Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust

Multizentrische Studie zur diagnostischen Validität der kontralateralen Suppression otoakustischer Emissionen bei auditiven Selektionsstörungen als Element der Phänotypisierung für genetische Untersuchungen

Ziele sind die Bestimmung der Validität der TEOAE-Suppressionsamplitude als diagnostisches Kriterium der Funktion des medialen olivocochleären Systems (MOCS) zur Diagnostik auditiver Selektionsstörungen und die Suche nach Cutoff-Kriterien mit hinreichender Sensitivität und Spezifität. Einschlusskriterien waren: regelgerechtes Tonaudiogramm, Sprachaudiogramm und Tympanogramm, IQ >=85 und Ausschluss von AD/-HS. Die Phänotypisierung der bislang 91 Kinder erfolgte über die Hörtests "Sprache im Störgeräusch" und "BILD-Test" sowie die Messung der TEOAE-Suppressionsamplitude (Cutoff-Kriterium <0,7 dB) in vier Inanspruchnahme-Gruppen (auditive Selektionsstörung, MOCB-Störung, beides, keine) und einer Kontrollgruppe. Kinder mit Selektionsstörung (n=16) zeigen beidseits eine signifikant niedrigere mittlere TEOAE-Suppression gegenüber der Kontrollgruppe (n=29) bei vergleichbaren TEOAE-Ausgangsamplituden. Die Daten deuten eine gute Spezifität der TEOAE-Suppression für auditive Selektionsstörungen an. Für statistisch gesicherte Analysen und die Bestimmung von Cutoff-Werten mittels ROC-Kurven erscheinen die Fallzahlen noch zu gering. Weiterhin wird mit Hilfe von genomweiten Assoziationsanalysen und Kandidatengenanalysen untersucht, ob die auditive Selektionsstörung/MOCS-Dysfunktion genetische Entitäten darstellen

A Cross-Over Medication Trial For Patients With Autosomal-Dominant Hypertension With Brachydactyly

We examined a family with autosomal-dominant hypertension and brachydactyly from northeastern Turkey. The hypertension was defined as severe, resulting in stroke before age 50 years, featuring normal renin, aldosterone, and catecholamine responses, and did not appear to be salt-sensitive. The responsible gene resides on chromosome 12p. To determine which medications were most effective, we performed a prospective clinical trial. We studied 13 affected individuals in a randomized double-blind, cross-over trial including a betablocker (BBL), alpha-blocker (ABL), calcium channel blocker (CCB), converting enzyme inhibitor (CEI), and hydrochlorothiazide (HCT) and placebo (PLA). We then added moxonidine (MOX) and continued the trial for an additional period in a single-blind fashion. Each drug was given for four weeks with an option to double the dose after two weeks; each washout period comprised two weeks. Blood, 24-hour urine, and saliva were studied at the outset, and blood and urine samples were obtained at the end of each phase. Blood pressure (BP) and heart rate measurements were with the patient ambulatory at 24 hours. All regimens required doubled doses at two weeks. Beta blocker, CCB, CEI, and ABL lowered BP (6 to 10 mm Hg) and BP load compared to PLA, while HCT and MOX did not. Converting enzyme inhibitor and HCT increased plasma renin activity (PRA), while BBL lowered PRA. The 24-hour urine analysis indicated a high dietary salt intake with a low potassium and calcium intake. The salivary electrolytes showed similar sodium and potassium concentrations, while chloride values were significantly higher in affected than nonaffected subjects. Thus, this monogenic form of hypertension resembles nonsalt-sensitive essential hypertension in that BBL, CCB, CEI, and ABL were effective, while HCT was not. The BP reduction was similar to other single drug trials in essential hypertension. The high salivary chloride values suggest an additional intermediary phenotype that may be related to electrolyte transport. These results raise the possibility that an as yet unknown hypertensive mechanism is operative in these subjects.Wo

Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 x 10(-24). The odds ratio was 2.57 (95% CI = 2.02-3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88-9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9\ub77\u2008 7\u200810(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5\ub76\u2008 7\u200810(-8) (odds ratio 0\ub756, 95% CI 0\ub745-0\ub769). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0\ub756, 95% CI 0\ub745-0\ub769; likelihood ratio test p=3\ub74 7 10(-9), after adjustment for age and stratification by cohort). Mortality was 9\ub75% in patients carrying the CC genotype, 15\ub72% in those carrying the TC genotype, and 25\ub73% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification