Variation within genes encoding interleukin-1 and the interleukin-1 receptor antagonist influence the severity of meningococcal disease.

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.

Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus.

OBJECTIVE: Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location. METHODS: We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs). RESULTS: Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 x 10(-5)) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P = 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and PG8 (P = 0.003). CONCLUSION: At least 1 additional non-DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes.

The Influence of Interleukin Gene Polymorphism on Expression of Interleukin-1ß and Tumor Necrosis Factor-α in Periodontal Tissue and Gingival Crevicular Fluid.

BACKGROUND: A specific composite genotype of the polymorphic interleukin-1 (IL-1) gene cluster has recently been associated with severe periodontitis. One polymorphism of the composite periodontitis-associated genotype (PAG) has been functionally linked with expression of high levels of IL-1. The purpose of this study was to test whether gingival crevicular fluid (GCF) levels of IL-1ß and tumor necrosis factor-alpha (TNFα), and gingival tissue levels of IL- 1α, IL-1ß, and TNFα correlate with PAG, and to examine the effec; of conservative periodontal therapy on these levels. METHODS: Twenty-two adults with moderate to advanced periodontal disease were enrolled. Polymerase chain reaction amplification and restriction enzymes were used to identify specific polymorphisms from peripheral blood samples. GCF samples were collected at baseline and 3 weeks following conservative treatment and analyzed by ELISA for IL-1ß and TNFα. An interproximal gingival biopsy was collected at baseline and follow-up and analyzed for IL-1α, IL-1ß, and TNFα by ELISA. RESULTS: The genotyping identified 7 as PAG(+) and 15 as PAG(-). The 2 groups were comparable in terms of existing periodontitis and age. In shallow sites (<4 mm), total IL-1ß in GCF was 2.5 times higher for PAG(+) patients prior to treatment (P = 0.03), and 2.2 times higher after treatment (P = 0.04), while differences were less apparent in deeper sites. Following treatment, a reduction in IL-1ß concentration in GCF was seen for PAG(-) but not for PAG(+) patients. While not statistically significant, a trend was observed in mean tissue levels of IL-1ß which were 3.6 times higher in PAG(+) versus PAG(-) patients (P = 0.09). CONCLUSIONS: These data suggest that PAG(+) patients may demonstrate phenotypic differences as indicated by elevated levels of IL-1ß in GCF. J Periodontol 1999;70:567-573.