Variation within Genes Encoding Interleukin-1 and the Interleukin-1 Receptor Antagonist Influence the Severity of Meningococcal Disease[dhelix]

Variation within Genes Encoding Interleukin-1 and the Interleukin-1 Receptor Antagonist Influence the Severity of Meningococcal Disease[dhelix]

Robert C. Read, MD, FRCP;
Chris Cannings, PhD;
Simone C. Naylor, BSc;
Janine M. Timms, BSc;
Ravi Maheswaran, MD, MFPH;
Raymond Borrow, PhD;
Edward B. Kaczmarski, MD, MRCPath; and
Gordon W. Duff, PhD, FRCP

From University of Sheffield Medical School, Sheffield, and Meningococcal Reference Unit for England and Wales, Manchester Public Health Laboratory, Manchester, United Kingdom.

Abstract

Background: Genetically determined variation in proinflammatory cytokine release influences severity of meningococcal disease and other serious infections.

Objective: To ascertain the relative frequencies of single nucleotide polymorphisms within the interleukin-1 gene locus among patients who survived and those who died of meningococcal disease and a control population of blood donors.

Design: Association study.

Setting: England and Wales.

Patients: 1106 consecutively received blood samples from persons with microbiologically confirmed meningococcal disease and 839 samples from blood donors.

Measurements: Patient demographic and outcome data, infecting meningococcal serogroups, and genotype at the IL1B(−511) and IL1RN(+2018) loci of patients and blood donor controls.

Results: Genotype frequency did not differ between patients with meningococcal disease and blood donor controls. Logistic regression analysis revealed that the likelihood of death was significantly influenced by age but not socioeconomic status and was higher in patients who were infected with serogroup C (odds ratio for survival, 0.50 [95% CI, 0.33 to 0.78]). Patients carrying the common allele at IL1B(−511) were more likely to survive (odds ratio, 2.01 [CI, 1.11 to 3.79]). Patients with this allele were less likely to survive if they also carried the rare allele at IL1RN(+2018) (odds ratio, 0.61 [CI, 0.38 to 0.993]).

Conclusion: Genotype at the interleukin-1 gene locus influences likelihood of survival of meningococcal disease but has no effect on susceptibility to the infection. Increasing age and infection with serogroup C also influence the likelihood of death.

Article and Author Information

For definitions of terms, see Glossary.
Acknowledgments: The authors thank Dr. M.W. McKendrick for helpful discussions, Pauline A. Whitaker for administrative assistance, and all Consultants in Communicable Disease who helped obtain demographic information.
Grant Support: By the Meningitis Research Foundation (award 4/00), Thornbury, Bristol, United Kingdom.
Potential Financial Conflicts of Interest:Consultancies: C. Cannings (Interleukin Genetics, Myriad Genetics), G.W. Duff (Interleukin Genetics); Stock ownership or options (other than mutual funds): R.C. Read (Interleukin Genetics; University of Sheffield is a stockholder), C. Cannings (Myriad Genetics), G.W. Duff (Interleukin Genetics; University of Sheffield is a stockholder); Grants received: G.W. Duff (Interleukin Genetics); Patents received: G.W. Duff (Interleukin Genetics).
Requests for Single Reprints: Robert C. Read, MD, FRCP, Division of Genomic Medicine, F Floor, University of Sheffield School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, United Kingdom; e-mail, r.c.read{at}sheffield.ac.uk.
Current Author Addresses: Drs. Read, Cannings, Duff, Ms. Naylor, and Ms. Timms: Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom.
Dr. Maheswaran: School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield S1 4DA, United Kingdom.
Drs. Borrow and Kaczmarski: Meningococcal Reference Unit, Manchester Public Health Laboratory, Withington Hospital, Manchester M20 8LR, United Kingdom.
Author Contributions: Conception and design: R.C. Read, R. Borrow, E.B. Kaczmarski, G.W. Duff.
Analysis and interpretation of the data: R.C. Read, C. Cannings, S.C. Naylor, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski.
Drafting of the article: R.C. Read.
Critical revision of the article for important intellectual content: R.C. Read, C. Cannings, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski, G.W. Duff.
Final approval of the article: R.C. Read, C. Cannings, S.C. Naylor, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski, G.W. Duff.
Provision of study materials or patients: R. Borrow, E.B. Kaczmarski.
Statistical expertise: C. Cannings, R. Maheswaran.
Obtaining of funding: R.C. Read, E.B. Kaczmarski, G.W. Duff.
Administrative, technical, or logistic support: S.C. Naylor, J.M. Timms.
Collection and assembly of data: R.C. Read, S.C. Naylor, R. Maheswaran, R. Borrow, E.B. Kaczmarski.