Glutathione S-transferase genotypes modify lung function decline in the general population: SAPALDIA cohort study

Imboden, Medea; Downs, Sara H; Senn, Oliver; Matyas, Gabor; Brändli, Otto; Russi, Erich W; Schindler, Christian; Ackermann-Liebrich, Ursula; Berger, Wolfgang; Probst-Hensch, Nicole M

doi:10.1186/1465-9921-8-2

Respiratory Research

Table 4 Adjusted* associations of GST genotypes† with excess annual decline in FEV1, FVC and FEF_25–75 stratified by smoking status and sex, the SAPALDIA Cohort.

From: Glutathione S-transferase genotypes modify lung function decline in the general population: SAPALDIA cohort study

MEN	Difference in mean annual change in lung function (ml/yr) ‡
	FEV1 (ml/yr)				FVC (ml/yr)				FEF _25–75 (ml/yr)
Male Never Smokers	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §
GSTT1 non-null	750	---		---	731	---		---	723	---		---
GSTT1 null	154	-5.6	-10.6, -0.7	0.025¶	150	-1.0	-7.8, 5.7	0.76	148	-8.5	-19.0, 1.9	0.11
GSTM1 non-null	432	---		---	424	---		---	420	---		---
GSTM1 null	472	-2.4	-6.1, 1.4	0.22	457	-1.8	-6.8, 3.3	0.50	451	-4.4	-12.3, 3.5	0.27
GSTP1 105 Ile/Ile	433	---		---	426	---		---	420	---		---
GSTP1 105 Ile/Val	389	-0.2	-4.2, 3.7	0.90	377	-0.1	-5.5, 5.2	0.96	375	-4.3	-12.5, 4.0	0.31
GSTP1 105 Val/Val	82	-2.0	-8.8, 4.7	0.56	78	-5.9	-15.1, 3.3	0.21	76	-4.5	-18.9, 9.9	0.54
GSTM1T1 both non-null	351	---		---	344	---		---	342	---		---
GSTM1T1 either null	480	-2.2	-6.2, 1.7	---	467	0.9	-4.4, 6.3	---	459	-4.8	-13.1, 3.5	---
GSTM1T1 both null	73	-9.7	-16.9, -2.5	0.029¶	70	-7.1	-16.9, 2.7	0.26	70	-14.4	-29.6, 0.78	0.15
	FEV1 (ml/yr)				FVC (ml/yr)				FEF25–75 (ml/yr)
Male Persistent Smokers	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §
GSTT1 non-null	428	---		---	417	---		---	410	---		---
GSTT1 null	111	-8.0	-14.2, -1.7	0.013¶	109	-9.3	-17.6, -1.1	0.027¶	106	-3.7	-16.9, 9.5	0.58
GSTM1 non-null	256	---		---	249	---		---	244	---		---
GSTM1 null	283	-4.2	-9.3, 1.0	0.11	277	-4.1	-10.8, 2.7	0.24	272	-6.1	-16.9, 4.7	0.27
GSTP1 105 Ile/Ile	258	---		---	252	---		---	246	---		---
GSTP1 105 Ile/Val	228	0.2	-5.3, 5.6	0.95	222	-4.6	-11.7, 2.5	0.20	218	4.7	-6.6, 16.0	0.41
GSTP1 105 Val/Val	53	-1.0	-10.0, 7.9	0.82	52	-1.0	-12.7, 10.7	0.87	52	-4.7	-23.1, 13.7	0.62
GSTM1T1 both non-null	207	---		---	200	---		---	197	---		---
GSTM1T1 either null	270	-4.9	-10.4, 0.5	---	266	-6.6	-13.8, 0.6	---	260	-5.8	-17.3, 5.7	---
GSTM1T1 both null	62	-11.5	-20.1, -2.9	0.022¶	60	-11.5	-22.8, -0.2	0.072	59	-9.3	-27.3, 8.8	0.48
*GenotypePackyears Interaction** ††
GSTT1*during follow-up				0.029¶				0.67				0.89
GSTT1*up to baseline				0.001¶				0.02¶				0.41
GSTM1*during follow-up				0.50				0.30				0.33
GSTM1*up to baseline				0.39				0.70				0.83
GSTP1*during follow-up				0.96				0.37				0.65
GSTP1*up to baseline				0.31				0.84				0.32
GSTM1T1*during follow-up				0.75				0.11				0.40
GSTM1T1*up to baseline				0.31				0.34				0.88
WOMEN	Difference in mean annual change in lung function (ml/yr) ‡
	FEV1 (ml/yr)				FVC (ml/yr)				FEF25–75 (ml/yr)
Female Never Smokers	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §
GSTT1 non-null	1091	---		---	1072	---		---	1053	---		---
GSTT1 null	263	-0.7	-3.6, 2.3	0.66	260	-1.7	-5.7, 2.3	0.40	256	0.5	-6.2, 7.2	0.88
GSTM1 non-null	629	---		---	617	---		---	607	---		---
GSTM1 null	725	0.5	-1.8, 2.8	0.67	715	0.9	-2.2, 4.1	0.56	702	-0.7	-6.0, 4.6	0.79
GSTP1105Ile/Ile	644	---		---	631	---		---	621	---		---
GSTP1105Ile/Val	582	-1.2	-3.6, 1.2	0.32	575	-1.4	-4.7, 1.9	0.41	564	-2.5	-8.0, 3.1	0.38
GSTP1105Val/Val	128	-0.8	-4.9, 3.3	0.69	126	0.3	-5.3, 5.9	0.91	124	1.0	-8.5, 10.4	0.84
GSTM1T1 both non-null	506	---		---	496	---		---	488	---		---
GSTM1T1 either null	708	-1.5	-3.9, 1.0	---	697	-0.6	-4.0, 2.7	---	684	-3.8	-9.5, 1.9	---
GSTM1T1 both null	140	1.8	-2.3, 5.9	0.20	139	0.44	-5.1, 6.0	0.89	137	3.3	-5.9, 12.6	0.19
	FEV1 (ml/yr)				FVC (ml/yr)				FEF25–75 (ml/yr)
Female Persistent Smokers	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §	n	Coeff.	95%CI	p-value §
GSTT1 non-null	428	---		---	385	---		---	376	---		---
GSTT1 null	111	4.8	-0.3, 9.8	0.065	92	3.5	-3.1, 10.2	0.30	92	12.7	1.7, 23.6	0.029¶
GSTM1 non-null	256	---		---	230	---		---	227	---		---
GSTM1 null	283	1.2	-2.9, 5.2	0.57	247	1.8	-3.6, 7.1	0.51	241	-0.5	-9.4, 8.3	0.91
GSTP1 105 Ile/Ile	258	---		---	227	---		---	223	---		---
GSTP1 105 Ile/Val	228	1.9	-2.3, 6.0	0.38	214	6.0	0.6, 11.5	0.03¶	210	-2.1	-11.1, 7.0	0.66
GSTP1 105 Val/Val	53	4.3	-3.4, 12.1	0.27	36	3.0	-7.2, 13.3	0.56	35	10.5	-6.5, 27.5	0.23
GSTM1T1 both non-null	207	---		---	194	---		---	191	---		---
GSTM1T1 either null	270	3.2	-1.1, 7.4	---	227	1.5	-4.1, 7.2	---	221	5.8	-3.6, 15.1	---
GSTM1T1 both null	62	4.0	-2.7, 10.7	0.27	56	5.3	-3.5, 14.1	0.50	56	7.4	-7.1, 21.8	0.40
*GenotypePackyears Interaction** ††				Persistent				Persistent				Persistent
GSTT1*during follow-up				0.23				0.75				0.09¶
GSTT1*up to baseline				0.20				0.52				0.19
GSTM1*during follow-up				0.79				0.58				0.44
GSTM1*up to baseline				0.69				0.72				0.58
GSTP1*during follow-up				0.33				0.065				0.50
GSTP1*up to baseline				0.80				0.41				0.44
GSTM1T1*during follow-up				0.67				0.82				0.81
GSTM1T1*up to baseline				0.68				0.88				0.82

* The effects of GST genotypes are adjusted for the respective baseline lung function parameter, smoking status at baseline and follow-up, pack-years smoked at baseline and during follow-up, height, weight change between surveys, study area, gas and dust exposure at baseline and education level.
† GSTM1 and GSTT1 genotypes were dichotomized into absence vs. presence of homozygous gene deletions (non-null vs. null). The effect of the GSTP1 genotype on lung function change was investigated in a co-dominant genetic model with the Ile/Ile genotype as the reference group. The combined GSTM1 /GSTT1 genotype (GSTM1T1) was coded as "presence of zero, one and two homozygous gene deletion polymorphisms" and included as ordinal variable in the linear regression model.
‡ Change in lung function parameter represented the difference between lung function parameter measured at follow-up [ml] and the one measured at baseline [ml] divided by the duration of follow-up period [yr]. Coefficient values below zero correspond to an excess decline in lung function [ml/yr] compared to the decline in the reference group and coefficient values above zero correspond to a less steep decline in lung function compared of the reference group.
§Uncorrected P-values for differences between categories. Bonferroni corrected significance level for multiple comparisons: P < 0.0017.
ll Interaction between pack-years and genotype in smokers was assessed by including interaction terms in the models. Cumulative cigarette smoking exposure was summarized in two separate variables: "pack-years smoked up to baseline" and "pack-years smoked during follow-up".
¶Statisically significant (uncorrected P-value > 0.05).

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