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Ainsley M Sutherland

Publications and source records attributed to Ainsley M Sutherland.

5 recordsLinked to original sources
PubMed2006

Fibrinogen-beta gene haplotype is associated with mortality in sepsis.

OBJECTIVES: Fibrinogen plays a key role in coagulation and inflammation. Transcription of the fibrinogen-beta gene (FGB) is the rate-limiting step in fibrinogen production. Our aim was to determine whether haplotypes of FGB are associated with mortality and organ dysfunction in a cohort of patients with sepsis. METHODS: A prospective cohort of 631 consecutive Caucasian patients with sepsis from a tertiary care medical-surgical ICU were enrolled in a gene association study. Patients were genotyped for three polymorphisms in FGB: -854 G/A, -455 G/A, and +9006 G/A. Haplotypes were inferred using PHASE. The primary outcome was mortality. Secondary outcomes were severity of organ dysfunction as measured by days alive and free (DAF) of organ dysfunction. RESULTS: Haplotype GAA was associated with a significantly lower 28-day mortality (28.9% vs. 36.9% for all other haplotypes, p=0.03). Carriers of two copies of haplotype GAA (vs. one and zero copies) had more DAF of organ dysfunction. In a multivariate analysis, haplotype GAA was an independent predictor for lower mortality (OR=0.66, 95% CI=0.46-0.94, p=0.02). CONCLUSIONS: Haplotype GAA in FGB is associated with lower mortality and lower severity of organ dysfunction. Haplotype GAA encompasses a previously described haplotype -1420A/-854G/-455A/-249C/-148T/+1690G that is associated with higher fibrinogen levels.

APACHE↗
PubMed2005

Issues with polymorphism analysis in sepsis.

Genetic variation has been shown to play a large role in determining susceptibility to and outcome of such complex diseases as sepsis. There is a much higher heritability of death due to infection than death due to cancer or heart disease. More than 8 million single nucleotide polymorphisms (SNPs) have been detected in the human genome, and there is very little understanding of their effect on gene expression and protein function. The use of haplotypes, which are inherited sets of linked SNPs, as the unit of genetic variation in association studies and the marking of these haplotypes with unique "tag SNPs" may help to narrow down the search for causal SNPs. Future studies must be large (thousands of patients) and must be carefully designed to avoid false associations resulting from ethnic differences in genotype frequencies and disease prevalence in order to find true, reproducible associations between genotype and phenotype. Functional studies and careful characterization of intermediate phenotypes must be done to lend biological plausibility to genotype-phenotype associations. Examination of the association between genetic polymorphisms and sepsis promises to provide clinicians with new tools to evaluate prognosis, to intervene early and aggressively in treating high-risk persons, and to avoid the use of therapies with adverse effects in treating low-risk persons.

Confounding Factors, Epidemiologic↗
PubMed2005

The association of interleukin 6 haplotype clades with mortality in critically ill adults.

BACKGROUND: Interleukin 6 (IL-6) is a key proinflammatory cytokine in the systemic inflammatory response syndrome (SIRS). A G-->C polymorphism at position -174 of the IL-6 gene is associated with an adverse outcome in a number of inflammatory diseases, although its association with sepsis as an outcome remains unclear. We tested the hypothesis that specific haplotype clades of IL-6 may be associated with an outcome of SIRS. METHODS: We studied a cohort of 228 critically ill white patients who met at least 2 of 4 SIRS criteria. Clinical data were collected over 28 days after hospital admission. Haplotypes of IL-6 were inferred from publicly available data using PHASE (software for haplotype reconstruction and recombination rate estimation from population data), and cladistic structure was determined using Molecular Evolutionary Genetic Analyses (MEGA2) software. Then, a minimum set of "haplotype tag" single nucleotide polymorphisms (-174G/C, 1753C/G, and 2954G/C) that defined all 4 major haplotype clades of the IL-6 gene was chosen for further genotyping. RESULTS: Patients who had 2 copies of haplotypes from within the haplotype clades -174C/1753C/2954G (C/C/G), G/G/G, or G/C/C had a greater 28-day mortality compared with patients who carried 1 or no copies of these haplotypes (40.0% vs 26.0%; P = .02). These patients also had fewer days alive and free of multiple system organ dysfunction (P<.05). There were no associations between individual single nucleotide polymorphisms (including -174G/C) and survival or organ dysfunction. CONCLUSIONS: The C/C/G, G/G/G, and G/C/C haplotype clades of IL-6 were strongly associated with increased mortality and more organ dysfunction in a cohort of critically ill patients who had SIRS. Haplotype-based analysis succeeded in identifying this association, whereas individual single nucleotide polymorphism-based analysis failed.

Adult↗
PubMed2005

Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults.

OBJECTIVE: To test for the association of single nucleotide polymorphisms of the innate immunity receptors cluster of differentiation (CD)-14, mannose-binding lectin, and Toll-like receptor-2 with clinical phenotype in critically ill patients with systemic inflammatory response syndrome. DESIGN: Genetic association study. SETTING: Tertiary care mixed medical-surgery intensive care unit at St. Paul's Hospital, Vancouver, BC, a teaching hospital associated with the University of British Columbia. PATIENTS: A cohort of 252 critically ill Caucasians with systemic inflammatory response syndrome. INTERVENTIONS: DNA was extracted from discarded blood. Clinical data were gathered by retrospective chart review. MEASUREMENTS AND MAIN RESULTS: C-159T CD14, the X/Y and B, C, and D polymorphisms of mannose-binding lectin, and T-16933A Toll-like receptor-2 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. We tested for association of genotype with prevalence of positive bacterial cultures, type of organism (Gram-positive, Gram-negative, other), sepsis and septic shock at admission to the intensive care unit, and 28-day survival. CD14 -159TT was associated with increased prevalence of positive bacterial cultures and with Gram-negative bacteria. Mannose-binding lectin haplotype pairs XO/O and O/O were also associated with increased prevalence of positive bacterial cultures but not with a specific organism class. Toll-like receptor-2 -16933AA was associated with increased prevalence of sepsis and with Gram-positive bacteria. In contrast, the polymorphisms were not associated with increased prevalence of septic shock or altered 28-day survival. CONCLUSIONS: Single nucleotide polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of positive bacterial cultures and sepsis but not with altered prevalence of septic shock or decreased 28-day survival. Furthermore, CD14 single nucleotide polymorphisms were associated with Gram-negative bacteria and Toll-like receptor-2 with Gram-positive bacteria, whereas mannose-binding lectin was not associated with a particular organism class. Thus, single nucleotide polymorphisms in innate immunity receptors may alter recognition and clearance of bacteria without changing outcomes of critically ill adults with systemic inflammatory response syndrome.

Adult↗