The effect of occupational farming on lung function development in young adults: a 15-year follow-up study.

OBJECTIVES: Longitudinal studies on the effect of farming on lung function in young participants are few. Our objective was to explore if exposure to farming impaired lung function in young adults. METHODS: We studied 1964 farming students and 407 controls in 1992/2004, and carried out follow-up in 2007/2008. Spirometry, skin prick test and bronchial hyper-responsiveness (BHR) were assessed, height and weight measured, and questionnaires covering health and occupation were collected. Cumulative dust and endotoxin exposures were estimated from modelled personal dust measurements. Lung function effect was expressed as change in z-score during follow-up using the Global Lung Initiative 2012 project prediction equations. Longitudinal data were available for 1134 young participants ≤25 years at baseline. RESULTS: We found no differences in lung function Δz-scores between farmers and controls, however, adjusted multivariable linear regression showed a negative effect among current farmers on ΔzFEV1 (forced expiratory volume in 1 s; -0.12, p=0.006) and ΔzFEV1/FVC (forced vital capacity; -0.15, p=0.009) compared to ex-farmers. An interaction was found between sex and farming, showing that current farming suppresses ΔzFEV1 and ΔzFVC more among females. Smoking in farmers had a deleterious effect on ΔzFEV1, which was not seen in controls, though no significant interaction was found. Farm upbringing protected against impairment of lung function, and BHR at baseline had a deleterious effect on ΔzFEV1 only in those not raised on a farm. CONCLUSIONS: We conclude that being a current farmer is associated with a negative effect on lung function, when compared to ex-farmers, with females being more susceptible. Being raised on a farm protects against the adverse effect of BHR on change in lung function.

B3GAT3-related linkeropathy and an in-frame homozygous deletion in an adult patient.

BACKGROUND: Proteoglycans (PGs) are complex macromolecules consisting of a core protein and glycosaminoglycan (GAG) side chains. PGs are important for the constitution and functioning of the connective tissue. The normal composition of the GAG side chains defines the nature of the PGs and a wide range of biological events. Deficiencies of specific enzymes involved in the linkage of GAGs to the core protein to form functional PGs, lead to a heterogeneous disease group called Linkeropathies. This is a group of multisystem conditions characterized by different phenotypes that include skeletal dysplasia and various extra-skeletal features: developmental delay/intellectual disability, ophthalmological abnormalities including blue sclerae, facial characteristics, cardiac defects, abdominal wall defects (hernias), cutis laxa, hypermobility and hypotonia. The conditions show variable severity and often overlapping phenotypes. The enzyme ß-1,3-glucuronyltransferase 3, encoded by B3GAT3, is involved in the linkage process to form functional PGs. Biallelic pathogenic variants in B3GAT3 hence lead to Linkeropathy due to loss of function or decreased activity of this enzyme. PATIENT PRESENTATION: We describe a 22-year-old female patient, born of consanguineous parents. The disease history includes congenital severe joint malalignment of elbows, hips, knees and feet, hypermobility, severe kyphoscoliosis, osteoporosis with multiple fractures in childhood, congenital diaphragmatic hernia, minor dental anomalies, digital malformations, and characteristic facial features. Whole exome sequencing was performed, and homozygosity for a novel in-frame deletion in B3GAT3, (c.61_63delCTC (p.(Leu21del))) was detected. Both unaffected parents (double second cousins) were shown to be heterozygous carriers. CONCLUSION: This is the first report to describe homozygosity for this specific in-frame deletion in B3GAT3 (p.(Leu21del)). We present a young adult phenotype and a summary of previous reported patients with other biallelic B3GAT3-variants for comparison. Previously described patients of B3GAT3-deficiency were, however, all children with phenotypes ranging from prenatal manifestation and early lethality to less severe. We suggest that this novel homozygous in-frame deletion in B3GAT3 may be the cause of a recessive form of Linkeropathy.

New-onset COPD and Decline in Lung Function Among Wood Dust-Exposed Workers: Re-analysis of a 6-year Follow-up Study.

Objectives: There is a lack of longitudinal studies exploring the association between organic wood dust exposure and new-onset chronic obstructive pulmonary disease (COPD) and change in lung function. We have re-investigated these associations in a 6-year follow-up cohort of furniture workers exposed to wood dust using improved outcome measures and methods. Methods: A large follow-up study of 1112 woodworkers (63%) from the Danish furniture industry and 235 controls (57%) was conducted between 1998 and 2004. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and the ratio (FEV1/FVC) standardized for age, height, and sex using the Global Lung Function Initiative 2012 equations were assessed at baseline and follow-up. Questionnaires on respiratory symptoms, wood dust exposure, and smoking habits were collected. Exposure was assessed as exposure level at baseline and as cumulative exposure in the follow-up period from quantitative task specific job exposure matrix available at both baseline and follow-up based on personal dust sampling using passive dust monitors. The association between exposure to wood dust and new-onset COPD was assessed with logistic regression, whereas the association between wood dust and the longitudinal change in z-score for lung function was assessed with linear regression. Results: Similar associations were seen for different exposure metrics. An exposure-response relation was seen for new-onset COPD for female smokers with an odds ratio (OR) (95% confidence interval [CI]) of 8.47 (0.9-82.4) in the highest exposed group compared to controls, and a significant test for trend P = 0.049. No such association was seen among males for whom only smoking was strongly associated to new-onset COPD. For change in lung function, a significant exposure-response was seen for females, confirming previous findings, with increasing levels of wood dust exposure showing larger decline in lung function (ß [95% CI]: -0.32 ΔzFEV1 (-0.56 to -0.08, P = 0.009) for third quartile exposure compared to controls, test for trend, P = 0.005, equivalent to an excess loss of 125 ml in the 6 years of follow-up). An opposite association was seen for men. Conclusion: In conclusion, we found that female woodworkers have a dose-dependent increased OR of new-onset COPD and an excess decline in lung function suggesting that female woodworkers may be more susceptible to wood dust exposure than male woodworkers. Among male woodworkers, only smoking and asthma were significant predictors for new-onset COPD and excess decline in lung function. These results emphasize that reduction in both smoking and wood dust exposure should continuously be an effort to prevent adverse pulmonary health effects.

Lung function discordance in monozygotic twins and associated differences in blood DNA methylation.

Background: Lung function is an important predictor of morbidity and mortality, with accelerated lung function decline reported to have immense consequences for the world's healthcare systems. The lung function decline across individual's lifetime is a consequence of age-related changes in lung anatomical structure and combination of various environmental factors; however, the exact molecular mechanisms contributing to this decline are not fully understood. DNA methylation is an epigenetic modification that changes across individual's lifetime, as well as allows for interplay between environmental and genetic factors. DNA methylation plays a crucial role in regulation of gene expression, with increasing evidence linking aberrant DNA methylation levels with a number of common human diseases. In this study, we investigated possible associations between genome-wide DNA methylation levels and lung function in 169 pairs of middle-aged monozygotic twins (86 male pairs: mean age (min-max) = 66 years (57-79); 83 female pairs: mean age (min-max) = 66 years (56-78)). The twins were collected from the Danish Twin Registry and were examined at baseline (1998-1999) and follow-up (2008-2011) visits. Using the twin design, we correlated intra-pair differences in cross-sectional and longitudinal lung function with intra-pair blood DNA methylation differences at follow-up by linear regression analyses adjusted for sex, age, BMI, smoking, and blood cell composition measured for each individual with the use of flow cytometry. Results: We identified several differentially methylated CpG sites associated with forced expiratory volume the first second (FEV1) and forced vital capacity (FVC). Three probes identified for level of FVC were located in GLIPR1L2 gene (lowest p value = 7.14 × 10-8), involved in innate immunity and tumour-suppressor/pro-oncogenic mechanisms. Change in FEV1 during the 11-year follow-up period was associated with blood DNA methylation level in TRIM27 gene (p value = 1.55 × 10-6), a negative regulator of CD4 T cells, and also involved in cancer development. Several enriched pathways were identified, especially for FEV1, with one being "TGFBR" (Benjamini-Hochbergadjp value = 0.045), the receptor for TGFß, a growth factor involved in normal lung tissue repair through pro-fibrotic effects. Conclusions: Our findings suggest that epigenetic regulation of immunological- and cancer-related genes, as well as TGF-ß-receptor-related genes, may be involved in the cross-sectional level and longitudinal change in lung function in middle-aged monozygotic twins.