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Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia - PubMed

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

J K Trittmann et al. Acta Paediatr. 2018 Dec.

Abstract

Aim: Pulmonary hypertension significantly increases morbidity and mortality in infants with bronchopulmonary dysplasia. The frequency of single nucleotide polymorphisms in arginase-1 (ARG1 rs2781666) and dimethylarginine dimethylaminohydrolase-1 (DDAH1 rs480414) genes has been found to differ in a cohort of bronchopulmonary dysplasia patients with pulmonary hypertension (cases) and without pulmonary hypertension (controls). Therefore, we tested the hypothesis that combining these genotypes with phenotypic data would better predict pulmonary hypertension in bronchopulmonary dysplasia patients.

Methods: Bronchopulmonary dysplasia patients (n = 79) born at <35 weeks gestation were studied. Pulmonary hypertension was diagnosed by echocardiographic criteria (n = 20). ROC curves to predict pulmonary hypertension in bronchopulmonary dysplasia were generated from genotype and/or clinical data.

Results: Cases were born at an earlier gestation and weighed less at birth than did controls. ROC curves for rs2781666 had an AUC of 0.61, while rs480414 had an AUC of 0.66. Together, the AUC was 0.70. When clinical data were added to the genetic model, AUC was 0.73.

Conclusion: These findings demonstrate that ROC predictive modelling of pulmonary hypertension in bronchopulmonary dysplasia improves with inclusion of both genotypic and phenotypic data. Further refinement of these types of models could facilitate the implementation of precision medicine approaches to pulmonary hypertension in bronchopulmonary dysplasia.

Keywords: Arginase; Dimethylarginine dimethylaminohydrolase; Neonatology; Predictive model; Prematurity.

©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

FIGURE 1:
FIGURE 1:. Frequency distribution for wildtype (G-allele) genotype status for ARG1 or DDAH1 independently.

ARG1 SNP rs2781666 and DDAH1 SNP rs48041 were evaluated by chi-square analysis. DDAH1.GG at locus rs480414 has a significantly greater frequency in BPD-PH patients (75%) than did BPD alone patients (44%, *p<0.05). BPD, bronchopulmonary dysplasia; BPD-PH, bronchopulmonary dysplasia-associated pulmonary hypertension; ARG1, arginase-1; DDAH1, dimethylarginine dimethylaminohydrolase-1. ARG1.GT, wildtype heterozygote; ARG1.GG, wildtype homozygote; DDAH1.GA, wildtype heterozygote; DDAH1.GG, wildtype homozygote.

FIGURE 2:
FIGURE 2:. Frequency distribution for wildtype (G-allele) genotype status for ARG1 and DDAH1 combined.

ARG1 SNP rs2781666 and DDAH1 SNP rs48041 were evaluated by chi-square analysis for differences in frequency of wildtype (WT) allele. Groups 1–4 as defined in table 3. ARG1+DDAH1 group 1 has a significantly greater frequency in BPD-PH patients (45%) than did BPD alone patients (22%, *p<0.05). ARG1+DDAH1 group 3 has a significantly greater frequency in BPD-PH patients (85%) than did BPD alone patients (47%, *p<0.05).

FIGURE 3.
FIGURE 3.. ROC curves for clinical and SNP data:

Clinical characteristics included birthweight and gestational age. SNP data included ARG1.WT, DDAH1.WT, and ARG1.WT+DDAH1.WT. ROC curves were generated and AUC was calculated for clinical and SNP data, separately and combined. AUC was greatest (0.74) for clinical data + ARG1.WT+DDAH1.WT group. Clinical data was recorded as a 0–3 variable (quartiles) and genotype data was recorded as a 0–4 variable dependent on number of WT alleles. Wildtype allele (G) was considered a positive genetic PH test for echocardiographic BPD-PH.

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