Positive association between social capital and the quality of health care service: A cross-sectional study.

BACKGROUND: Social capital is an acknowledged theoretical concept in work environment research focusing on collective resources that arise from social networks between employees in the workplace. Social capital is divided into bonding (in the work unit), bridging (between work units), and linking social capital (between the work units and management). However, only a few studies have investigated the relationship between social capital and the quality of health care, which is the key outcome of hospital services. OBJECTIVE: We investigated the associations between bonding, bridging and two types of linking social capital with the self-reported quality of health care services among Danish hospital employees. Next, we directly compared how social capital, workload and work pace each affected the quality of health care. DESIGN: A cross-sectional study at Regional Hospital West Jutland, Denmark. DATA: Questionnaire data were collected from 1589 Danish hospital employees. We used validated scales for social capital, workload, and work pace and self-developed scales for clinical quality, quality of patient involvement, and overall professional quality. METHODS: Binary logistic regression analyses were conducted. RESULTS: The analyses showed significant, positive associations of bonding and bridging social capital with all types of quality and negative associations between workload and all types of quality. The work pace was negatively associated with clinical quality. When covariates were included in the model, the associations remained statistically significant and showed no decrease in odds ratios. The marginal effects showed that when bonding and bridging social capital were increased by a single scale point, the predicted probability for a high clinical quality increased by an average of 0.5 percentage points. This increase corresponds to a change in the predicted probability of self-reported high clinical quality from 10% for the lowest reported bridging social capital to 54% for the highest reported bridging social capital. For workload and work pace, the effects were -0.2 and -0.3 percentage points, respectively. DISCUSSION & CONCLUSIONS: This study adds to the literature on positive work environment factors by focusing on social capital and the importance of well-functioning relationships within and especially between hospital units for high-quality health care. Hence, bridging and bonding social capital should be included in theoretical frameworks, as well as in hospital strategies and work environment guidelines to potentially improve the quality of health care services. However, further studies are needed to develop and test the effects of specific social capital interventions on the quality of health care services.

Comparison of the clinical presentation across two waves of COVID-19: a retrospective cohort study.

BACKGROUND: Only a few studies have performed comprehensive comparisons between hospitalized patients from different waves of COVID-19. Thus, we aimed to compare the clinical characteristics and laboratory data of patients admitted to the western part of Denmark during the first and second waves of COVID-19 in 2020. Furthermore, we aimed to identify risk factors for critical COVID-19 disease and to describe the available information on the sources of infection. METHODS: We performed a retrospective study of medical records from 311 consecutive hospitalized patients, 157 patients from wave 1 and 154 patients from wave 2. The period from March 7 to June 30, 2020, was considered wave 1, and the period from July 1st to December 31, 2020, was considered wave 2. Data are presented as the total study population, as a comparison between waves 1 and 2, and as a comparison between patients with and without critical COVID-19 disease (nonsurvivors and patients admitted to the intensive care unit (ICU)). RESULTS: Patients admitted during the first COVID-19 wave experienced a more severe course of disease than patients admitted during wave 2. Admissions to the ICU and fatal disease were significantly higher among patients admitted during wave 1 compared to wave 2. The percentage of patients infected at hospital decreased in wave 2 compared to wave 1, whereas more patients were infected at home during wave 2. We found no significant differences in sociodemographics, lifestyle information, or laboratory data in the comparison of patients from waves 1 and 2. However, age, sex, smoking status, comorbidities, fever, and dyspnea were identified as risk factors for critical COVID-19 disease. Furthermore, we observed significantly increased levels of C-reactive protein and creatinine, and lower hemoglobin levels among patients with critical disease. CONCLUSIONS: At admission, patients were more severely ill during wave 1 than during wave 2, and the outcomes were worse during wave 1. We confirmed previously identified risk factors for critical COVID-19 disease. In addition, we found that most COVID-19 infections were acquired at home.

Hand hygiene compliance among healthcare workers before and during the COVID-19 pandemic.

BACKGROUND: Healthcare workers' (HCWs) adherence to hand hygiene is vital in combatting COVID-19 in hospitals. We aimed to investigate HCWs hand hygiene compliance before and during the COVID-19 pandemic and hypothesised that hand hygiene compliance would increase during the pandemic. METHODS: We conducted a prospective observational study in three medical departments at the Regional Hospital of West Jutland, Denmark from April 2019 to August 2020. A total of 150 HCWs participated before the COVID-19 pandemic and 136 during the pandemic. Hand hygiene observations were assessed using an automated hand hygiene monitoring system. Students unpaired t-test was used to assess differences in hand hygiene compliance rates in each department. RESULTS: Comparison analyses showed, that hand hygiene compliance in department A and B was significantly higher before the COVID-19 pandemic than during the pandemic; a 7% difference in department A and a 5% difference in department B. For department C, the total hand hygiene compliance was unchanged during the pandemic compared to before. CONCLUSION: The COVID-19 pandemic did not raise hand hygiene compliance. Further studies are needed to verify these findings and further identify barriers to hand hygiene compliance among HCWs.

Obstructive sleep apnoea in pycnodysostosis: A three-dimensional upper airway analysis.

AIM: To assess the upper airway (UA) morphology in patients with pycnodysostosis with a 3D analysis, compare results with normative data and investigate the correlation of the total volume (TV) with other UA morphology variables. MATERIALS AND METHODS: Cone beam computed tomography (CBCT) images of eight Danish patients with pycnodysostosis (4 males and 4 females with a mean age of 31.8 years, SD: 16.3 years) were analyzed using Mimics® (Materialise® ) and compared with a sex- and age-matched control group (6 males and 8 females with a mean age of 33.6 years, SD: 18.6 years). RESULTS: The distance from the tip of the epiglottis (E) to the Frankfurt horizontal plane (Fp) was significantly shorter in the pycnodysostosis group (P < .042). Regarding the cross-sectional measurements, at the 'maximum constriction' (P < .005), the 'upper airway limit' (P < .001) and the 'lower airway limit' (P < .035) cross-sections were significantly smaller in the pycnodysostosis group. The volumes 'nasopharynx' (P < .002) and 'total airway' (TV) (P < .01) were also significantly smaller. CONCLUSION: Patients with pycnodysostosis have a reduced total airway as well as nasopharyngeal volume compared with matched controls. Additionally, they have a reduced cross-sectional area in the upper and lower borders of the UA, and the area of maximum constriction is also reduced. These factors might explain the high prevalence of obstructive sleep apnoea in pycnodysostosis. Total airway is positively correlated with total length and cross-sections at all levels including the maximum constriction area as well as the anteroposterior dimension at the upper and lower airway borders.

Exploring associations between constipation, severity of neurofibromatosis type 1 and NF1 mutational spectrum.

Neurofibromatosis type 1 (NF1) is inherited in an autosomal dominant manner and is a rather common rare disease. Until recently, studies on gastrointestinal symptoms in patients with NF1 have been few and mostly described as case reports. In three previously published studies, the frequency of constipation in patients with NF1 has been found to be as high as 30%. In this study, associations between the frequency of constipation and NF1 disease severity and NF1 mutational spectrum were investigated. Among 277 patients with NF1, 49 had constipation. The highest rate of constipation was found among patients with a high perception of NF1 illness burden, and patients with constipation had a significantly higher NF1 illness burden when comparing the "not bothered" and the "very bothered" (p = 0.013). We found no significant association between constipation and the remaining measures on severity of NF1, nor between constipation and genetic variants. When observing the NF1 mutational spectrum, one variant (c.1013A>G (p.Asp338Gly/p.?) was identified in three patients with constipation of which two patients were related. The variant c.2970_2972delAAT (p.Met992del) associated with a mild NF1 phenotype was identified in two related patients with constipation. This study is the first to explore the association between symptoms of constipation, NF1 severity, and NF1 mutational spectrum. The results suggest an association between constipation and a high degree of illness burden. Awareness of this association among physicians could lead to more patients with NF1 being diagnosed with constipation. Constipation impacts on quality of life, hence a timely diagnosis and treatment will improve quality of life.

Three-dimensional analysis of craniofacial morphology in patients with pycnodysostosis.

OBJECTIVE: To perform a 3D cephalometric analysis of the craniofacial characteristics of patients with pycnodysostosis and compare this with a matched control group. SETTING AND SAMPLE POPULATION: This cross-sectional descriptive study assessed eight CBCTs obtained in patients with pycnodysostosis (4 males, 4 females, mean age: 31.8 years). MATERIALS AND METHODS: Eight Danish patients with pycnodysostosis were seen at the University's Orthodontic Clinic. All CBCTs were analysed using the Mimics 21.0 software (Materialise®, Belgium) and compared with a control group (6 males, 8 females, mean age: 33.6 years). RESULTS: Interclass correlation coefficient showed excellent intra-rater reliability (> 0.93). All measurements in the 3D cephalometric analysis revealed statistical significance (P < .05) when compared with controls. Patients with pycnodysostosis generally had significantly smaller maxilla in the transverse (P < .001), sagittal (P < .002) and vertical (P < .001) dimensions. Their mandibles were also smaller vertically (P < .001) and in length (P < .001). Gonial angle was significantly larger than controls (P < .001), while mandibular volumes were considerably smaller (P < .001). CONCLUSION: Patients with pycnodysostosis have significantly smaller jaws in the vertical, sagittal and transverse dimensions compared with controls. Furthermore, the gonial angle was significantly larger, while the volume of the mandible was significantly smaller.

Clinical and genetic evaluation of Danish patients with pycnodysostosis.

BACKGROUND: Pycnodysostosis is a rare autosomal recessive osteosclerotic skeletal dysplasia caused by variants in the cathepsin K gene (CTSK). Clinical features include short stature, bone fragility, characteristic facial features and acro-osteolysis of the distal phalanges. Usually, patients suffer from multiple bone fractures. The purpose of this study was to describe the Danish population of pycnodysostosis patients with respect to genotype, phenotype and the prevalence of complications. We collected medical history, performed clinical examination, collected blood- and urine samples, performed dual-energy x-ray absorptiometry scan (DXA) and high-resolution peripheral quantitative computed tomography scan (HRpQCT) and obtained clinical photos. Information about complications, bone mineral density and bone markers in the blood were collected and analysed. RESULTS: Ten patients with a median age of 32 years ranging from five to 51 years participated. The pycnodysostosis phenotype varied with respect to the number of bone fractures and degree of complications. DXA and HRpQCT showed high bone mineral density. A tendency of growth hormone treatment escalating growth and increasing final height was seen. A marker of bone resorption measured in blood was within normal range in nine patients and elevated in one patient. A novel pathogenic variant in CSTK causing pycnodysostosis was detected in two related patients. Moreover information about the patients' own health perception was reported. An example being they rated their mental health to be good despite multiple bone fractures. CONCLUSION: This study provides information about genotypes and phenotypes in a Danish pycnodysostosis population. It reports new data about the complications such as bone fractures and it elucidates the levels of bone turnover markers as well as the density of the bones in one of the biggest cohort of pycnodysostosis patients ever published. An individualised approach to treatment in this patient group is necessary as the phenotype including complications varies between patients. Additional studies are needed to further understand genotype-phenotype correlations.

Novel TRPV4 variant causes a severe form of metatropic dysplasia.

We present a girl born with a frontal bossing, short neck, bell-shaped thorax, short limbs with prominent joints, and a tail-like coccygeal appendage. Genetic screening of TRPV4 identified a novel de novo heterozygous missense variant. We believe the variant causes the severe form of metatropic dysplasia in this patient.

Gastrointestinal Symptoms in Children and Adolescents With Neurofibromatosis Type 1.

OBJECTIVES: Neurofibromatosis type 1 (NF1) is a complex genetic disorder characterized by symptoms of the skin and nervous system. A previous study indicated that constipation is common in children with NF1. The aim of the present study was to investigate the phenotype and prevalence of gastrointestinal (GI) symptoms in a population of 4 to 17-year-olds with NF1 compared with their unaffected siblings. METHODS: GI symptoms were assessed with a web-based, parent or self-administered, validated, Rome III diagnostic questionnaire. Participants were recruited from 1 of 2 Danish National Centers of Expertise for NF1. Logistic regression was used to estimate the prevalence of functional dyspepsia, irritable bowel syndrome (IBS), and constipation in each group and the groups were compared using odds ratio (OR). RESULTS: We compared 102 NF1 patients (median age 10.3 years) and 46 of their unaffected siblings (median age 10 years). The overall likelihood of having GI symptoms usually attributed to either functional dyspepsia, IBS, or constipation was 30.4% in patients versus 10.9% in siblings, OR 3.58 (95% confidence interval 1.30 to 9.79). The prevalence of constipation was 22.5% in patients and 4.3% in siblings, OR 6.41 (95% confidence interval 1.45 to 28.24). The use of laxatives was 16% (n = 16) in patients and 2% (n = 1) in siblings. CONCLUSIONS: Overall, GI symptoms attributed to functional dyspepsia, IBS or constipation are more common in 4 to 17-year-olds with NF1 when compared with their unaffected siblings. The high prevalence indicates that GI dysfunction in NF1 is not functional but may be part of the underlying NF1 disorder.

Constipation in adults with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal-dominant disease characterised by symptoms of the skin, eyes, nervous system and bones. A previous study indicated that constipation, large rectal diameters and prolonged colorectal transit times are common in children with NF1. The aim of the present study was to investigate and compare the prevalence of gastrointestinal symptoms in adult patients with NF1 to their unaffected relatives serving as the control group. Patients with NF1 were recruited from one of two Danish National Centres of Expertise for NF1 and their unaffected relatives were invited to participate as controls. Gastrointestinal symptoms were assessed with a web-based, self-administered, validated, Rome® III diagnostic questionnaire. Logistic regression was used to estimate the prevalence of functional dyspepsia, IBS and functional constipation in each group and the groups were compared using their odds ratios. RESULTS: The response rates for patients and controls were 66.4% and 82.4%, respectively. We compared 175 patients, median age 34.2 (IQR = 20.1) and 91 of their unaffected relatives, median age 42.0 (IQR = 12). The overall likelihood of fulfilling the diagnostic criteria for functional constipation, irritable bowel syndrome or functional dyspepsia was 33.1% among patients vs. 14.3% among controls, (odds ratio (OR): 2.97; 95% CI: 1.56-5.66) and after adjustment for age and gender (OR: 3.06; 95% CI: 1.62-5.79). The likelihood of functional constipation was higher among patients (OR: 3.80; 95% CI: 1.27-11.31), and this was still true after adjustment (OR: 3.49; 95% CI: 1.14-10.64). The likelihood of irritable bowel syndrome (OR: 2.29; 95% CI: 0.98-5.33) was evident after adjustment (OR: 2.46; 95% CI: 1.10-5.47), whereas there was no difference in the likelihood of functional dyspepsia (OR: 2.35; 95% CI: 0.67-8.32) after adjustment (OR:2.25; 95% CI: 0.70-7.17). CONCLUSIONS: Overall, having symptoms usually attributed to either functional dyspepsia, IBS or functional constipation is more common in adults with NF1 compared to unaffected relatives. Of the three, the likelihood of constipation is markedly higher. The high prevalence of constipation indicates that it is not functional but part of the NF1 disorder.

Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2.

Since the original description of the IARS2-related cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia syndrome (CAGSSS; OMIM 616007) in an extended consanguineous family of French-Canadian descent, no further patients have been reported. IARS2 (OMIM 612801) encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family, and has been implicated in CAGSSS and a form of Leigh syndrome. Here, we report on a female Danish patient with a novel homozygous IARS2 mutation, p.Gly874Arg, who presented at birth with bilateral hip dislocation and short stature. At 3 months, additional dysmorphic features were noted and at 18 months her radiographic skeletal abnormalities were suggestive of an underlying spondyloepimetaphyseal dysplasia (SEMD). Retrospective analysis of the neonatal radiographs confirmed that the skeletal changes were present at birth. It was only with time that several of the other manifestations of the CAGSSS emerged, namely, cataracts, peripheral neuropathy, and hearing loss. Growth hormone deficiency has not (yet) manifested. We present her clinical features and particularly highlight her skeletal findings, which confirm the presence of a primary SEMD skeletal dysplasia in a growing list of mitochondrial-related disorders including CAGSSS, CODAS, EVEN-PLUS, and X-linked SEMD-MR syndromes.

Constipation in children with neurofibromatosis type 1.

BACKGROUND AND OBJECTIVES: Neurofibromatosis type 1 (NF1) is a hereditary, heterogenic, and multiorganic disease. The NF1 phenotype shows great variability in expressivity and often includes symptoms from the central and peripheral nervous systems. Bowel symptoms have been reported, but gastrointestinal function in NF1 remains to be described in detail. In this first systematic study of bowel function in children with NF1, we aimed to investigate symptoms of constipation and test the hypotheses that children with NF1 have abnormally large rectum and prolonged colonic transit time (CTT). METHODS: A total of 20 children with NF1 (age 8.2 ± 2.4 years) were evaluated with medical history; clinical examination; digital rectal examination; bowel and dietary diaries; Rome III criteria; measurement of rectal diameter by transabdominal ultrasound; and radiographic estimation of CTT. The control group for assessment of rectal diameter comprised 23 healthy children (mean age 9.1 ± 2.7 years). RESULTS: A total of 6 children with NF1 (30%) were constipated according to Rome III criteria. Average rectal diameter was significantly larger than for healthy children (32.9 ± 7.2 mm vs 21.4 ± 5.9 mm, P < 0.0001). Median CTT in NF1 children was 53 hours (range 26-101). Compared with existing normative data, CTT was prolonged (>84 hours) in 3 (19%). CONCLUSIONS: Symptoms of constipation were surprisingly common in children with NF1. Correspondingly, rectal diameters were abnormally large and a higher proportion than expected had prolonged CTT. The underlying pathophysiology remains obscure, but we hypothesise that abnormalities of the enteric nervous system or disturbed cellular growth could be present.

A genome-wide search for linkage to allergic rhinitis in Danish sib-pair families.

Allergic rhinitis (AR) is a complex disorder with a polygenic, multifactorial aetiology. Twin studies have found the genetic contribution to be substantial. We collected and clinically characterised a sample consisting of 127 Danish nuclear families with at least two siblings suffering from AR or allergic conjunctivitis including 540 individuals (286 children and 254 parents). A whole-genome linkage scan, using 424 microsatellite markers, was performed on both this sample and an earlier collected sample consisting of 130 families with atopic dermatitis and other atopic disorders. A third sib-pair family sample, which was previously collected and genotyped, was added to the analysis increasing the total sample size to 357 families consisting of 1508 individuals. In total, 190 families with AR was included. The linkage analysis software Genehunter NPL, Genehunter MOD, and Genehunter Imprinting were used to obtain nonparametric and parametric linkage results. Family-based association analysis of positional candidate SNPs was carried out using the FBAT program. We obtained genome-wide significant linkage to a novel AR locus at 1p13 and suggestive linkage to two novel regions at 1q31-q32 and 20p12, respectively. Family-based association analysis of SNPs in the candidate locus DNND1B/CRB1 at 1q31 showed no significant association and could not explain the linkage signal observed. Suggestive evidence of linkage was also obtained at three AR loci previously reported (2q14-q23, 2q23, and 12p13) and indication of linkage was observed at a number of additional loci. Likely maternal imprinting was observed at 2q23, and possible maternal imprinting at 3q28.

Linkage of atopic dermatitis to chromosomes 4q22, 3p24 and 3q21.

Atopic dermatitis (AD) is a common, itchy skin disease of complex inheritance characterized by dermal and epidermal inflammation. The heritability is considerable and well documented. To date, four genome scans have examined the AD phenotype, showing replicated linkage at 3p26-22, 3q13-21 and 18q11-21. Our previous AD scan showed evidence of linkage to loci at 3p and 18q, and furthermore at 4p15-14. In order to further investigate the genetic basis of AD, we collected and analysed a new Danish family sample consisting of 130 AD sib pair families (555 individuals including 295 children with AD). AD was diagnosed after clinical examination, AD severity was scored and specific IgE was determined. A linkage scan of chromosome 3, 4 and 18 was performed using 91 microsatellite markers. Linkage analyses were performed of dichotomous phenotypes and semi-quantitative traits including the AD severity score. We analysed the novel AD sample alone and together with the previously examined sample. AD severity showed a maximum Z-score of 3.7 at 4q22.1 suggesting the localization of a novel gene for AD severity. A maximum MOD score of 4.6 was obtained at 3p24 for the AD phenotype, providing the first significant linkage of AD at this locus. A maximum MLS score of 3.3 was obtained at 3q21 for IgE-associated AD, and evidence of linkage was also obtained at 3p22.2-21.31, 3q13, 4q35, and 18q12. The results presented should provide a firm basis for gene-targeting studies of AD and related disorders.

A functional CD86 polymorphism associated with asthma and related allergic disorders.

BACKGROUND: Several studies have documented a substantial genetic component in the aetiology of allergic diseases and a number of atopy susceptibility loci have been suggested. One of these loci is 3q21, at which linkage to multiple atopy phenotypes has been reported. This region harbours the CD86 gene encoding the costimulatory B7.2 protein. The costimulatory system, consisting of receptor proteins, cytokines and associated factors, activates T cells and regulates the immune response upon allergen challenge. METHODS: We sequenced the CD86 gene in patients with atopy from 10 families that showed evidence of linkage to 3q21. Identified polymorphisms were analysed in a subsequent family-based association study of two independent Danish samples, respectively comprising 135 and 100 trios of children with atopy and their parents. Functional analysis of the costimulatory effect on cytokine production was performed in an autologous cell-based system based on cells expressing CD86 variants. RESULTS: Two polymorphisms were identified, encoding the amino acid changes Ile179Val and Ala304Thr, respectively. Significant associations were observed between the Ile179Val polymorphism and allergy phenotypes in both samples (eg, asthma, p = 4 x 10(-3) in the two samples combined). The undertransmitted (protective) Val179 allele was found to induce higher production of both Th1 and Th2 cytokines than the overtransmitted (risk) Ile179 allele, suggesting a functional impact of the polymorphism. CONCLUSION: The CD86 gene, and specifically the Ile179Val polymorphism, may be a novel aetiological factor in the development of asthma and related allergic disorders.

No signature of Y chromosomal resemblance between possible descendants of the Cimbri in Denmark and Northern Italy.

Two European populations are believed to be related to the ancient Germanic tribe Cimbri: one living in Northern Italy, the other living in Jutland, Denmark. The people called Cimbri are documented in the ancient Roman historical record. Arriving from the far north their movements can be tracked from successive battles with the Romans. The Cimbri finally entered Italy from the northeast and were defeated at Vercellae (present day Vercelli) in 101 BC by Gaius Marius and his professional legions. Classical sources from the first centuries AD relate the homeland of the Cimbri to the coasts around the Elb estuary (northern Germany) or specifically towards the north (Himmerland in northern Jutland). In the alpine parts of Veneto, northeast of the historical battlefield, local traditions dating back to late medieval time, identify a local population as Cimbri living in Terra dei Cimbri. They are considered the descendents of the Germanic combatants that fled the battlefield at Vercelli. As the defeated Cimbri that possibly fled to the mountains of Northern Italy most likely would have been male (warriors), the present study investigated the possible Y chromosomal diversity of the two present populations using microsatellite markers and single nucleotide polymorphisms. While Cimbri from Himmerland resembled their geographical neighbors from Denmark for the Y-chromosome markers, Cimbri from Italy were significantly differentiated both from Cimbri from Himmerland and from Danes. Therefore, we were not able to show any biological relationship for uniparentally transmitted markers.

Family based association analysis of the IL2 and IL15 genes in allergic disorders.

Allergic diseases affect an increasing number of individuals and are a major global health problem. A substantial genetic contribution in the aetiology of allergic diseases is well documented. We have previously reported linkage of allergic diseases and atopy to the region harbouring the IL2 gene (4q27). IL15 is located approximately 20 Mb distal to IL2. The two genes encode cytokines that are structurally and functionally related, both inducing T-cell activation and proliferation. We screened the two genes for sequence variation and applied the seven single-nucleotide polymorphisms (SNPs) identified in a family based association study of two Danish samples comprising a total of 235 families with allergic diseases. None of the IL15 SNPs showed significant association and the haplotype analysis yielded inconsistent results in the two samples. In contrast, the two IL2 SNPs showed association both separately and in haplotypes with several atopic phenotypes, most significantly with IgE-mediated allergy. (single SNP P-value 0.0005 for positive skin prick test, haplotype P-value 0.019 for positive RAST test). To our knowledge, this is the first study reporting association between IL2 and IgE-mediated allergy, asthma and atopic eczema. The SNP (rs2069762) that showed the most consistent results is located in the promoter and has previously been shown to influence the level of IL2 expression. We suggest that the observed overtransmission of the T allele of this SNP may convey increased susceptibility to allergic disease by skewing the Th1/Th2 balance towards Th2.

Atopic dermatitis -- a total genome-scan for susceptibility genes.

Atopic dermatitis is one of the most common chronic diseases of childhood and closely related to other clinical manifestations of allergy. The incidence is high and still increasing. The genetic contribution to disease development is substantial and complex. Only recently genetic research has begun to focus on this phenotype, and specific susceptibility genes remain to be found. To identify candidate regions holding genes for atopic dermatitis we performed a genome-scan in Danish affected sib-pair families containing sib-pairs matching a phenotype definition of both clinical atopic dermatitis and confirmed specific allergy. The scan was undertaken using 446 microsatellite markers and non-parametric linkage results were obtained from the MAPMAKER/SIBS computer program. We found evidence of linkage to three candidate regions in chromosomes 3p (MLS=2.14), 4p (MLS=2.00) and 18q (MLS=2.25), one of which has not been reported previously. Eight additional regions showed weaker but positive results.

Possible gene dosage effect of glutathione-S-transferases on atopic asthma: using real-time PCR for quantification of GSTM1 and GSTT1 gene copy numbers.

Asthma is a complex genetic disorder characterized by chronic inflammation in the airways. As oxidative stress is a key component of inflammation, variations in genes involved in antioxidant defense could therefore be likely candidates for asthma. Three enzymes from the superfamily glutathione-S-transferase (GST) involved in the antioxidant defense were tested for association to asthma using 246 Danish atopic families in a family-based transmission disequilibrium test (TDT) design. A real-time PCR assay for relative quantification of gene copy number of GSTM1 and GSTT1 was developed. The assay made it possible to distinguish individuals with zero, one, and two copies and thereby to investigate whether the GST genes influenced susceptibility to asthma in a dose-dependent manner. We found that asthmatic patients with two copies of GSTM1 were significantly underrepresented (p<0.0005) and the significance increased by 10-fold when only atopic asthmatics were analyzed (p<0.00005). GSTT1 was significantly associated in an additive model to asthma, in which the alleles carrying the deletion of the gene were transmitted to affected offspring more often than expected by chance (p=0.019). The same transmission disequilibrium of the null GSTT1 allele was seen in patients with atopic asthma (p=0.021). The polymorphism c.342A>G (p.I105V) in GSTP1 has previously been suggested as a risk factor for asthma. However, significant association with asthma or related atopic phenotypes could not be established in our study. We conclude that deletions of GSTM1 and GSTT1 could be risk factors for asthma and that the genes might have a protective role in the development of atopic asthma.