Northern European Populations Research Articles

An Indel Polymorphism in the MtnA 3' Untranslated Region Is Associated with Gene Expression Variation and Local Adaptation in Drosophila melanogaster.

Insertions and deletions (indels) are a major source of genetic variation within species and may result in functional changes to coding or regulatory sequences. In this study we report that an indel polymorphism in the 3’ untranslated region (UTR) of the metallothionein gene MtnA is associated with gene expression variation in natural populations of Drosophila melanogaster. A derived allele of MtnA with a 49-bp deletion in the 3' UTR segregates at high frequency in populations outside of sub-Saharan Africa. The frequency of the deletion increases with latitude across multiple continents and approaches 100% in northern Europe. Flies with the deletion have more than 4-fold higher MtnA expression than flies with the ancestral sequence. Using reporter gene constructs in transgenic flies, we show that the 3' UTR deletion significantly contributes to the observed expression difference. Population genetic analyses uncovered signatures of a selective sweep in the MtnA region within populations from northern Europe. We also find that the 3’ UTR deletion is associated with increased oxidative stress tolerance. These results suggest that the 3' UTR deletion has been a target of selection for its ability to confer increased levels of MtnA expression in northern European populations, likely due to a local adaptive advantage of increased oxidative stress tolerance.

Identification of coeliac disease triggering glutenin peptides in adults

ABSTRACTObjective: Coeliac disease affects approximately 1% of Northern American and European populations. It is caused by an inappropriate immune response to dietary gluten. Gluten comprises of two major protein fractions: gliadins and glutenins. Glutenins have recently been found to be toxic to coeliac individuals. Proliferation assays suggest in some but not all paediatric coeliac individuals there may be immunological stimulation with high molecular weight (HMW) glutenins. Less evidence pertains to low molecular weight (LMW) glutenins. The aim is to assess adaptive, T-cell driven, and innate immune response in adult coeliac individuals towards HMW glutenin peptide, glut04, and LMW glutenin peptide, glt156.Materials and methods: Coeliac patients were recruited attending endoscopy for routine monitoring. Adaptive immune response towards glut04 and glt156 was measured by proliferation assays and measurement of interferon-γ secretion in 28 T-cell lines. The innate immune response was assessed by measurement of enterocyte cell height (ECH) in coeliac small intestinal biopsies following overnight incubation in organ culture chambers in a further nine individuals.Results: There were 3/28 and 2/28 positive proliferation results using gluten-sensitive T-cells with glut04 and glt156, respectively. All coeliac biopsies tested in organ culture chambers demonstrated clear reduction in ECH with peptic-tryptic digest of whole industrial gluten, glut04 and glt156 when compared to negative control ovalbumin (p < 0.005). Three individuals had both T-cell and organ culture study data. Their proliferation assays showed no stimulation of the T-cells.Conclusions: This study demonstrates glutenin epitopes glut04 and glt156, while minor T-cell epitopes, are important in their ability to trigger the innate immune response.

Iberian red deer: paraphyletic nature at mtDNA but nuclear markers support its genetic identity.

Red deer populations in the Iberian glacial refugium were the main source for postglacial recolonization and subspecific radiation in north-western Europe. However, the phylogenetic history of Iberian red deer (Cervus elaphus hispanicus) and its relationships with northern European populations remain uncertain. Here, we study DNA sequences at the mitochondrial control region along with STR markers for over 680 specimens from all the main red deer populations in Spain and other west European areas. Our results from mitochondrial and genomic DNA show contrasting patterns, likely related to the nature of these types of DNA markers and their specific processes of change over time. The results, taken together, bring support to two distinct, cryptic maternal lineages for Iberian red deer that predated the last glacial maximum and that have maintained geographically well differentiated until present. Haplotype relationships show that only one of them contributed to the northern postglacial recolonization. However, allele frequencies of nuclear markers evidenced one main differentiation between Iberian and northern European subspecies although also supported the structure of both matrilines within Iberia. Thus, our findings reveal a paraphyletic nature for Iberian red deer but also its genetic identity and differentiation with respect to northern subspecies. Finally, we suggest that maintaining the singularity of Iberian red deer requires preventing not only restocking practices with red deer specimens belonging to other European populations but also translocations between both Iberian lineages.

Iron Age and Anglo-Saxon genomes from East England reveal British migration history.

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain.

Cross-species amplification of microsatellite loci for non-invasive genetic monitoring of the snowy owl (Bubo scandiacus)

Genetic analysis has shown to be an important and efficient method for monitoring species, but the lack of genetic markers constrains such monitoring for many species. Here, we cross-amplified microsatellite loci in the snowy owl (Bubo scandiacus) using primers previously characterized in other species. Among polymorphic loci, we selected 12 loci that amplified relatively short fragments (<250 base pairs) to facilitate genotyping of moulted feathers and other non-invasively collected samples. These 12 loci, and a sex-typing marker, were amplified in two multiplex PCR sets and used to screen 49 snowy owls from a northern European population. The number of alleles observed at single loci was 2 to 17. Expected and observed heterozygosity ranged from 0.12 to 0.91 and from 0.12 to 0.96, respectively. The combined probability of identity for the 12 loci was 5.7 × 10−11. Our multiplex PCR assays are expected to be useful for genetic monitoring, parentage analysis, and population genetic studies of the snowy owl.

An alien fish threatens an endangered parasitic bivalve: the relationship between brook trout (Salvelinus fontinalis) and freshwater pearl mussel (Margaritifera margaritifera) in northern Europe

AbstractHost–parasite interactions may play a significant role in biological invasions: for example, an invader may benefit from lower infectivity by native parasites in competition against the native hosts (‘enemy release hypothesis’).The invasive North American brook trout (Salvelinus fontinalis) is replacing the native salmonid hosts of the freshwater pearl mussel (FPM,Margaritifera margaritifera) in northern Europe, but the suitability of brook trout as a host for FPM is poorly known. In this study its suitability was investigated using an array of laboratory and field experiments, and several FPM populations from a catchment in northern Finland. The occurrence of brook trout in FPM rivers in the area was also studied.There were differences with respect to numbers and size of FPM larvae among the fish exposed to FPM, but generally brook trout was an unsuitable host or was clearly a poorer host for FPM than the native European salmonids, brown trout (Salmo trutta) or Atlantic salmon (Salmo salar). However, in one river a few FPM glochidia remained encysted in wild brook trout for at least 9 months, suggesting successful development – the first observation of its kind in Europe.A tendency was found for higher occurrence of brook trout in brown trout rivers with FPM than in brown trout rivers without FPM, being consistent with the enemy release hypothesis: as FPM infection is costly to the host, a higher glochidial load in brown trout may offer a competitive advantage to brook trout in FPM rivers.Generally, these results indicate that northern European FPM populations cannot typically use brook trout as their host fish. Therefore, the invasion and dispersal of brook trout, potentially leading to the disappearance of native salmonids, should also be considered as a potential threat to the endangered FPM populations.Copyright © 2016 John Wiley &amp; Sons, Ltd.

The Urban-Rural Gradient In Asthma: A Population-Based Study in Northern Europe.

The early life environment appears to have a persistent impact on asthma risk. We hypothesize that environmental factors related to rural life mediate lower asthma prevalence in rural populations, and aimed to investigate an urban-rural gradient, assessed by place of upbringing, for asthma. The population-based Respiratory Health In Northern Europe (RHINE) study includes subjects from Denmark, Norway, Sweden, Iceland and Estonia born 1945–1973. The present analysis encompasses questionnaire data on 11,123 RHINE subjects. Six categories of place of upbringing were defined: farm with livestock, farm without livestock, village in rural area, small town, city suburb and inner city. The association of place of upbringing with asthma onset was analysed with Cox regression adjusted for relevant confounders. Subjects growing up on livestock farms had less asthma (8%) than subjects growing up in inner cities (11%) (hazard ratio 0.72 95% CI 0.57–0.91), and a significant urban-rural gradient was observed across six urbanisation levels (p = 0.02). An urban-rural gradient was only evident among women, smokers and for late-onset asthma. Analyses on wheeze and place of upbringing revealed similar results. In conclusion, this study suggests a protective effect of livestock farm upbringing on asthma development and an urban-rural gradient in a Northern European population.

International long-term trends and recent patterns in the incidence of leukemias and lymphomas among children and adolescents ages 0-19 years.

To enhance understanding of etiology, we examined international population-based cancer incidence data for lymphoid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma and myeloid leukemia among children aged 0-19. Based on temporal trends during 1978-2007 in 24 populations, lymphoid leukemia and myeloid leukemia incidence rates generally have not changed greatly and differences in rates for non-Hodgkin and for Hodgkin lymphoma have diminished in some regions. Lymphoid leukemia rates during 2003-2007 in 54 populations varied about 10-fold, with rates highest in US white Hispanics (50.2 per million person-years) and Ecuador (48.3) and lowest in US blacks (20.4), Tunisia (17.7) and Uganda (6.9). Non-Hodgkin lymphoma rates varied 30-fold, with very high rates in sub-Saharan Africa (146.0 in Malawi and 54.3 in Uganda) and low rates (≤ 10) in some Asian populations (China, Japan, India, the Philippines and Thailand) and U.S. Asian-Pacific Islanders, eastern and northern European populations and Puerto Rico. Hodgkin lymphoma rates varied 15-fold, with rates highest in Italy (21.3) and lowest in China (1.7). Myeloid leukemia rates varied only about fivefold, with rates highest in the Philippines and Korea (exceeding 14.0) and lowest in Eastern Europe (5.9 in Serbia and 5.3 in the Czech Republic) and Uganda (2.7). The boy/girl average incidence rate ratios were 2.00 or lower. Age-specific patterns differed among the four hematopoietic malignancies, but were generally consistent within major categories world-wide, except for non-Hodgkin lymphoma. A systematic world-wide approach comparing postulated etiologic factors in low- versus high-risk populations may help clarify the etiology of these childhood malignancies.

High genotypic diversity found among population of Phytophthora infestans collected in Estonia

Potato late blight, caused by the oomycete pathogen Phytophthora infestans, is one of the most important diseases of potato worldwide. This is the first study characterising Estonian P. infestans population using the SSR marker genotyping method. 70 P. infestans isolates collected during the growing season in 2004 from eight potato fields in three different regions of Estonia were characterised with nine polymorphic SSR markers. A1 and A2 mating type isolates were detected from every studied field indicating the high potential for sexual reproduction, which raises the genotypic diversity in P. infestans population. Results revealed highly diverse P. infestans population in Estonia resembling the Northern European populations. Most of the multilocus genotypes were detected only once among the collected isolates. Subpopulations collected from different geographical regions of Estonia showed no differentiation from each other but instead formed one highly diverse group.

Y chromosome haplotype distribution of brown bears (Ursus arctos) in Northern Europe provides insight into population history and recovery

High-resolution, male-inherited Y-chromosomal markers are a useful tool for population genetic analyses of wildlife species, but to date have only been applied in this context to relatively few species besides humans. Using nine Y-chromosomal STRs and three Y-chromosomal single nucleotide polymorphism markers (Y-SNPs), we studied whether male gene flow was important for the recent recovery of the brown bear (Ursus arctos) in Northern Europe, where the species declined dramatically in numbers and geographical distribution during the last centuries but is expanding now. We found 36 haplotypes in 443 male extant brown bears from Sweden, Norway, Finland and northwestern Russia. In 14 individuals from southern Norway from 1780 to 1920, we found two Y chromosome haplotypes present in the extant population as well as four Y chromosome haplotypes not present among the modern samples. Our results suggested major differences in genetic connectivity, diversity and structure between the eastern and the western populations in Northern Europe. In the west, our results indicated that the recovered population originated from only four male lineages, displaying pronounced spatial structuring suggestive of large-scale population size increase under limited male gene flow within the western subpopulation. In the east, we found a contrasting pattern, with high haplotype diversity and admixture. This first population genetic analysis of male brown bears shows conclusively that male gene flow was not the main force of population recovery.

Eco‐genomic analysis of the poleward range expansion of the wasp spider Argiope bruennichi shows rapid adaptation and genomic admixture

Poleward range expansions are commonly attributed to global change, but could alternatively be driven by rapid evolutionary adaptation. A well-documented example of a range expansion during the past decades is provided by the European wasp spider Argiope bruennichi. Using ecological niche modeling, thermal tolerance experiments and a genome-wide analysis of gene expression divergence, we show that invasive populations have adapted to novel climatic conditions in the course of their expansion. Their climatic niche shift is mirrored in an increased cold tolerance and a population-specific and functionally differentiated gene expression response. We generated an Argiope reference genome sequence and used population genome resequencing to assess genomic changes associated with the new climatic adaptations. We find clear genetic differentiation and a significant admixture with alleles from East Asian populations in the invasive Northern European populations. Population genetic modeling suggests that at least some of these introgressing alleles have contributed to the new adaptations during the expansion. Our results thus confirm the notion that range expansions are not a simple consequence of climate change, but are accompanied by fast genetic changes and adaptations that may be fuelled through admixture between long separated lineages.

Menopause as a predictor of new-onset asthma: A longitudinal Northern European population study

There is limited and conflicting evidence on the effect of menopause on asthma. We sought to study whether the incidence of asthma and respiratory symptoms differ by menopausal status in a longitudinal population-based study with an average follow-up of 12 years. The Respiratory Health in Northern Europe study provided questionnaire data pertaining to respiratory and reproductive health at baseline (1999-2001) and follow-up (2010-2012). The study cohort included women aged 45 to 65 years at follow-up, without asthma at baseline, and not using exogenous hormones (n= 2322). Menopausal status was defined as nonmenopausal, transitional, early postmenopausal, and late postmenopausal. Associations with asthma (defined by the use of asthma medication, having asthma attacks, or both) and respiratory symptoms scores were analyzed by using logistic (asthma) and negative binomial (respiratory symptoms) regressions, adjusting for age, body mass index, physical activity, smoking, education, and study center. The odds of new-onset asthma were increased in women who were transitional (odds ratio, 2.40; 95% CI, 1.09-5.30), early postmenopausal (odds ratio, 2.11; 95% CI, 1.06-4.20), and late postmenopausal (odds ratio, 3.44; 95% CI, 1.31-9.05) at follow-up compared with nonmenopausal women. The risk of respiratory symptoms increased in early postmenopausal (coefficient, 0.40; 95% CI, 0.06-0.75) and late postmenopausal (coefficient, 0.69; 95% CI, 0.15-1.23) women. These findings were consistent irrespective of smoking status and across study centers. New-onset asthma and respiratory symptoms increased in women becoming postmenopausal in a longitudinal population-based study. Clinicians should be aware that respiratory health might deteriorate in women during reproductive aging.

Abstract A01: Genome-wide changes in expression of small RNAs in human testis cancer tissue

Abstract Testicular germ cell tumor (TGCT) is the most common malignancy in young men in most western countries. The incidence is highest in Northern European populations, where the incidence rates have increased significantly over the past decades. Genetic predisposition and conditions during pregnancy play a central role in TGCT development, and the disease arises from primordial germ cells that develop into carcinoma in situ (CIS) lesions. These lesions may develop into cancer from puberty onwards. Like primordial germ cells, CIS cells retain a permissive chromatin structure, indicating the involvement of epigenetic components in TGCT. To assess the role of small RNAs in testicular carcinogenesis, we quantified small RNAs (19 to 35 bp) in 25 human cancer samples with differing TGCT histology and 12 normal testis samples using small RNA sequencing. piRNA expression levels were calculated for piRNA clusters built on the small RNA dataset generated from the 37 samples. Most piRNA clusters differ substantially in expression between TGCT samples and healthy controls, indicating a common mechanism for this genome-wide effect. In addition, a total of 101 miRNAs show differential expression between healthy tissue and TGCT samples (p&amp;lt;0.1 when adjusting for multiple testing with the Benjamini-Hochberg procedure). Twenty miRNAs have p&amp;lt;1×10-6, including miRNAs previously implicated in TGCT development and in cisplatin sensitivity. Furthermore, clustering demonstrates unique miRNA expression in different TGCT histological subtypes. These results indicate that small RNAs could be used as TGCT markers and potentially be a powerful tool in aiding diagnosis and identification of histological subtypes in TGCT patients, as well as in development of new therapeutic interventions. Citation Format: Trine Ballestad Rounge, Kari Furu, Rolf Inge Skotheim, Espen Enerly, Trine Berit Haugen, Tom Grotmol. Genome-wide changes in expression of small RNAs in human testis cancer tissue. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A01.

The burden of multiple sclerosis variants in continental Italians and Sardinians

Background: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. Objective: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. Methods: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke’s R2 and the area under the Receiver Operating Characteristic (ROC) curves. Results: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. Conclusions: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.

The potential drug-drug interaction between proton pump inhibitors and warfarin.

Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values. The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test. We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63-78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5-2.8) and 2.6 (95%CI 2.5-2.7) in the period 1-3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs. We found no evidence of a clinically meaningful drug-drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to "cautiously monitor" users of warfarin initiating PPI treatment.

Winter Activity and Aboveground Hybridization Between the Two Biotypes of the West Nile Virus Vector Culex pipiens.

Culex (Cx.) pipiens mosquitoes are important vectors of West Nile virus (WNV). In Europe, the species Cx. pipiens consists of two biotypes, pipiens and molestus, which are morphologically identical, but differ in behavior. Typical behavior of the molestus biotype is the ability to remain active during winter, whereas the pipiens biotype enters diapause. The current paradigm is that the two biotypes occur sympatrically in southern Europe, but occur in isolated above- and belowground populations in northern Europe. In northern Europe, hybridization between biotypes is considered to be low because of the barrier that exists between typical habitats. Data on the occurrence of the biotypes and hybrids in northern Europe, however, are scarce, because identification to the level of biotype is often not performed. Our objective was to clarify the distribution of the Cx. pipiens biotypes and to determine hybridization rates in The Netherlands. Cx. pipiens mosquitoes were collected using three different approaches. First, traps were deployed randomly throughout The Netherlands during the summers of 2011 and 2012 (active surveillance). Second, using a web-based reporting platform and media campaign, Dutch citizens were asked to send dead mosquitoes to our laboratory during the winter and summer of 2014 (passive surveillance). Third, larvae and adults were collected during the summer of 2014 from aboveground locations in Amsterdam to identify molestus larval habitats. Real-time PCR was used for identification to the level of biotype. We found that biotype molestus and hybrids were feeding indoors during winter and summer in The Netherlands and that hybridization rates ranged between 6% and 15%. Larval habitats of biotype molestus were found to occur aboveground. The high percentage of hybridization has implications for assessing the risk of WNV transmission, because hybrids are thought to have ideal characteristics for bridging WNV between birds and humans.

Age-Stratified Prevalence of Mild Cognitive Impairment and Dementia in European Populations: A Systematic Review.

The prevalence of mild cognitive impairment (MCI) and dementia according to age remain uncertain. We systematically extracted age-stratified estimates of MCI and dementia prevalence reported in European studies published since 1995, and performed meta-analyses for dementia. We identified 10 relevant studies on MCI and 26 studies on dementia. Studies on MCI presented substantial heterogeneity preventing a meta-analysis, with a majority reporting an increase in prevalence at ≥75 years old. Pooled prevalence of dementia rose continuously from 55 years of age, reaching 44.7% (39.8; 49.6) in those ≥95 years of age. Homogenization of MCI criteria, and additional studies in Northern European population would be warranted.

Codeine--Restrictions on use for children and teenagers

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency has issued European-wide restrictions on the use of codeine-containing medicines for cough and cold in children at the age of 0-12 because of the risk of serious side effects, including the risk of breathing problems. The PRAC further recommended that "codeine must not be used in people of any age who are known to convert codeine into morphine at a faster rate than normal ('ultra-rapid metabolisers')". The reasons for this variability in codeine biotransformation lay in a genetic polymorphism in the liver enzyme CYP2D6 leading to 3% of the northern European population being ultrarapid metabolisers due to a gene duplication of the enzyme.This is the first restriction of a common drug in CYP2D6 ultrarapid metabolizers, and more use of pharmacogenetic biomarkers for stratified benefit-risk assessment in drug regulation can be expected and will be a first step to Individualized Medicine Regulation.

Respiratory Health in Cleaners in Northern Europe: Is Susceptibility Established in Early Life?

RationaleThere is some evidence that maternal smoking increases susceptibility to personal smoking’s detrimental effects. One might question whether early life disadvantage might influence susceptibility to occupational exposure.ObjectivesIn this cross-sectional study we investigated respiratory symptoms, asthma and self-reported chronic obstructive pulmonary disease (COPD) as related to working as a cleaner in Northern European populations, and whether early life factors influenced susceptibility to occupational cleaning’s unhealthy effects.MethodsThe RHINE III questionnaire study assessed occupational cleaning in 13,499 participants. Associations with respiratory symptoms, asthma and self-reported COPD were analysed with multiple logistic regressions, adjusting for sex, age, smoking, educational level, parent´s educational level, BMI and participating centre. Interaction of occupational cleaning with early life disadvantage (maternal smoking, severe respiratory infection <5 years, born during winter months, maternal age at birth >35 years) was investigated.Main ResultsAmong 2138 ever-cleaners the risks of wheeze (OR 1.4, 95% CI 1.3–1.6), adult-onset asthma (1.5 [1.2–1.8]) and self-reported COPD (1.7 [1.3–2.2]) were increased. The risk increased with years in occupational cleaning (adult-onset asthma: ≤1 year 0.9 [0.7–1.3]; 1–4 years 1.5 [1.1–2.0]; ≥4 years 1.6 [1.2–2.1]). The association of wheeze with cleaning activity ≥4 years was significantly stronger for those with early life disadvantage than in those without (1.8 [1.5–2.3] vs. 1.3 [0.96–1.8]; pinteraction 0.035).ConclusionsOccupational cleaners had increased risk of asthma and self-reported COPD. Respiratory symptom risk was particularly increased in persons with factors suggestive of early life disadvantage. We hypothesize that early life disadvantage may increase airway vulnerability to harmful exposure from cleaning agents later in life.

Geographical Distribution of Myasthenia Gravis in Northern Europe - Results from a Population-Based Study from Two Countries

Objectives: To compare the prevalence of myasthenia gravis (MG) subgroups based on immunological markers and clinical presentation in two geographically complete MG populations in northern Europe. Methods: This cross-sectional study included all living MG patients in Norway and a regional cohort from the Netherlands. Patients were identified using their hospital registration codes. Medical charts of subjects >16 years were reviewed. Inclusion criteria were clinical MG, a positive antibody test for acetylcholine receptor (AChR MG) or muscle-specific kinase (MuSK MG), or if seronegative MG, confirmed by an electrophysiological test. Results: 1,205 MG patients (534 Norwegians and 671 Dutch) fulfilled the criteria, giving a higher point prevalence in the Netherlands (167/million, 95% CI 155-180) than in Norway (138/million, 95% CI 126-150). In particular, rates of AChR MG (143 vs. 111/million), MuSK MG (6.5 vs. 0.5/million), and ocular phenotype (62 vs. 24/million) were higher in the Netherlands. Conclusion: Novel findings are an AChR MG geographical north-south gradient and a 2.6-fold more ocular MG patients in the Netherlands than in Norway. The MuSK MG latitudinal gradient supports the notion of a north-south gradient in Europe, with a higher prevalence in the south. The variation is probably explained by genetic differences between the populations, in addition to environmental interactions.