The Association of Interleukin 6 Haplotype Clades With Mortality in Critically Ill Adults

Sutherland, Ainsley M.; Walley, Keith R.; Manocha, Sanjay; Russell, James A.

doi:10.1001/archinte.165.1.75

Cited by 106 publications

(72 citation statements)

References 43 publications

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“…Although it has been speculated that there may be a potential glucocorticoid receptor at position Ϫ557 to Ϫ552, the sequence around the Ϫ572 site does not have a strong homology to any known transcriptional factor binding site. Thus, these observations, together with the wealth of IL-6 Ϫ174 genotype-association studies (45)(46)(47)(48)(49)(50), indicate that, in Northern Europeans, the IL-6 Ϫ174 genotype is probably the main promoter polymorphism determining variation in IL-6 induction.…”

Section: Discussionmentioning

confidence: 89%

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Sawczenko

Azooz

Paraszczuk

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

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Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzenesulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P ‫؍‬ 0.023) and increased IGF-I (P ‫؍‬ 0.05). In humans, the IL-6 ؊174 G͞C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 ؊174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growthretarded than those with the GC or CC genotypes (height SD score, ؊0.51 vs. ؊0.10; P ‫؍‬ 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg͞dl, P ‫؍‬ 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P ‫؍‬ 0.7). Thus, the IL-6 ؊174 genotype mediates growth failure in children with Crohn's disease.Crohn's disease ͉ height ͉ insulin-like growth factor I ͉ C-reactive protein ͉ food intake

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Section: Discussionmentioning

confidence: 89%

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Sawczenko

Azooz

Paraszczuk

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Recently, it was suggested that IL-6-haplotypes, which could be determined by three polymorphisms at position À172, 1753 and 2954 of the IL-6-gene, are better predictors of mortality in critical ill adults than the IL-6-174 genotype alone. 9 However, only 228 patients participated in this study and the results have not been confirmed so far.…”

mentioning

confidence: 82%

Interleukin-6-174-genotype, sepsis and cerebral injury in very low birth weight infants

et al. 2005

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We investigated the association between the interleukin 6 (IL-6)-174-genotype and unfavorable outcomes in preterm infants since it has been reported that the IL-6-174GG-genotype is associated with increased susceptibility to sepsis, and the IL-6-174CC-genotype is more common in preterm infants with severe intraventricular hemorrhage (IVH). We studied 1206 preterm infants with a birth weight below 1500 g. In contrast to previously published data, the frequency of IVH grade IV, periventricular leukomalacia, ventricular-peritoneal-shunting or death was not different between infants with different IL-6-genotypes: IL-6-174GG (n ¼ 430) 8%, IL-6-174GC (n ¼ 605) 9% and IL-6-174CC (n ¼ 167) 12% (P ¼ 0.2 for IL-6-174CC vs GG þ GC). Furthermore, we were not able to confirm previously reported association between sepsis and the IL-6-174GG-genotype. Blood-culture-proven sepsis occurred in 19% of IL-6-174GG-carriers (n ¼ 157), 26% of IL-6-174GC-carriers (n ¼ 193) and 27% of infants carrying the IL-6-174CC-genotype (n ¼ 67). We were not able to confirm previously reported associations between sepsis, cerebral injury and the IL-6-174-genotype in VLBW-infants.

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“…One such group of haplotypes consists of polymorphisms at the -174 (G/C), +1753 (C/G), and +2954 (G/C) nucleotide positions. In a cohort of critically ill adult patients with SIRS, while no association between each of the SNPs individually and worse clinical outcomes is observed, individuals with the C/C/G, G/G/G or G/C/C haplotype demonstrate a higher mortality and more organ dysfunction [142]. In addition to suggesting that genetic variations within the IL-6 gene influence the severity of sepsis, these observations support the concept that in some instances haplotype analysis may be more valuable in identifying genetic associations compared with individual SNP analysis.…”

Section: Interleukin 6 (Il-6)mentioning

confidence: 89%

“…The association with lower mortality is independent of age and APACHE II score at admission [265]. The association with reduced mortality may be related to the increased fibrinogen A2 allele associated with variable levels of IL-1RA; A2 associated with increased risk of in adults but not children with sepsis; A2 associated with increased mortality in adults with sepsis; +2018 "2 allele" associated with increased mortality in children with meningococcal disease and more severe lung disease in children with pneumonia [120,122,[125][126][127][128] IL-6 -174 G/C G associated with increased IL-6 levels in adult patients but decreased levels in neonates; C associated with increased levels in monocytes from neonates, sepsis in neonates, and severe sepsis and organ dysfunction in children [130,[142][143][144][145][146]281] levels among patients with the GAA haplotype since the 455 A allele within the haplotype is associated with increased transcription. Another polymorphism in the fibrinogen gene, the Val34Leu polymorphism is known to alter the fibrin meshwork with variable permeation characteristics.…”

Section: Fibrinogenmentioning

confidence: 99%

Host Genetics and Pediatric Sepsis

Quasney¹

2011

TOINFJ

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Susceptibility to, and outcome from, sepsis in children is highly variable due in part to genetic variation in genes coding for components of the innate immune response. This review article will discuss evidence for the influence of host genetic variability on the susceptibility to, and outcome from, sepsis in children and adults. Polymorphisms in genes coding for proteins involved in the recognition of bacterial pathogens (TLR4, CD-14, Fc RIIa, and mannose binding lectin) and the response to bacterial pathogens (TNF-, IL-1 , IL-1 , IL-1 RA , IL-6, IL-10, heat shock proteins, ACE, plasminogen activator inhibitor-1) can influence the amount or function of the protein produced in response to bacterial stimuli. Evidence is discussed suggesting that some of these genetic polymorphisms influence the susceptibility to, and outcome from, sepsis. Conclusion:Host genetic variability in the regulatory and coding regions of genes for components of the innate immune system may influence the susceptibility to and/or outcome from sepsis. The disparate results observed in many studies of polymorphisms in sepsis emphasize the need for future studies to be larger, to include the analysis of multiple polymorphisms, and to be better designed with respect to control populations in order to identify the degree of influence that genetic variability has on sepsis.

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The Association of Interleukin 6 Haplotype Clades With Mortality in Critically Ill Adults

Cited by 106 publications

References 43 publications

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Interleukin-6-174-genotype, sepsis and cerebral injury in very low birth weight infants

Host Genetics and Pediatric Sepsis

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