Genome-wide population structure and evolutionary history of the Frizarta dairy sheep.

In the present study, we used genomic data, generated with a medium density single nucleotide polymorphisms (SNP) array, to acquire more information on the population structure and evolutionary history of the synthetic Frizarta dairy sheep. First, two typical measures of linkage disequilibrium (LD) were estimated at various physical distances that were then used to make inferences on the effective population size at key past time points. Population structure was also assessed by both multidimensional scaling analysis and k-means clustering on the distance matrix obtained from the animals' genomic relationships. The Wright's fixation F ST index was also employed to assess herds' genetic homogeneity and to indirectly estimate past migration rates. The Wright's fixation F IS index and genomic inbreeding coefficients based on the genomic relationship matrix as well as on runs of homozygosity were also estimated. The Frizarta breed displays relatively low LD levels with r 2 and |D'| equal to 0.18 and 0.50, respectively, at an average inter-marker distance of 31 kb. Linkage disequilibrium decayed rapidly by distance and persisted over just a few thousand base pairs. Rate of LD decay (ß) varied widely among the 26 autosomes with larger values estimated for shorter chromosomes (e.g. ß=0.057, for OAR6) and smaller values for longer ones (e.g. ß=0.022, for OAR2). The inferred effective population size at the beginning of the breed's formation was as high as 549, was then reduced to 463 in 1981 (end of the breed's formation) and further declined to 187, one generation ago. Multidimensional scaling analysis and k-means clustering suggested a genetically homogenous population, F ST estimates indicated relatively low genetic differentiation between herds, whereas a heat map of the animals' genomic kinship relationships revealed a stratified population, at a herd level. Estimates of genomic inbreeding coefficients suggested that most recent parental relatedness may have been a major determinant of the current effective population size. A denser than the 50k SNP panel may be more beneficial when performing genome wide association studies in the breed.

Effect of angiotensin converting enzyme gene I/D polymorphism and its expression on clinical outcome in acute respiratory distress syndrome.

BACKGROUND: The role of the D allele of the angiotensin-converting enzyme (ACE) gene I/D polymorphism in the clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains controversial. Our aim was to assess simultaneously the effect of the ACE I/D polymorphisms as well as the serum and BALF ACE levels on prognosis of patients with ARDS. METHODS: Sixty-nine mechanically ventilated patients with ALI/ARDS were recruited. ACE activity levels both in serum and BALF were assessed by chemical methods. Patients were genotyped for ACE I/D polymorphisms. Time-to-event analysis evaluated the variables associated with the 28-day and 90-day mortality. Finally, we performed a meta-analysis of studies examining the association between ACE I/D polymorphisms and mortality of ALI/ARDS patients. RESULTS: In the multivariable model, age, lung compliance, serum lactate and serum ACE levels were significantly associated with both 28- and 90-day mortality. No significant correlation was found between serum and BALF ACE levels (Spearman's rho=0.054; P=0.66). Serum ACE concentrations were significantly higher (P=0.046) in patients with D/D genotype versus the two other groups combined (I/D and I/I genotypes). The meta-analysis of 6 studies (including ours) provided evidence that D allele is significantly associated with increased mortality in ALI/ARDS patients, yielding a per-allele odds ratio of 1.76 (95% CI: 1.19, 2.59). CONCLUSION: Serum ACE levels appear to be affected by the I/D polymorphism and are correlated with prognosis in patients with ALI/ARDS indicating that further investigation of the clinical significance of the ACE in ARDS might be of value.

The effect of homocysteine on the clinical outcomes of ventilated patients with severe sepsis.

BACKGROUND: There is considerable evidence that elevated plasma homocysteine levels are associated with a prothrombotic milieu, whereas activation of the coagulation cascade is an important component of the pathogenesis of sepsis. The protein C pathway has been reported to play a central role both in the propagation of sepsis and a hyperhomocysteinemia-induced hypercoagulable state. Our primary aim was to measure plasma homocysteine levels in mechanically ventilated patients with severe sepsis/septic shock and to assess the association of these levels with relevant clinical outcomes. METHODS: The study cohort included 102 mechanically ventilated patients with severe sepsis or septic shock. Demographics, comorbidities, clinical data and severity scores were recorded. Plasma homocysteine, vitamin B12, folate, creatinine, and protein C levels were measured in all study subjects upon enrollment, and genotyping for the C677T and A1298C polymorphisisms of the methylenetetrahydrofolate reductase (MTHFR) gene and for factor V Leiden (FVL) mutations was performed as well. The primary outcomes were mortality at 28 and 90 days; secondary outcomes included the number of days without renal or cardiovascular failure and the ventilator-free days during the study period. RESULTS: Homocysteine levels were not significantly associated with any primary or secondary outcomes in the multivariable analysis. In addition, a synergistic effect of homocysteine with protein C levels was not detected. CONCLUSION: Our data suggest that plasma homocysteine levels may not inform the prognosis of mechanically ventilated patients with severe sepsis/septic shock.