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. Author manuscript; available in PMC: 2013 May 1.
Published in final edited form as: J Perinatol. 2011 Sep 29;32(5):349–355. doi: 10.1038/jp.2011.104

Genetic Associations of Surfactant Protein D and Angiotensin-Converting Enzyme with Lung Disease in Preterm Neonates

Kelli K Ryckman 1, John M Dagle 1, Keegan Kelsey 1,2, Allison M Momany 1, Jeffrey C Murray 1,*
PMCID: PMC3370386  NIHMSID: NIHMS379178  PMID: 21960125

Abstract

Objective

To replicate genetic associations with respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in genes related to surfactant deficiency, inflammation and infection and the renin-angiotensin system.

Study Design

We examined eight candidate genes for associations with RDS and BPD in 433 preterm (PTB - <37 weeks) infants (251 with RDS and 134 with BPD). Both case-control and family-based analyses were performed in preterm (<37 weeks) and very preterm (VPTB - <32 weeks) infants.

Results

We replicated a previous finding that rs1923537, a marker downstream of surfactant protein D (SFTPD) is associated with RDS in VPTB infants in that the T allele was over-transmitted from parents to offspring with RDS (p=8.4×10−3). We also observed the A allele of rs4351 in the angiotensin-converting enzyme (ACE) gene was over-transmitted from parents to VPTB offspring with BPD (p=9.8×10−3).

Conclusion

These results give further insight into the genetic risk factors for complex neonatal respiratory diseases and provide more evidence of the importance of SFTPD and ACE in the etiology of RDS and BPD, respectively.

Keywords: bronchopulmonary dysplasia, respiratory distress syndrome, single nucleotide polymorphism

Introduction

Respiratory disease is the largest contributor to morbidity and mortality in infants born preterm and low-birth weight (LBW).1,2 The two most common types of respiratory disorders observed in preterm infants are respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). RDS is caused by surfactant deficiency and a lack of lung development and is extremely frequent in very preterm birth (VPTB - <32 weeks gestation) infants.1,3 RDS can develop into BPD, which is characterized by chronic lung damage and inflammation; however, the etiology is complex and studies have shown that chronic lung disease may also develop in infants with little or no initial pulmonary disease.4,5 BPD occurs in approximately 20–30% of very low birth weight (VLBW - <1,500 grams) infants.4,6,7 Originally, these respiratory illnesses were attributed to preterm birth (PTB), LBW and in the case of BPD to the effects of ventilation and supplemental oxygen on underdeveloped lungs. However, other environmental influences have been identified to play a role in the complexity of these diseases. For example, chorioamnionitis, defined by intrauterine inflammation, is associated with a decreased risk of RDS and an increased risk of BPD.8,9 Identifying other underlying risk factors is extremely important for understanding the pathogenesis of these complex diseases to improve treatment and prevention strategies.

In addition to environmental influences, genetic factors play a role in the pathogenesis of both RDS and BPD.2,10 Twin studies show shared genetic and environmental risk factors explain 65% of the risk for developing BPD after controlling for gender, gestational age and birth weight.11 The heritability of RDS, based on several twin studies, is estimated between 20–82%.12–15 Specific genetic associations have been identified with both BPD and RDS. Due to decreased concentrations of surfactant in the lungs of infants with RDS and BPD, the majority of genetic association studies have focused on surfactant protein genes. Associations in surfactant protein genes A (SFTPA2), B (SFTPB), C (SFTPC) and D (SFTPD) with both RDS and BPD have been identified.2,14,16–24 Additionally, several studies have discovered associations between BPD and the mannose-binding lectin gene (MBL2), which is involved in the complement system and inflammatory process.25,26 A few studies have identified associations between BPD and other inflammatory genes including tumor necrosis factor (TNF) and interferon gamma (IFNG).27,28 The insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene was associated with BPD; however, this association failed to replicate.29,30 Many of these associations with BPD and RDS have not been tested in multiple independent populations or have not consistently replicated across studies.4,30,31

To determine if genetic associations previously identified replicate, we examined eight candidate genes for association with BPD and RDS susceptibility: SFTPA2, SFTPB, SFTPC, SFTPD, MBL2, TNF, IFNG and ACE. Several single nucleotide polymorphisms (SNPs) from each gene were tested for association using both family-based and case-control analyses. A total of 433 PTB infants/families (251 with RDS and 134 with BPD) were evaluated.

Materials and Methods

Study Population

Infants born PTB and admitted to the Neonatal Intensive Care Unit at the University of Iowa Children's Hospital between 2000 and 2009 were enrolled. This was an observational study, in that enrollment generally occurred 2–4 weeks after birth and in some cases this would be after the development of a particular condition such as BPD. Blood or buccal swabs were collected from infants and both parents if available. These individuals were recruited to examine PTB and neonatal complications of prematurity.32,33 Approval was obtained from the Institutional Review Board (200506792) for sample collection and access clinical information. RDS was defined radiologically in combination with the requirement of oxygen for 2 hours or more. BPD was diagnosed by radiologic findings as well as an infant that required supplemental oxygen at 36 weeks gestational age. Treatment strategy varied over the 10 year time span of this study. In general, surfactant was not administered as prophylaxis but instead treatment occurred within the first hour after birth using an early rescue approach. A total of 433 singleton PTB Caucasian infants without congenital anomalies were included in the analysis of RDS and BPD.

DNA Processing and Genotyping

Aliquots of sample DNA (2 ng) were transferred to a 384-well plate. Thirty-four SNP markers from eight candidate genes that were previously genotyped for associations with prematurity and complications of prematurity were examined. These genes and SNPs were: SFTPA2 (rs1965708), SFTPB (rs2040349, rs1130866, rs934774, rs1030862 and rs10204426), SFTPC (rs8192306, rs2070687 and rs7592), SFTPD (rs2256703, rs2256588, rs1923537, rs2243639, rs721917 and rs958865), MBL2 (rs2136892, rs10762864, rs10740509, rs1838065, rs5030737, rs7096206, rs930506, rs11003136, rs11003231 and rs2462479), IFNG (rs3181034 and rs2069718), TNF (rs1799964 and rs1800629) and ACE (rs4293, rs4341, rs4351, rs4267385 and rs8066114). In general, tagSNPs were selected to provide the most adequate coverage of each gene including markers both upstream and downstream of the given region. Emphasis was often given to SNPs in coding regions and promoter elements. Genotyping was performed using the Applied Biosystems (Foster City, CA, USA) TaqMan® chemistry under standard conditions. Allele determination was performed using the Applied Biosystems 7900 HT Sequence Detection System with SDS 2.3 software.

Statistical Analysis

Birth weight, gestational age, Apgar scores at 1 and 5 minutes, gender, days on ventilation, days on oxygen supplementation, antenatal treatment with corticosteroids, treatment with surfactant, mode of delivery and maternal chorioamnionitis were compared between infants with and without BPD and between infants with and without RDS. Ranksum tests were used for comparisons of quantitative traits and Fisher's exact tests were used for categorical traits. Analyses were performed with STATA version 10.1 (Stata Corp, College Station, Texas).

Markers were tested for deviations from Hardy-Weinberg Equilibrium (HWE) in RDS and BPD cases and controls separately. All markers were in HWE in RDS and BPD cases and controls using a threshold of p>0.001. Deviations greater than p=0.001 but less than p=0.05 are noted in Supplemental Table 1. Fisher's exact tests were performed to compare allele and genotype frequencies for each SNP between cases and controls (i.e., infants with BPD compared to infants without BPD and infants with RDS compared to infants without RDS). This analysis was performed in PTB (<37 weeks) and VPTB (<32 weeks) infants. Significant (p<0.01) associations were analyzed using logistic regression adjusting for covariates that differed between cases and controls and are known confounders with BPD or RDS. Associations with RDS were adjusted for gestational age and mode of delivery and associations with BPD were adjusted for gestational age, chorioamnionitis and mode of delivery. Haplotype association testing for 2, 3 and 4 sliding window haplotype blocks were performed in PTB and VPTB infants. Analyses were performed using PLINK (http://pngu.mgh.harvard.edu/purcell/plink/).34 Family-based association tests (FBAT) were performed on BPD or RDS case parent-infant trios including any genotyped siblings in PTB and VPTB groups to determine if the transmission of parental alleles to affected offspring is associated with either BPD or RDS.35,36 Analyses were also performed including twins and in general similar trends were observed (data not shown) but due to problems with additional confounding only analyses excluding twins are presented. Family based haplotype association tests (HBAT) were performed in PTB and VPTB families.37

Linear regression was performed to test for additive genetic association of infant genotype with days on a ventilator or days on supplemental oxygen adjusting for gestational age. Days on ventilator and days on oxygen were transformed using the Box Cox transformation due to the non-normal distribution. Analyses were performed with STATA version 10.1 (Stata Corp, College Station, Texas). Quantitative disequilibrium tests (QTDT), adjusting for gestational age, were also performed on the parent-infant trios including any genotyped siblings to determine if the transmission of parental alleles to the offspring were associated with days on a ventilator or days on oxygen. QTDT is based on the same principles as the transmission disequilibrium test (TDT), building upon the methods developed for linkage-disequilibrium mapping and using variance components to construct tests that utilize information from all available offspring.38 Permutation tests were used to correct for the non-linear distribution of days on oxygen and a ventilator. Correcting for thirty four markers, a Bonferroni threshold of p<0.001 was used to determine significant associations. None of the associations between a single marker and RDS or BPD met this significance threshold. However, as this study is a replication analysis of previous work, p-values <0.01 were still considered to be of interest and are also discussed in the results.

Results

Birth weight, gestational age, Apgar score at 1 minute and Apgar score at 5 minutes were significantly lower (p<0.05) in infants with RDS or BPD than controls (Table 1). There were more infants whose mothers received antenatal corticosteroids, more treatment with surfactant, more caesarean deliveries and more time spent on supplemental oxygen or a ventilator in infants with RDS or BPD compared to controls. Additionally, there was significantly more maternal chorioamnionitis in infants with BPD than controls; however there was no difference comparing infants with RDS to controls. As expected, the vast majority of BPD cases were less than 32 weeks gestation, therefore, for BPD only the results in VPTB infants are presented. For RDS the results were similar for PTB and VPTB infants; therefore, only the results for VPTB infants is presented and all other results can be found in the supplemental material. No single locus associations met the Bonferroni significance threshold (p<0.001); however, we present findings of interest with RDS and BPD at a significance of p<0.01.

Table 1.

Demographic and Clinical Characteristics.

Trait (total n=433) No BPD (n=255) BPD (n=134) p-value No RDS (n=154) RDS (n=251) p-value
Birth weight - grams (n=433) 1962 (728) 947 (398) 1×10−41 2038 (694) 1423 (776) 2×10−16
Gestational Age - weeks (n=433) 32 (3) 27 (2) 5×10−46 33 (3) 29 (4) 7×10−22
Gestational Age <32 weeks (n=230) 92 (36%) 130 (97%) 2×10−36 40 (26%) 178 (71%) 6×10−19
Apgar Score 1 min (n=427) 6 (2) 5 (2) 5×10−11 7 (2) 5 (2) 1×10−9
Apgar Score 5 min (n=428) 8 (1) 7 (2) 4×10−11 8 (1) 7 (2) 2×10−9
Infant Gender - Male (n=433) 134 (53%) 80 (60%) 0.20 76 (49%) 150 (60%) 0.05
Mechanical Ventilation - days (n=398) 3 (7) 37 (28) 1×10−45 3 (7) 22 (27) 2×10−27
Oxygen Supplementation - days (n=402) 13 (16) 89 (43) 6×10−54 12 (17) 55 (50) 3×10−26
Antenatal Corticosteroids (n=402) 4 (2%) 67 (51%) 3×10−32 5 (4%) 67 (29%) 1×10−10
Treatment with Surfactant (n=425) 69 (27%) 119 (89%) 9×10−33 4 (3%) 196 (79%) 5×10−58
Mode of Delivery (n=433)
Vaginal 126 (49%) 50 (37%) 0.03 89 (58%) 101 (40%) 7×10−4
Caesarean 129 (51%) 84 (63%) 65 (42%) 150 (60%)
Maternal Chorioamnionitis (n=366) 20 (9%) 21 (19%) 0.01 12 (9%) 28 (14%) 0.23
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Means and standard deviation in parentheses or counts and percent in parentheses are presented.

P-values compare BPD cases to controls or RDS cases to controls.

Genetic Associations with RDS

The most significant association with RDS was rs2256588 downstream of SFTPD, where the AA genotype was more frequent in VPTB cases compared to controls (p=5.9×10−3) (Table 2, Supplemental Table 2); however, this did not remain significant when adjusting for gestational age and mode of delivery (p=0.21). The T allele at rs1923537 downstream of SFTD was over-transmitted in VPTB offspring with RDS (p=8.4×10−3). Additionally, the T allele was marginally more prevalent in RDS cases compared to controls (p=0.14) and the TT genotype was associated (p=0.02) with more days on oxygen compared to the CC genotype (62 versus 55 days on oxygen, respectively). There were several haplotype effects including these signals in the family-based but not case-control analyses (Figure 1 and Supplemental Table 3). The most significant haplotype effect included rs1923537 and rs2243639, where the T-C haplotype was significantly over-transmitted to VPTB offspring with RDS (p=4.7×10−4) (Supplemental Table 4).

Table 2.

Significant Single Locus Associations with BPD or RDS in very preterm infants.

Allele and Genotype Frequencies p-value
Gene Locus (A/B) Status N A AA AB BB Allelic Genotypic over-transmitted allele FBAT p-value
SFTPD rs2256588 RDS 127 0.61 0.42 0.39 0.19 1.0 5.9×10−3 A 0.15
(A/G) Controls 28 0.61 0.25 0.71 0.04
rs1923537 BPD 93 0.65 0.41 0.48 0.11 0.48 0.72 T 0.03
(T/C) Controls 69 0.61 0.36 0.49 0.14
RDS 124 0.65 0.44 0.44 0.13 0.14 0.08 T 8.4×10−3
Controls 31 0.55 0.23 0.65 0.13
rs721917 BPD 51 0.44 0.20 0.49 0.31 0.03 0.07 C 0.07
(T/C) Controls 46 0.60 0.33 0.54 0.13
ACE rs8066114 BPD 91 0.58 0.32 0.52 0.16 5.0×10−3 0.02 C 0.47
(C/G) Controls 61 0.74 0.54 0.39 0.07
rs4351 BPD 106 0.56 0.31 0.49 0.20 0.83 0.46 A 9.8×10−3
(A/G) Controls 73 0.54 0.25 0.59 0.16
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N= number of observations

Figure 1.

Figure 1

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Single locus and haplotype associations between SFTPD and RDS or BPD in VPTB infants. Each gene is represented by a solid line and SNPs within exons are represented by a box. Dotted lines represent SNPs outside the gene or in the promoter region. The 3′ end of the gene is represented by an arrow. R2 values are given in each box and shading indicates the strength of LD determined by the 95% confidence bounds of D′. White shading indicates strong evidence for recombination, light grey indicates lack of information to determine the strength of LD and dark grey indicates strong LD.

Genetic Associations with BPD

The most significant association with BPD was rs8066114, downstream of the ACE gene, where the G allele was more frequent in VPTB cases compared to controls (p=5.0×10−3) (Table 2). Additionally the GG genotype was more frequent in BPD cases compared to controls (p=0.02) and this effect remained significant after adjusting for gestational age, chorioamnionitis and mode of delivery (p= 0.03). There were no significant associations with this SNP in the family-based analysis (p=0.47). The A allele of rs4351 in ACE was significantly over-transmitted to VPTB offspring with BPD (p=9.8×10−3). This effect was not significant in the case-control analysis (p=0.83). There were several significant haplotype associations, all of which included either rs8066114 or rs4351 in both the case-control and family-based analyses (Figure 2 and Supplemental Table 3). Most notably was the T-C haplotype at rs4267385 and rs8066114 which was significantly more frequent in the BPD cases (p=3.8×10−4) compared to controls and marginally over-transmitted in the family-based analysis (p=0.06) (Supplemental Table 4).

Figure 2.

Figure 2

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Single locus and haplotype associations between ACE and RDS or BPD in VPTB infants. Each gene is represented by a solid line and SNPs within exons are represented by a box. Dotted lines represent SNPs outside the gene or in the promoter region. The 3′ end of the gene is represented by an arrow. R2 are values given in each box and shading indicates the strength of LD determined by the 95% confidence bounds of D′. White shading indicates strong evidence for recombination, light grey indicates lack of information to determine the strength of LD and dark grey indicates strong LD.

Other significant associations with BPD include rs721917 in SFTPD, where the C allele was more frequent in VPTB cases compared to controls (p=0.03) (Table 2 and Supplemental Table 2). There was also marginal over-transmission of the C allele to offspring affected with BPD (p=0.07). The T allele of rs1923537 downstream of SFTPD was over-transmitted to VPTB infants with BPD (p=0.03). There were several significant haplotype associations in the family based analyses only (Figure 1 and Supplemental Table 3). Most notably was the T-C haplotype at rs1923537 and rs2243639 (p=1.8×10−3) (Supplemental Table 4).

Discussion

Very PTB (<32 weeks gestation), very LBW (<1,500 grams) infants are at a particularly high risk for development of RDS and BPD.1,3,4,6,7 The etiology and precise mechanisms of RDS and BPD development and progression in PTB infants remains largely undiscovered. In addition to environmental factors, genetic factors are implicated in increasing the risk of RDS and BPD and while these two diseases are related, the underlying genetic mechanisms and causes for each disease may be quite distinct and complex. Genetic studies have largely focused on surfactant protein genes and many studies have suggested genetic associations with RDS or BPD but few have been replicated or tested in independent populations.

The C allele of a polymorphism downstream of SFTPD (rs1923537) was associated with a lower incidence of RDS in a German population of VPTB infants.22 We replicated this association as the C allele was under-transmitted in the family-based analysis of VPTB infants with RDS and was marginally (p=0.1) protective in the case-control analysis.. Similar to the previous study we also observed fewer days on oxygen in infants with the CC genotype. SFTPD encodes a hydrophilic protein that is involved in surfactant homeostasis and pulmonary innate immunity.39 The heritability of serum surfactant protein D levels is 0.91 according to a twin study, indicating that mutations in this gene could lower concentrations of surfactant protein D which is associated with more severe respiratory disease.40 Our results are a direct replication of a previous association using two analytical methods (i.e., family-based and case-control).

Additionally, the C allele (Thr11) of a missense variant (Thr11Met, position 31 from the transcriptional start site, rs721917) in SFTPD was marginally associated with BPD in both the case-control and family-based analyses. The C allele was previously associated with lower serum SP-D levels and tuberculosis.41–43 Interestingly, the opposite allele (Met11) was previously associated with respiratory syncytial virus bronchiolitis in infants.44 Higher levels of SP-D were observed in acute respiratory distress syndrome in adults, while lower levels are associated with the risk of infection and surfactant deficiency is the underlying cause of RDS in preterm infants.45,46 It is unclear why the results for this effect are conflicting; however, may be due to type I error as our sample sizes were small and our results are only marginally significant. However, due to the predicted deleterious effects on protein structure and associations with respiratory syncytial virus bronchiolitis, tuberculosis and now BPD further investigation of the associations with this SNP and respiratory phenotypes is warranted.

Another gene implicated in increasing the risk for BPD is ACE. One study found that an insertion/deletion polymorphism in intron 16 (rs1799752) was associated with BPD in VLBW (<1250 grams) infants; however, this effect has not been replicated.29,47 While we did not genotype this SNP in our population, we observed several single locus and haplotype associations with BPD in the ACE gene. The insertion/deletion polymorphism is 100 base pairs away from rs4341 which was involved in eight haplotypic associations with BPD (Figure 2); therefore we likely captured the effect previously identified with the insertion/deletion polymorphism in our haplotype analysis. There is increasing evidence that the renin-angiotensin system plays a role in lung disease and injury. One possible explanation for the role of ACE in BPD is that mutations in ACE may influence circulating concentrations of ACE and its product angiotensin II (AII) and higher levels of these enzymes may enhance lung inflammation and disease.29 While this is not a direct replication, there is indication that the ACE gene is involved in BPD but not RDS and that haplotypes, more so than single variants, play a strong role in this effect.

Additionally, we identified weaker associations in genes that have been previously associated with RDS or BPD, specifically, SFTPB, MBL2, and TNF (Supplemental Figure 1). However, these effects did not directly replicate previous associations. Also, we did not replicate associations in SFTPC or IFNG. This is possibly due to our relatively small sample size and lack of power to detect these effects, which may explain why we often saw differing results between family-based and case-control methods. Additionally, our sample was a homogenous collection from Iowa that spanned a 10 year period and may be subject to selection bias as diagnosis, treatment and admission procedures changed during this time span. In general, subjects were enrolled in our study between 2–4 weeks after birth. Therefore, infants with RDS that died before enrollment were not captured in our cohort. The strength of our study was the ability to test multiple SNPs from genes previously shown to associate with RDS or BPD using both family-based and case-control analyses. Few studies have utilized both study designs to detect associations with neonatal complications. We verified that the associations observed with the family data were not surrogates for associations with PTB itself as there was no association with PTB for any of the significantly-associated markers when the full sample (RDS and BPD cases and controls; n=433) was analyzed. We directly replicated a previous association between SFTPD and RDS and pseudo-replicated associations in SFTPD and ACE with BPD. These results give further insight into the genetic risk factors for complex neonatal respiratory diseases and provide more evidence of the importance of SFTPD and ACE in the etiology of RDS and BPD.

Supplementary Material

Supplemental Figure 1

Single locus and haplotype associations with RDS and BPD. Each gene is represented by a solid line and SNPs within exons are represented by a box. Dotted lines represent SNPs outside the gene or in the promoter region. The 3′ end of the gene is represented by an arrow. R2 values are given in each box and shading indicates the strength of LD determined by the 95% confidence bounds of D′. White shading indicates strong evidence for recombination, light grey indicates lack of information to determine the strength of LD and dark grey indicates strong LD.

Tables

Acknowledgements

We would like to express our thanks to all the participating families in our study. We would also like to express our gratitude to the coordinating medical and research staff at the University of Iowa Children's Hospital in Iowa City, IA; including a special thanks to research coordinators Susan Berends and Laura Knosp. Additionally, we would like to thank the research technician involved in genotyping and sample management including Tamara Busch and students Rim Halaby and Jad al Danaf. This work was supported by the of Dimes (grants 1-FY05-126 and 6-FY08-260) and the NIH (grants R01 HD-52953 and R01 HD-57192). Dr. Ryckman's postdoctoral fellowship was supported by a NIH/NRSA T-32 training grant (5T32 HL 007638-24).

This work was supported by the March of Dimes (grants 1-FY05-126 and 6-FY08-260) and the NIH (grants R01 HD-52953 and R01 HD-57192). Dr. Ryckman's postdoctoral fellowship was supported by a NIH/NRSA T-32 training grant (5T32 HL 007638-24).

Footnotes

Conflicts of Interest: There are no conflicts of interest to disclose.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Figure 1

Single locus and haplotype associations with RDS and BPD. Each gene is represented by a solid line and SNPs within exons are represented by a box. Dotted lines represent SNPs outside the gene or in the promoter region. The 3′ end of the gene is represented by an arrow. R2 values are given in each box and shading indicates the strength of LD determined by the 95% confidence bounds of D′. White shading indicates strong evidence for recombination, light grey indicates lack of information to determine the strength of LD and dark grey indicates strong LD.

NIHMS379178-supplement-Figure.png (391.2KB, png)
Tables
NIHMS379178-supplement-Tables.doc (478.5KB, doc)

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