Dataset Information

ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.

ABSTRACT:

Rationale

Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI.

Objectives

To identify ALI risk variants after major trauma using a large-scale candidate gene approach.

Methods

We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot.

Measurements and main results

Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038).

Conclusions

An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.

SUBMITTER: Meyer NJ

PROVIDER: S-EPMC3114062 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.

Meyer Nuala J NJ Li Mingyao M Feng Rui R Bradfield Jonathan J Gallop Robert R Bellamy Scarlett S Fuchs Barry D BD Lanken Paul N PN Albelda Steven M SM Rushefski Melanie M Aplenc Richard R Abramova Helen H Atochina-Vasserman Elena N EN Beers Michael F MF Calfee Carolyn S CS Cohen Mitchell J MJ Pittet Jean-Francois JF Christiani David C DC O'Keefe Grant E GE Ware Lorraine B LB May Addison K AK Wurfel Mark M MM Hakonarson Hakon H Christie Jason D JD

American journal of respiratory and critical care medicine 20110121 10

<h4>Rationale</h4>Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI.<h4>Objectives</h4>To identify ALI risk variants after major trauma using a large-scale candidate gene approach.<h4>Methods</h4>We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotid ...[more]

PMID: 21257790

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Project description:ObjectivesOmega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids.MethodsThis observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis.ResultsUE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class.ConclusionsA large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake.

Dataset Information

ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.

Similar Datasets

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