Behavioural changes in exposure patterns after genetic counselling among asymptomatic first-degree relatives of patients with pulmonary fibrosis and carriers of a telomere-related gene variant

Extract

Exposure to tobacco and profibrotic agents contributes to pulmonary fibrosis in relatives of patients carrying a telomere-related gene (TRG) variant [1]. Relatives may know their genetic status in cascade testing, and most of them do not report any regrets about having genetic testing performed, whatever the results [2]. We hypothesised that the results of genetic cascade testing induce/trigger behavioural changes regarding environmental exposures. The study aims to describe past and current exposures among relatives of patients carrying a TRG variant, and to compare behaviour changes between carriers and non-carriers after genetic counselling.

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While most relatives of TRG-variant carriers report exposure to inhaled toxics, few make behavioural changes within a year of genetic counselling https://bit.ly/4iEGBBN

To the Editor:

Exposure to tobacco and profibrotic agents contributes to pulmonary fibrosis in relatives of patients carrying a telomere-related gene (TRG) variant [1]. Relatives may know their genetic status in cascade testing, and most of them do not report any regrets about having genetic testing performed, whatever the results [2]. We hypothesised that the results of genetic cascade testing induce/trigger behavioural changes regarding environmental exposures. The study aims to describe past and current exposures among relatives of patients carrying a TRG variant, and to compare behaviour changes between carriers and non-carriers after genetic counselling.

Between June 2021 and December 2024, all relatives of a TRG pathogenic variant carrier referred to the Bichat and Avicenne reference centres for rare pulmonary diseases were invited to complete a self-administered questionnaire about their smoke and environmental exposures between 6 and 12 months after receiving the results of their own genetic analysis [3]. In both centres, as part of genetic counselling, all relatives, received information on risks associated with smoking and other pro-fibrotic exposures. Genetic education was provided similarly at both centres, using standardised booklets [4] and systematically offering digital resources (websites, podcasts) in collaboration with Association Fibroses Pulmonaires France [5]. All subjects signed informed consent. The study was approved by ethics committee (CPP Ile de France 1; 0811760).

The questionnaire assessed exposure to inhaled toxins including smoke (tobacco, cannabis, hookah, electronic cigarettes), profibrotic agents from occupational (silica, asbestos, metal and wood dust) and environmental (birds, mould, fireplaces, living within 200 meters of a major road, handicraft activities) sources. We collected the highest level of education diploma as a socioeconomic indicator.

We described the prevalence of exposures and compared behavioural changes within the year post testing between carriers of TRG variant and non-carriers. Statistical analysis included t-test, Chi-squared, ANOVA, non-parametric univariate test, and a multivariate analysis using logistic regression.

A total of 81 asymptomatic relatives, (32 (40%) men, mean±sd age of 47±18 years) answered the survey; 46 (57%) carried the TRG variant (table 1). 37 (45%) had a university-grade diploma. We identified 11 family clusters consisting of two, or at most three, relatives; the remaining relatives were each uniquely related to their proband with pulmonary fibrosis who carried a TRG variant. These probands (n=68) were either symptomatic 43 (63%) or had passed away 25 (37%). Among 81 asymptomatic relatives, age, sex, university-grade diploma, rate of deceased proband were similar between variant carriers and non-carriers. Only the proportion belonging to a familial cluster differed significantly, being higher among carriers (41% versus 17%, p=0.03). Among overall relatives 71 (88%) reported current or past exposure to at least one inhaled toxic substance. At the time of counselling most TRG variant relatives (61 of 81, 75%) reported at least one harmful exposure.

TABLE 1.

Characteristics of behavioral changes after genetic testing

Proportion of relatives who stopped exposure (6–12 months after testing)	Relatives exposed at the time of genetic testing (n=61 of 81).
Smoking
Tobacco	14/22
Cannabis	10/12
E-cigarette	3/5
Hookah	3/3
Occupational exposure
Wood dust	0/4
Metal dust	0/1
Silica	0/2
Asbestos	0/0
Environmental exposure
Birds	1/10
Domestic mould	3/8
Handicrafts	0/14
Fireplaces	0/11
Air pollution#	0/22

Behavioural changes after genetic testing	Stopped ≥1 exposure n=25	Any exposure n=36	p overall
Mean age, years	51±23	47±16	0.51
Male	15 (60)	11 (31)	0.04*
University diploma	10 (40)	18 (50)	0.61
Carrier of TRG variant	16 (64)	20 (56)	0.69
Deceased proband	7 (50)	12 (52)	0.90
Part of a familial cluster	8 (32)	12 (33)	0.92
Active smoker ¶	16 (64)	6 (17)	0.001*
Mean number of exposures ¶	2.3±1.1	2.6±1.5	0.35

Data are presented as number stopping/number exposed at baseline, mean±sd or n (%), unless otherwise stated. TRG: telomere-related gene. ^#: Living <200 m from a major road. ^¶: At the time of genetic testing. *: p<0.05.

Tobacco smoke history was reported by 36 (45%) relatives, with a mean of 12±10 pack-years, and a mean of 14±15 cigarettes per day. Cannabis (12, including two current users), hookah (three, none current) and e-cigarette use (five, two current) were less frequent. Passive tobacco exposure was declared by in 38 (47%) relatives (three current).

Occupational exposures were reported by 11 (14%) relatives: wood dust (four current), metal dust (one current), asbestos (five, none current) and crystalline silica (two current). Environmental exposures were noted in 43 (53%): 10 to birds (nine current), eight to domestic mould (five current), 14 to handicrafts (14 current), and 11 with fireplaces as their primary heating source (11 current). 22 (27%) relatives lived within 200 meters of a major road (22 current). Exposure frequencies did not differ between carriers and non-carriers. The number of cumulated exposures (past or present) per individual ranged from 0 to 6, with a median of two exposures, with no difference between carriers and non-carriers.

Among the 61 relatives exposed at the time of counselling, 25 (41%) reported at least one behavioural change after genetic counselling (table 1). Changes were most frequent among active smokers (14 of 22 64%), cannabis users (10 of 12), e-cigarette users (3 of 5) and hookah users (3 of 3). Other behavioural changes were observed in a minority of relatives (4 of 18, 22%), fewer modified birds (1 of 10) or domestic mould (3 of 8) exposure, without influence between carriers and non-carriers. No changes were reported for occupational, handicrafts, or major road proximity exposures.

Behavioural change frequency was higher in men than in women and active smokers versus non-smokers (table 1). Behavioural change was not associated with age, education level, carrier status of the TRG variant, proband survival status, being part of a familial cluster or total number of exposures. In the multivariate analysis, both male sex and smoking remained significantly associated with behavioural changes, with odds ratios of 3.72 (95% CI 1.08–12.84, p=0.04) and 9.40 (95% CI 2.64–33.52, p<0.001), respectively. At survey time, in absence of behavioural change, 53 (65%) relatives remained exposed, with no difference by variant status.

At the time of counselling most TRG-variant relatives reported at least one harmful exposure. Genetic counselling was associated with tobacco cessation within the first year; while other behavioural changes were infrequent and did not differ between carriers and non-carriers.

First-degree relatives of individuals with familial pulmonary fibrosis (FPF) over the age of 40 have a 14–25% risk of high-resolution computed tomography abnormalities [6]. TRG mutations present in 5–20% of FPF cases, are dominantly inherited but show incomplete penetrance and variable expressivity [6]. Up to 40% of TRG carriers developed pulmonary fibrosis by the age of 51, with environmental exposures further increasing risk [1, 7]. Absence of a TGR variant does not exclude disease, as short telomeres inheritance or the MUC5B allele may also confer risk [8, 9].

Genetic counselling aims to communicate inherited and modifiable risks, as seen in alpha-1 antitrypsin deficiency and hereditary cancers [10, 11]. Our study shows that most FPF relatives are exposed to known risk factors, yet few modify their behaviour, emphasising the need for standardised prevention and education.

Smoking cessation occurred in 14 of 22 (64%) subjects, consistent with other high-risk populations. For comparison, ∼40% of COPD patients continue smoking despite their diagnosis [12]. Active smoking was the only exposure associated with behavioural changes, possibly because it is perceived as more controllable than factors like occupational exposures or air pollution. The rate of active smokers (36%) among relatives matched the general population data in France, but comparisons for other exposures are limited by scarce reference data [13]. 12 months after counselling, eight relatives still smoked, highlighting the need for stronger cessation support, given smoking's known link to pulmonary fibrosis risk [1, 7].

Handicraft and bird exposures persisted, suggesting the need for tailored physician guidance. No significant behavioural changes were observed for occupational or environmental exposures, likely due to practical constraints. These findings align with evidence linking occupational exposure and air pollution to pulmonary fibrosis risk in both the general population [14, 15] and FPF relatives [1].

Behavioural change was independent of carrier status, suggesting awareness of modifier risks regardless of genetic findings. Men were more likely than women to quit smoking, possibly reflecting identification with the affected male proband or gender differences in counselling.

Limitations include reliance on self-reported exposure data and lack of exposure intensity assessment, which may introduce recall bias. The timing of behavioural changes was not recorded. The questionnaire response rate was 100% among relatives followed in our centres, but those who declined genetic testing were not surveyed, leading to selection bias. Behavioural changes occurring after the study period may have been missed. Finally, the small sample size may reduce statistical power.

This study shows that most relatives of TRG variant carriers have at least one harmful respiratory exposure, yet few of them change their behaviour after genetic counselling. Future work should assess how counselling may be followed by long-term modifications in exposures and their effect on fibrosis outcome.