Association between AXL promoter methylation and lung function growth during adolescence

Figures & data

Table 1. Characteristics of participants with lung function testing.

	Primary study population (N = 923)	Replication population (N = 237)	P-value^a
Male sex, n (%)	431 (46.7)	99 (41.8)	0.17
Ethnicity, n (%)			0.0002
Hispanic	385 (41.7)	131 (55.3)
Non-Hispanic white	427 (46.3)	76 (32.1)
Asian/Black/Other	111 (12.0)	30 (12.7)
Parental Education, n (%)			0.11
High school or less	272 (30.4)	73 (33.0)
Some college	395 (44.2)	81 (36.7)
Finished college/some graduate school	227 (25.4)	67 (30.3)
Parental history of asthma at study entry, n (%)	229 (25.8)	31 (13.9)	0.0002
Ever MD-diagnosed asthma at first lung function testing, n (%)	198 (21.5)	35 (14.8)	0.02
In-utero tobacco smoke exposure, n (%)	209 (22.9)	21 (9.0)	< 0.0001
Ever smoked cigarettes by age 15, n (%)	82 (8.9)	10 (4.2)	0.02
Passive tobacco smoke exposure by age 15, n (%)	186 (20.2)	16 (6.8)	< 0.0001
Age (year) at first pulmonary function testing, mean (sd)	10.8 (1.1)	11.4 (0.8)	< 0.0001
Height (cm), mean (sd)
Age 11	148.6 (7.0)	147.8 (7.0)	0.26
Age 13	160.2 (7.8)	159.1 (7.2)	0.12
Age 15	167.3 (8.4)	165.4 (8.2)	0.05
Body mass index (BMI, kg/m^2), mean (sd)
Age 11	20.4 (4.2)	20.4 (4.1)	0.97
Age 13	21.9 (4.8)	21.7 (4.4)	0.68
Age 15	23.3 (4.6)	23.5 (4.5)	0.78

^a P-value for testing the difference between the two populations. Derived from a Pearson’s Chi-squared test for categorical variables and from an unequal variance 2-sample t-test for age, and an equal variance 2-sample t-test for height and BMI.

Figure 1. Genomic locations of AXL CpG sites under investigation.

Solid black box: CpG sites in the promoter region (CpG1-CpG 6); dashed gray box: CpG sites in the gene-body region (CpG 7-CpG 11); dashed black box: CpG site in the 3ʹuntranslated region (CpG 12).Cg number in parenthesis: corresponding CpG locus in HM450 array.

Table 2. Association between lung function growth and AXL promoter methylation stratified by sex in the primary study population (N = 923) and replication population (N = 237)^a.

	Primary study population		Replication population
	Growth from 10 to 18 years of age		Growth from 11 to 15 years of age
Lung function measurement	Coefficient (95% CI)	P value	Coefficient (95% CI)	P value
FEV1 (ml)
Overall	−48.4 (−100.2 to 3.4)	0.07	−53.9 (−104.3 to −3.5)	0.04
By sex
Girls	−33.0 (−94.1 to 28.0)	0.29	−17.5 (−87.8 to 52.8)	0.62
Boys	−69.4 (−139.9 to 1.1)	0.05	−93.6 (−166.1 to −21.1)	0.01
Interaction p-value	0.37		0.14
FVC (ml)
Overall	−61.6 (−117.5 to −5.7)	0.03	−44.6 (−97.2 to 8.1)	0.10
By sex
Girls	−45.0 (−112.3 to 22.3)	0.19	−45.5 (−119.2 to 28.3)	0.22
Boys	−84.0 (−161.9 to −6.0)	0.03	−45.3 (−122.4 to 31.7)	0.25
Interaction p-value	0.40		0.99
MMEF (ml/sec)
Overall	−89.6 (−192.8 to 13.7)	0.09	−166.2 (−278.4 to −54.1)	0.004
By sex
Girls	−75.3 (−194.4 to 43.8)	0.22	−87.0 (−244.6 to 70.5)	0.28
Boys	−110.7 (−249.3 to 28.0)	0.12	−249.7 (−410.5 to −88.9)	0.003
Interaction p-value	0.65		0.16

Figure 2. Mean lung function growth versus the average methylation level of AXL promoter region.

AXL promoter methylation levels were first categorized into equal-sized groups based on deciles. The mean growth in FEV₁, FVC and MMEF from 10 to 18 years of age in the primary study population (Panel A-C) and 11 to 15 years of age in the replication population (Panel D-F) are plotted against the corresponding levels of methylation in each decile. The corresponding coefficients and P-values are shown.FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal midexpiratory flow rate.