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UKPMC Funders Author Manuscripts logoLink to UKPMC Funders Author Manuscripts
. Author manuscript; available in PMC: 2013 Sep 1.
Published in final edited form as: Eur Respir J. 2013 Mar;41(3):756–757. doi: 10.1183/09031936.00171712

HHIP, HDAC4, NCR3 and RARB polymorphisms affect fetal, childhood and adult lung function

Samuel A Collins 1,2, Jane SA Lucas 1,2, Hazel M Inskip 3,4, Keith M Godfrey 3,4,5, Graham Roberts 1,2,3, John W Holloway 1,3; the Southampton Women’s Survey Study Group4
PMCID: PMC3691629  EMSID: EMS53574  PMID: 23456936

To the Editor;

Impaired lung function, and consequent respiratory morbidity including asthma and chronic obstructive pulmonary disease (COPD), may have their origins in early life[13]. Genome wide analysis studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) in those of European ancestry that affect adult lung function, as measured by FEV1 and FEV1/FVC ratio. 23 of these SNPs have directionally consistent effects on both FEV1 and FEV1/FVC in children and adults[4].

During 1998-2002, the Southampton Women’s Survey (SWS) recruited 12,579 women pre-conception through their general practitioners[5]. By the end of 2003 there had been 1973 babies born to these women, of which 147 had infant lung function measured between 5 and 14 weeks of age, according to previously published protocols[6] using raised volume/rapid compression techniques to measure V’maxFRC, FEV0.4, respiratory rate and compliance. DNA was obtained from cord blood samples or from buccal samples taken at the 6 year follow-up. DNA from these 147 children were analysed for each of the 23 SNPs identified as above. These SNPs are detailed in supplementary table 1.

Linear regression was used to analyse the minor allele count for each SNP (either 0, 1 or 2) against logarithmically transformed and age adjusted values for infant lung compliance, respiratory rate, FEV0.4 and V’maxFRC. Smoking in pregnancy, maternal BMI, social class, birth weight, gestation and crown-rump length were analysed as potential confounding factors. The average n per group (0,1 or 2 minor alleles) across all 23 SNPs was 71, 50 and 9, respectively, giving 80% power to detect a 3.7ml/mmH2O change in compliance per increase in minor allele count.

Five SNPs, relating to four genes, showed significant associations with infant lung function (Table I). Hedgehog interacting protein (HHIP) had one SNP (rs11100860) that was associated with increased compliance (p<0.001) and one (rs1032296) associated with decreased compliance (p<0.05). Retinoic acid receptor β (RARβ) (rs1529672) was associated with increased V’maxFRC (p<0.05), the natural cytotoxicity triggering receptor 3 (NCR3) SNP (rs2857595) was associated with a lower respiratory rate (p<0.05) and the histone deacetylase 4 (HDAC4) SNP (rs12477314) was associated with both increased compliance and V’maxFRC (both p<0.05). Table 1 summarises these findings. These effects were all directionally consistent with the previous GWAS analysis.

Table 1.

Single nucleotide polymorphisms (SNPs) and their target genes showing significant associations with lung function in infants along with the mean values of the relevant parameter according to the minor allele count, n/a indicates there were no subjects with 2 minor alleles. Effect size is shown as beta co-efficient following log transformation and regression, along with associated p value. Histone deacetylase 4 (HDAC4), natural cytotoxic receptor 3 (NCR3), retinoic acid receptor beta (RARβ), hedgehog interacting protein (HHIP).

SNP Gene Minor
Allele
Effect on Infant
Lung Function
Minor
allele
count
Mean Beta p
value
rs12477314
(downstream)
HDAC4 T ↑Compliance 0
1
2
47.4
51.0
58.1
0.07 0.02
rs12477314
(downstream)
HDAC4 T ↑ V’maxFRC 0
1
2
136.3
146.4
233.1
0.18 0.02
rs2857595
(upstream)
NCR3 G ↓RR 0
1
2
46.3
43.0
n/a
−0.06 0.04
rs1529672
(intron)
RARβ C ↑ V’maxFRC 0
1
2
133.1
161.1
n/a
0.20 0.03
rs11100860
(upstream)
HHIP T ↑Compliance 0
1
2
45.2
50.3
51.9
0.08 <0.001
rs1032296
(upstream)
HHIP G ↓ Compliance 0
1
2
51.8
47.5
46.7
−0.06 0.02

HHIP is known to have a role in lung development through fibroblast growth factor 10 (FGF10) and its control of lung branching[7], whilst RARβ regulates lung bud formation and branching through the Wnt pathway[8] with retinoic acid playing a central role in pre- and postnatal lung development in humans[9]. HDAC4 and NCR3 have uncertain roles in lung development, though the former may modulate epigenetic effects on lung function.

Branching of the lung occurs in the pseudoglandular phase and is complete by 16 weeks of gestation[10]; therefore RARβ and HHIP are likely to have their effects in the first trimester. Early branching is the primary determinant of resistance in normal lungs, and therefore compliance. This large airway function is reflected as FEV1 and FEV1/FVC in later life; thus there is a scientifically plausible link between these SNPs and lung function.

As there was a priori evidence of association between these SNPs and lung function, we have not corrected for the number of SNPs and lung function tests. However, even if a Bonferroni correction had been applied (23 SNPs x 4 lung function measurements), the rs11100860 HHIP SNP remains significant. As the original GWAS was in similar populations to our cohort, we feel it reasonable to assume the key SNPs identified may be good proxy markers of the causal locus. It is also possible that we are underpowered to detect significant associations between infant lung function and the other SNPs tested.

We accept that small numbers and multiple testing are limitations; however these results may link early fetal lung development, through infant lung function, to adult lung function and respiratory morbidity in later life. This is an interesting starting point for identification of the mechanisms of fetal origins of lung function.

Supplementary Material

01

Supplementary Table 1. SNP code, target gene, chromosome and minor allele of the 23 analysed SNPs associated with adult lung function and previously showing directionally consistent effects in children. Frequency of major allele (A) and minor allele (a) homozygotes/heterozygotes in our study also shown.

References

  • 1.Håland G, Carlsen KCL, Sandvik L, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med. 2006;355:1682–9. doi: 10.1056/NEJMoa052885. [DOI] [PubMed] [Google Scholar]
  • 2.Stern DA, Morgan WJ, Wright AL, et al. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet. 2007;370:758–64. doi: 10.1016/S0140-6736(07)61379-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Krauss-Etschmann S, Bush A, Bellusci S, et al. Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease. Thorax. 2012:1–6. doi: 10.1136/thoraxjnl-2012-201902. [DOI] [PubMed] [Google Scholar]
  • 4.Artigas MS, Loth DW, Wain LV, et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet. 2011;43:1082–90. doi: 10.1038/ng.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Inskip HM, Godfrey KM, Robinson SM, et al. Cohort profile: The Southampton Women’s Survey. Int J Epidemiol. 2006;35:42–8. doi: 10.1093/ije/dyi202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lucas JS, Inskip HM, Godfrey KM, et al. Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function. Am J Respir Crit Care Med. 2004;170:534–40. doi: 10.1164/rccm.200311-1583OC. [DOI] [PubMed] [Google Scholar]
  • 7.Warburton D, Bellusci S, Del Moral P-M, et al. Growth factor signaling in lung morphogenetic centers: automaticity, stereotypy and symmetry. Respir Res. 2003;4:5. doi: 10.1186/1465-9921-4-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Kam RKT, Deng Y, Chen Y, et al. Retinoic acid synthesis and functions in early embryonic development. Cell Biosci. 2012;2:11. doi: 10.1186/2045-3701-2-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Biesalski HK, Nohr D. Importance of vitamin-A for lung function and development. Mol Aspects Med. 2003;24:431–40. doi: 10.1016/s0098-2997(03)00039-6. [DOI] [PubMed] [Google Scholar]
  • 10.Kitaoka H, Burri PH, Weibel ER. Development of the human fetal airway tree: analysis of the numerical density of airway endtips. Anat Rec. 1996;244:207–13. doi: 10.1002/(SICI)1097-0185(199602)244:2<207::AID-AR8>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

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Supplementary Table 1. SNP code, target gene, chromosome and minor allele of the 23 analysed SNPs associated with adult lung function and previously showing directionally consistent effects in children. Frequency of major allele (A) and minor allele (a) homozygotes/heterozygotes in our study also shown.

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