Sudman, M., Thompson, S. D., Zeggini, E., Panoutsopoulou, K., Nalls, M. A., Singleton, A., Polychronakos, C., Bradfield, J. P., Hakonarson, H., Easton, D. F., Thompson, D., Tomlinson, I. P., Dunlop, M., Hemminki, K., Morgan, G., Eisen, T., Goldschmidt, H., Allan, J. M., Henrion, M., Whiffin, N., Wang, Y., Chubb, D., Iles, M. M., Bishop, D. T., Law, M. H., Hayward, N. K., Luo, Y., Nejentsev, S., Barbalic, M., Crossman, D., Sanna, S., Soranzo, N., Markus, H. S., Wareham, N. J., Rader, D. J., Reilly, M., Assimes, T., Harris, T. B., Hofman, A., Franco, O. H., Gudnason, V., Tracy, R., Psaty, B. M., Farrall, M., Watkins, H., Hall, A. S., Samani, N. J., März, W., Clarke, R., Collins, R., Kooner, J. S., Chambers, J. C., Kathiresan, S., McPherson, R., Erdmann, J., Kastrati, A., Schunkert, H., Stefánsson, K., Thorsteinsdottir, U., Walston, J. D., Tybjærg-Hansen, A., Alam, D. S., Al Shafi Majumder, A., Angelantonio, E. D., Chowdhury, R., Nordestgaard, B. G., Saleheen, D., Thompson, S. G., Danesh, J., & Houlston, R. S. (2015) Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis. The Lancet Diabetes and Endocrinology, 3(4), pp. 243-253.

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Abstract

Background

To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation.

Methods

We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants).

Findings

For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18–0·25; 12·5%; p=9·3 × 10−33), concentrations of interleukin 6 decreased by 0·02 SD (−0·04 to −0·01; −1·7%; p=3·5 × 10−3), and concentrations of C-reactive protein decreased by 0·03 SD (−0·04 to −0·02; −3·4%; p=7·7 × 10−14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08–1·22; p=1·8 × 10−6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02–1·04; p=3·9 × 10−10). Per-allele odds ratios were 0·97 (0·95–0·99; p=9·9 × 10−4) for rheumatoid arthritis, 0·99 (0·97–1·01; p=0·47) for type 2 diabetes, 1·00 (0·98–1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04–1·12; p=1·8 × 10−5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk.

Interpretation

Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations.

Funding

UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.

Impact and interest:

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ID Code: 89063
Item Type: Journal Article
Refereed: Yes
Keywords: C reactive protein, interleukin 1, interleukin 1 receptor blocking agent, interleukin 1alpha, interleukin 1beta, interleukin 6, low density lipoprotein cholesterol, recombinant interleukin 1 receptor blocking agent, abdominal aorta aneurysm, allele, Article, brain ischemia, cardiovascular effect, cardiovascular risk, controlled study, gene frequency, gene location, genetic association, genetic score, genetic variability, human, human cell, human tissue, IL1RN gene, inflammation, ischemic heart disease, lipid blood level, major clinical study, Mendelian randomization analysis, non insulin dependent diabetes mellitus, priority journal, protein blood level, rheumatoid arthritis, risk factor, risk reduction, scoring system, upregulation
DOI: 10.1016/S2213-8587(15)00034-0
ISSN: 2213-8587
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 15 Oct 2015 02:48
Last Modified: 16 Feb 2016 03:18

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