Gunnar Gudmundsson

A common MUC5B promoter polymorphism and pulmonary fibrosis.

BACKGROUND The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P=1.2×10(-15); allelic association with idiopathic pulmonary fibrosis, P=2.5×10(-37)). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10−8 to 1.1 × 10−19), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.

Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression

The aim of the present study was to analyse the risk of rehospitalisation in patients with chronic obstructive pulmonary disease and associated risk factors. This prospective study included 416 patients from a university hospital in each of the five Nordic countries. Data included demographic information, spirometry, comorbidity and 12 month follow-up for 406 patients. The hospital anxiety and depression scale and St. Georges Respiratory Questionnaire (SGRQ) were applied to all patients. The number of patients that had a re-admission within 12 months was 246 (60.6%). Patients that had a re-admission had lower lung function and health status. A low forced expiratory volume in one second (FEV1) and health status were independent predictors for re-admission. Hazard ratio (HR; 95% CI) was 0.82 (0.74–0.90) per 10% increase of the predicted FEV1 and 1.06 (1.02–1.10) per 4 units increase in total SGRQ score. The risk of rehospitalisation was also increased in subjects with anxiety (HR 1.76 (1.16–2.68)) and in subjects with low health status (total SGRQ score >60 units). When comparing the different subscales in the SGRQ, the closest relation between the risk of rehospitalisation was seen with the activity scale (HR 1.07 (1.03–1.11) per 4 unit increase). In patients with low health status, anxiety is an important risk factor for rehospitalisation. This may be important for patient treatment and warrants further studies.

Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study

BACKGROUND No population-based incidence studies of epilepsy have studied syndrome classification from the outset. We prospectively studied the incidence of a single unprovoked seizure and epilepsy in the population of Iceland, and applied the syndrome classification endorsed by the International League Against Epilepsy to this population. METHODS We used a nationwide surveillance system to prospectively identify all residents of Iceland who presented with a first diagnosis of a single unprovoked seizure or epilepsy between December 1995 and February 1999. All cases were classified by seizure type, cause or risk factors, and epilepsy syndrome. RESULTS The mean annual incidence of first unprovoked seizures was 56.8 per 100,000 person-years, 23.5 per 100,000 person-years for single unprovoked seizures, and 33.3 per 100,000 person-years for epilepsy (recurrent unprovoked seizures). Incidence was similar in males and females. Partial seizures occurred in 40% and a putative cause was identified in 33%. Age-specific incidence was highest in the first year of life (130 per 100,000 person-years) and in those 65 years and older (110.5 per 100,000 person-years). Using strict diagnostic criteria for epilepsy syndromes, 58% of cases fell into non-informative categories. Idiopathic epilepsy syndromes were identified in 14% of all cases. INTERPRETATION Findings are consistent with incidence studies from developed countries. Although the epilepsy syndrome classification might be useful in tertiary epilepsy centers, it has limited practicality in population studies and for use by general neurologists.

COPD in Never Smokers: Results From the Population-Based Burden of Obstructive Lung Disease Study

Background: Never smokers comprise a substantial proportion of patients with COPD. Their characteristics and possible risk factors in this population are not yet well defined. Methods: We analyzed data from 14 countries that participated in the international, population-based Burden of Obstructive Lung Disease (BOLD) study. Participants were aged ≥ 40 years and completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. A diagnosis of COPD was based on the postbronchodilator FEV1/FVC ratio, according to current GOLD (Global Initiative for Obstructive Lung Disease) guidelines. In addition to this, the lower limit of normal (LLN) was evaluated as an alternative threshold for the FEV1/FVC ratio. Results: Among 4,291 never smokers, 6.6% met criteria for mild (GOLD stage I) COPD, and 5.6% met criteria for moderate to very severe (GOLD stage II+) COPD. Although never smokers were less likely to have COPD and had less severe COPD than ever smokers, never smokers nonetheless comprised 23.3% (240/1,031) of those classified with GOLD stage II+ COPD. This proportion was similar, 20.5% (171/832), even when the LLN was used as a threshold for the FEV1/FVC ratio. Predictors of COPD in never smokers include age, education, occupational exposure, childhood respiratory diseases, and BMI alterations. Conclusion: This multicenter international study confirms previous evidence that never smokers comprise a substantial proportion of individuals with COPD. Our data suggest that, in addition to increased age, a prior diagnosis of asthma and, among women, lower education levels are associated with an increased risk for COPD among never smokers.

Abnormal Metabolism of γ-Trace Alkaline Microprotein : The Basic Defect in Hereditary Cerebral Hemorrhage with Amyloidosis

ALTHOUGH the total incidence of cerebral hemorrhage is high, comparatively few reports concerning the familial occurrence of this disease have been published.1 , 2 In 1935 Arnason described 10 fami...

Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity

BackgroundThe aim of this study was to analyse mortality and associated risk factors, with special emphasis on health status, medications and co-morbidity, in patients with chronic obstructive pulmonary disease (COPD) that had been hospitalized for acute exacerbation.MethodsThis prospective study included 416 patients from each of the five Nordic countries that were followed for 24 months. The St. Georges Respiratory Questionnaire (SGRQ) was administered. Information on treatment and co-morbidity was obtained.ResultsDuring the follow-up 122 (29.3%) of the 416 patients died. Patients with diabetes had an increased mortality rate [HR = 2.25 (1.28–3.95)]. Other risk factors were advanced age, low FEV1 and lower health status. Patients treated with inhaled corticosteroids and/or long-acting beta-2-agonists had a lower risk of death than patients using neither of these types of treatment.ConclusionMortality was high after COPD admission, with older age, decreased lung function, lower health status and diabetes the most important risk factors. Treatment with inhaled corticosteroids and long-acting bronchodilators may be associated with lower mortality in patients with COPD.

Hereditary cystatin C (γ-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage

Abstract Hereditary CNS amyloid angiopathy occurring in Icelanders is the first human disorder known to be caused by deposition of cystatin C amyloid fibrils in the walls of the brain arteries leading to single or or multiple strokes with fatal outcome. One or more affected members have been verified by histological examination in 8 families containing 127 affected. These originated from the same geographic area. Abnormally low value of cystatin C found in the cerebrospinal fluid of those affected can be used to support or make diagnosis of this disease, also in asymptomatic relatives. By amino acid sequence analysis the amyloid fibrils in the patients are found to be a variant of cystatin C (γ‐trace), a major cysteine proteinase inhibitor. The variant protein has an amino acid substitution (glutamine for leucine) at position 58 in the amyloid molecule. It is postulated that a point mutation has occurred leading to production of amyloidogenic protein causing the disorder.

Cause-Specific Mortality in Adults with Unprovoked Seizures

Purpose: To determine the cause-specific mortality relative to that expected in a population-based incidence cohort of people with unprovoked seizures. Methods: The cohort comprises 224 inhabitants of Iceland first diagnosed as suffering from unprovoked seizures during a 5-year period from 1960 to 1964. The expected number of deaths was calculated by multiplying person-years of observation within 5-year age categories for each year from diagnosis through 1995 by cause-specific and sex-specific national death rates for those aged 20 years and above. The standardized mortality ratio (SMR) and 95% confidence intervals (95% CI) were calculated. Results: All-cause mortality was increased among men (SMR 2.25, 95% CI 1.56–3.14) but not women (SMR 0.79, 95% CI 0.38–1.46). Among men, there were 8 deaths from accidents, poisoning and violence observed versus 2.82 expected (SMR 2.84, 95% CI 1.22–5.59) and 4 deaths from suicide versus 0.69 expected (SMR 5.80, 95% CI 1.56–14.84). All-cause mortality for men was still elevated after restriction of analysis to those with seizures of unknown etiology (SMR 1.73, 95% CI 1.05–2.67) with the excess deaths attributable to suicide (SMR 5.26, 95% CI 1.06–15.38). Both males and females with remote symptomatic unprovoked seizures had an increase in all-cause mortality due to excess mortality from all cancers, cerebrovascular disease and accidents. Conclusion: When compared with the age-, time-period- and gender-specific mortality in the general population, there is excess mortality in men but not women. The increased mortality for men is partly attributable to excess mortality from accidents and suicides.

Chronic airflow obstruction and markers of systemic inflammation: Results from the BOLD study in Iceland

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible chronic airflow obstruction and by an accelerated decline in lung function. Elevated circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both markers of systemic inflammation, have been found in COPD. Their possible associations with chronic airflow obstruction have mostly been evaluated in highly selected patient samples. Our objective was to evaluate the association between postbronchodilator lung function CRP and IL-6 in a randomly selected sample of the Icelandic population, 40 years and older, while adjusting for gender, age, smoking, and body weight. METHODS Serum CRP and IL-6 values were measured among participants in the Burden of Obstructive Lung Disease (BOLD) study. RESULTS Of the 938 subjects invited a total of 403 men and 355 women participated (response rate 81%) in the study. Their mean age (+/-SD) was 57.7 (+/-12.7) years. Both CRP and IL-6 were independently related to lower FEV1 and FVC values. Individuals in the highest quartiles of CRP and IL-6 had a 7.5% and 3.9%, respectively, lower FEV1% than predicted after adjustment for smoking, age, and body weight. High CRP levels were more strongly related to lower FEV1 levels in men (-11.4%) than in women (-0.4%). CONCLUSIONS In a random population-based sample both CRP and IL-6 were significantly related to lower spirometric values. The association with CRP was stronger in men than in women. This finding underscores the possible importance of systemic inflammation in irreversible airflow limitation.