SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility-A Joint Analysis in Four European Populations.

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren's syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E-07, OR = 1.9) and eight with Löfgren's syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E-12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression.

ACE gene variants and sarcoidosis in a Finnish population.

Background: Sarcoidosis is a systemic inflammatory disease with unknown etiology. However, there is a strong evidence of genetic influence in sarcoidosis. Objectives: We wanted to extend our knowledge of the role of the whole ACE gene, not only insertion/deletion (I/D) polymorphism, in a Finnish sarcoidosis population by genotyping the ACE gene region from 5' upstream to the 3' downstream. Methods: We genotyped 29 single nucleotide polymorphisms (SNPs) spanning the ACE gene from 188 sarcoidosis patients (resolved disease, n=90; persistent disease, n=98) and from 150 controls. These SNPs included tag SNP rs4343 for I/D polymorphism. To replicate the study we genotyped 11 of these SNPs from 139 Czech sarcoidosis patients (resolved disease, n=47; persistent disease, n=92) and 176 healthy controls. Results: No association was detected between I/D genotypes and disease susceptibility or prognosis. We found a novel SNP (rs9905945) in the 5'upstream region of the ACE gene to be moderately associated with favourable disease prognosis in Finnish patients [p=0.035, OR=2.034 (95%CI 1.045-3.960)]. However, in the replication study in Czechs, the SNP rs9905945 did not show association with prognosis of sarcoidosis. Conclusions: This study further characterizes genetic distinctions between Finnish sarcoidosis patients with different prognosis and population-specific genotype distribution of ACE variants. Nevertheless it seems that variants in the ACE gene do not considerably influence the course of the disease in Finnish sarcoidosis patients. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 104-114).

No change in prevalence of symptoms of COPD between 1996 and 2006 in Finnish adults - a report from the FinEsS Helsinki Study.

BACKGROUND: The age-dependent increase of chronic obstructive pulmonary disease (COPD) prevalence caused by smoking and other inhalational exposures in the general population is well-known worldwide. However, time trends are poorly known, due to lower number of high-quality studies especially following nationwide efforts on diminishing exposure levels. This study aimed to compare the prevalence of COPD symptoms and their major determinants in Finnish adults in 1996 and 2006. METHODS: Two identical postal surveys were conducted among two random population samples from Helsinki using identical methodologies in 1996 and 2006, with 6,062 (76%) and 2,449 (62%) participants, respectively. RESULTS: The physician-diagnoses of COPD remained at 3.7%, whereas physician-diagnoses of asthma and use of asthma medicines increased in both genders. Current smoking reduced from 33.4 to 27.3% (p<0.001), and the amount of cigarettes smoked also reduced significantly. The crude prevalence of chronic productive cough was 12.1 and 11.1%, wheezing with dyspnoea without a cold (wheezing triad) 7.3 and 7.7%, and dyspnoea grade II 13.8 and 13.6%, in 1996 and 2006, respectively. Among subjects with physician-diagnosed COPD, the prevalences of chronic productive cough and recurrent wheeze reduced significantly, from 60.6 to 40.7% and 53.5 to 38.5%, respectively. CONCLUSION: From 1996 to 2006, the prevalence of obstructive airway symptoms common in different phenotypes of COPD did not increase in Finnish adults. This suggests that the upward trend of COPD prevalence might have reached a plateau. Current smoking and the quantities smoked diminished suggesting a wider impact of stronger legislation and smoking-cessation efforts during the Finnish National Programme for COPD.

Proteomic changes of alveolar lining fluid in illnesses associated with exposure to inhaled non-infectious microbial particles.

BACKGROUND: Hyperresponsiveness to inhaled non-infectious microbial particles (NIMPs) has been associated with illnesses in the airways. Hypersensitivity pneumonitis (HP) is considered to be the prototype for these NIMPs-related diseases; however, there is no consensus on the definitions or diagnostic criteria for HP and the spectrum of related illnesses. METHODS AND FINDINGS: In order to identify the possible diagnostic markers for illnesses associated with NIMPs in alveolar lining fluid, we performed a proteomic analysis using a two-dimensional difference gel electrophoresis on bronchoalveolar lavage (BAL) fluid from patients with exposure to NIMPs in the context of damp building-related illness (DBRI) or conditions on the borderline to acute HP, designated here as agricultural type of microbial exposure (AME). Samples from patients with HP and sarcoidosis (SARC) were included for reference. Results were compared to results of healthy subjects (CTR). Western blot was used for validation of potential marker proteins from BAL fluid and plasma. Protein expression patterns suggest a close similarity between AME and HP, while DBRI was similar to CTR. However, in DBRI the levels of the inflammation associated molecules galectin-3 and alpha-1-antitrypsin were increased. A novel finding emerging from this study was the increases of semenogelin levels in BAL fluid from patients with AME, HP and SARC. Histone 4 levels were increased in AME, HP and SARC. Elevated plasma levels of histone 2B were detected in HP and SARC, suggesting it to be a potential blood indicator for inflammatory diseases of the lungs. CONCLUSIONS: In this study, the proteomic changes in bronchoalveolar lavage of DBRI patients were distinct from other NIMP exposure associated lung diseases, while changes in AME overlapped those observed for HP patient samples. Some of the proteins identified in this study, semenogelin and histone 4, could function as diagnostic markers for differential diagnosis between DBRI and HP-like conditions.

Increase in prevalence of physician-diagnosed asthma in Helsinki during the Finnish Asthma Programme: improved recognition of asthma in primary care? A cross-sectional cohort study.

BACKGROUND: The continuing rise in asthma prevalence has been questioned, with recent reports suggesting a plateau. AIMS: To assess a 10-year trend in the age-adjusted prevalence of physician-diagnosed asthma, respiratory and allergic symptoms, and use of asthma medication in the adult population of Helsinki during the Finnish Asthma Programme from 1994 to 2004. METHODS: Two cross-sectional postal surveys were conducted among random Finnish National Population Registry samples 10 years apart using the same protocol. A total of 6,062 subjects (75.9%) and 2,449 subjects (61.9%) participated in 1996 and 2006, respectively. RESULTS: The prevalence of physician-diagnosed asthma increased from 6.5% in 1996 to 10.0% in 2006 (p<0.001). This was evident in both genders aged <60 years, but particularly in women aged <40 years, paralleling an increased use of asthma medication. Concurrently, the prevalence of allergic rhinoconjunctivitis increased from 37.2% to 44.4% (p<0.001). The prevalence of physician-diagnosed chronic obstructive pulmonary disease remained unchanged (3.7%), while current smoking abated. Subjects with a smoking history had more respiratory symptoms (p<0.001). Among subjects without physician-diagnosed asthma, those reporting allergic rhinoconjunctivitis had a higher prevalence of lower respiratory tract symptoms. CONCLUSIONS: The prevalence of allergic rhinoconjunctivitis and physician-diagnosed asthma has increased in Helsinki during 10 years in adults, especially in women aged <40 years. Concomitantly, the use of asthma medication increased and subjects with physiciandiagnosed asthma were less symptomatic. The increase in the prevalence of physician-diagnosed asthma may partly be due to improved diagnostic recognition of asthma in primary care during the Finnish Asthma Programme, but the concurrent rise in allergic rhinoconjunctivitis may reflect a true rise in prevalence.

HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis.

Sarcoidosis is a multiorgan immune-mediated disease of unknown etiology with varying clinical pictures. We studied 3 genes in the major histocompatibility complex region (HLA-DRB1 and complement C4A and C4B) in patients with resolved disease after a 2-year follow-up (n = 90) and in patients whose disease was still active at that time point (n = 98) and compared them with controls (n = 150). Our primary aim was to detect genetic differences between the patient groups. We observed that the susceptibility allele for sarcoidosis was HLA-DRB1*15:01 (p = 0.011; odds ratio [OR] = 1.67) and the protective allele was HLA-DRB1*01:01 (p = 0.001; OR = 0.43). HLA-DRB1*03:01 was associated with resolving disease when compared with the persistent group (p = 0.011; OR = 2.22). The probability of having resolving disease was even greater if the patient had HLA-DRB1*03:01 and did not have extrapulmonary lesions (p = 0.001; OR = 3.39). By evaluating amino acid variants of the HLA-DRB1 gene, we determined that specific amino acids in pockets 4, 7, and 9 were associated with the prognosis of sarcoidosis. Our results support the importance of HLA-DRB1 as a predisposing gene for sarcoidosis. Particularly, HLA-DRB1*03:01 and polymorphisms of DRB1 pocket residues were associated with a favorable prognosis. Thus, accurate categorization of disease phenotype and HLA-DRB1 sequencing offer a basis for disease course estimation of sarcoidosis.

Use of spirometry and recording of smoking habits of COPD patients increased in primary health care during national COPD programme.

BACKGROUND: In Finland, a national programme for COPD prevention and treatment was developed in 1998. The main goals of the programme were to diagnose COPD as early as possible and to encourage people to quit smoking. The role of primary health care was emphasized in the programme. Our aim was to investigate the use of spirometry and recording of smoking habits of COPD patients in primary health care before and during the COPD programme. METHODS: We compared patients with respiratory symptoms or diseases visiting primary health care during 1997 (before programme) and 2002 (during programme). Patients with respiratory symptoms were divided into two groups: COPD patients and "others". Patient records were thoroughly investigated and data retrieved from them. RESULTS: There was a significant increase in the whole study group from 8.0% to 38.9% in the use of spirometry (p < 0.001). This increase was significant both in the COPD group (from 32.0% to 79.6%, p < 0.001) and "others" (from 5.6% to 32.8%, p < 0.001). Written information on smoking habits in patient records increased from 16.6% of all patients in 1997 to 53.2% in 2002 (p < 0.001), and in COPD group from 45.0% to 84.3% (p < 0.001). CONCLUSIONS: We observed a significant increase in the use of spirometry and knowledge of smoking habits in COPD patients, which may be a result of the Finnish national COPD programme.

The 10-year COPD Programme in Finland: effects on quality of diagnosis, smoking, prevalence, hospital admissions and mortality.

BACKGROUND: The Finnish National Programme for Chronic Bronchitis and Chronic Obstructive Pulmonary Disease (COPD) 1998-2007 was set up to reduce the prevalence of COPD, improve COPD diagnosis and care, reduce the number of moderate to severe cases of the disease, and reduce hospitalisations and treatment costs due to COPD. Over 900 events for 25,000 participating healthcare workers were arranged. The major strengths of this programme included multidisciplinary strategies and web-based guidelines in nearly all primary health care centres around the country. METHODS: Data from national registries, epidemiological studies and questionnaires were used to measure whether the goals had been reached. RESULTS: The prevalence of COPD remained unchanged. Smoking decreased in males from 30% to 26% (p<0.001) and in females from 20% to 17% (p<0.001). Significant improvements in the quality of spirometry were obtained. Hospitalisation decreased by 39.7% (p<0.001). COPD costs were 88% lower than had been anticipated from earlier investigations. No increase in COPD mortality was observed. CONCLUSIONS: In combination with other efforts, the Finnish 10-year COPD Programme had significant positive consequences: no further increases in COPD prevalence, reduced smoking prevalence, improved quality of diagnosis, and reduction in COPD-related hospitalisations.

The quality of spirometric examinations in Finland: results from a national questionnaire survey.

National treatment programmes for asthma and chronic obstructive pulmonary disease (COPD) have in the past few years increased the need for spirometry in Finland. The purpose of this study was to determine, by means of a national questionnaire survey, the quality and number of spirometric examinations performed in Finland in 1998, the year when the national COPD programme was initiated. We estimated that 395 000-425 000 spirometric examinations were performed in Finland in 1998. The mean quality of spirometry was evaluated as moderate, and the quality index developed for this study indicated an average of scores of 67 (max 100), ranging between 43 and 88 in the whole country. The most common qualitative insufficiencies in spirometric examinations were found in preparation of the subject for the examination, performance of the examination, recognition of a successful spirometric curve and evaluation of reproducibility of the examination. Furthermore, the time reserved in the reports for performing the examination was often very short. However, in comparison with the previous questionnaire survey in Finland (in 1990), the quality of spirometry had markedly improved.

Early treatment of stage II sarcoidosis improves 5-year pulmonary function.

STUDY OBJECTIVE: To evaluate the 5-year prognosis of patients with stage I and stage II newly detected (< 3 months) pulmonary sarcoidosis treated immediately after diagnosis with prednisolone for 3 months followed by inhaled budesonide for 15 months. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study for 18 months. Thereafter, open follow-up without treatment. SETTING: Twenty pulmonary medicine departments in Finland. PATIENTS: One hundred eighty-nine adult patients, most of them with normal lung function, were randomized to treatment. One hundred forty-nine patients were followed up for 5 years: 79 patients with initial stage I disease and 70 patients with stage II disease. TREATMENT: Oral prednisolone for 3 months followed by inhaled budesonide for 15 months (800 microg bid), or placebo tablets followed by placebo inhaler therapy. Thereafter, treatment only on an individual basis in the case of clinical deterioration. MEASUREMENTS: Yearly follow-up visits with chest radiographs, lung function tests (FEV(1), FVC), diffusion capacity of the lung for carbon monoxide (DLCO), serum angiotensin-converting enzyme (SACE), and serum and urinary calcium measurements. RESULTS: No initial differences were observed in chest radiographic findings between the active-treatment and placebo-treatment groups, either in patients with initial stage I or stage II(-III) disease. However, after the 5-year follow-up, 18 steroid-treated patients (26%) and 30 placebo-treated patients (38%) still had remaining chest radiographic changes. Placebo-treated patients more frequently required treatment with corticosteroids during the 5-year follow-up (p < 0.05). Steroid-treated patients with initial stage II(-III) disease improved more in FVC and DLCO (p < 0.05). No differences in reported adverse events or in SACE, serum calcium, or urinary calcium values were seen. CONCLUSION: Immediate treatment of pulmonary stage II(-III) sarcoidosis-but not stage I disease-improved the 5-year prognosis with regard to lung function variables.