Summary Background Congenital anomalies are a leading cause of infant death and disability and their incidence varies between ethnic groups in the UK. Rates of infant death are highest in children of ...Pakistani origin, and congenital anomalies are the most common cause of death in children younger than 12 in this ethnic group. We investigated the incidence of congenital anomalies in a large multiethnic birth cohort to identify the causes of the excess of congenital anomalies in this community. Methods We obtained questionnaire data from the mothers of children with one or more anomalies from the Born in Bradford study, a prospective birth cohort study of 13 776 babies and their families in which recruitment was undertaken between 2007 and 2011. Details of anomalies were prospectively reported to the study and we cross checked these details against medical records. We linked data for anomalies to maternal questionnaire and clinical data gathered as part of the Born in Bradford study. We calculated univariate and multivariate risk ratios (RRs) with 95% CIs for various maternal risk factors. Findings Of 11 396 babies for whom questionnaire data were available, 386 (3%) had a congenital anomaly. Rates for congenital anomaly were 305·74 per 10 000 livebirths, compared with a national rate of 165·90 per 10 000. The risk was greater for mothers of Pakistani origin than for those of white British origin (univariate RR 1·96, 95% CI 1·56–2·46). Overall, 2013 (18%) babies were the offspring of first-cousin unions. These babies were mainly of Pakistani origin—1922 (37%) of 5127 babies of Pakistani origin had parents in first-cousin unions. Consanguinity was associated with a doubling of risk for congenital anomaly (multivariate RR 2·19, 95% CI 1·67–2·85); we noted no association with increasing deprivation. 31% of all anomalies in children of Pakistani origin could be attributed to consanguinity. We noted a similar increase in risk for mothers of white British origin older than 34 years (multivariate RR 1·83, 95% CI 1·14–3·00). Maternal education to degree level was protective (0·53, 95% CI 0·38–0·75), irrespective of ethnic origin. Interpretation Consanguinity is a major risk factor for congenital anomaly. The risk remains even after adjustment for deprivation, and accounts for almost a third of anomalies in babies of Pakistani origin. High levels of educational attainment are associated with reduced risk in all ethnic groups. Our findings will be valuable in health promotion and public health, and to those commissioning antenatal, paediatric, and clinical genetic services. Sensitive advice about the risks should be provided to communities at increased risk, and to couples in consanguineous unions, to assist in reproductive decision making. Funding National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care programme.
Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a ...perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3′ → 5′ DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1−/− mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objectives: The aim of this paper is to describe the current knowledge about inherited diseases in UK children of Pakistani origin, who now number over 300,000, and to investigate disease ...associations with parental consanguinity. Methods: Published data on the overall prevalence of inherited diseases were reviewed in conjunction with published and unpublished information from the city of Bradford where there is a large resident Pakistani community. Results: There is significant literature on infant mortality, congenital anomalies, disabilities and many clinical conditions, often drawing attention to ethnic variations and an increased disease prevalence in UK Pakistani children. A further analysis is frequently necessary to differentiate both between genetic and non-genetic causes, and Pakistani and non-Pakistani children, who collectively have been labelled as ‘Asian' or ‘South Asian'. Conclusions: The analysis suggests that much of the increased mortality and morbidity in UK Pakistani children is due to autosomal recessive conditions. Evidence suggests that this finding is associated with the custom of consanguineous marriage, but future studies might also explore the role of community endogamy. Prevalence data from the first and second post-migration generations could additionally be useful in informing health planning in Pakistan.
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of ...mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACTInfant mortality rates vary considerably among ethnic groups in the United Kingdom, with the highest rates in Pakistani infants. The most common causes of infant death are related to ...immaturity, but in Pakistani babies, the most common cause is congenital anomalies, including consanguineous unions. The disparity in risk of congenital anomalies cannot be totally explained by socioeconomic differences between Pakistani and white British groups. Bradford is an ethnically diverse city with high levels of socioeconomic deprivation. This study was undertaken to determine the causes for the excess of congenital anomalies seen in babies born in Bradford.The Born in Bradford study is an ongoing prospective birth cohort study of 12,453 women with 13,776 pregnancies recruited in 2007 to 2011. Data included information on demographics, clinical outcomes, and risk factors, which included ethnic origin (white British, Pakistani, other), maternal age (<20, 20–34, ≥34 y), educational attainment, socioeconomic status, smoking, alcohol consumption, and consanguinity. Risks were calculated for all ethnic groups and separately for white British, Pakistani, and other groups. The population attributable risk was calculated for the offspring of first-cousin parents in the Pakistani community.Congenital anomalies were identified in 386 (3%) of 11,396 cases for whom questionnaire data were available. The national rate for congenital anomalies, excluding chromosomal disorders, was 165.90 per 10,000 live births compared with a rate of 305.74 per 10,000 live births in this study. Ethnic origins included 39% white British, 45% Pakistani, and 15% other (43 different ethnicities). Sixty percent of Pakistani babies had anomalies compared with 45% in the cohort overall. In the white British subgroup, significantly more babies with an anomaly were born to mothers 34 years or older than to those 20 years or younger to 34 years. Mothers with a higher level of education were less likely to have babies with an anomaly than were mothers of other educational levels. Maternal smoking, alcohol consumption, and obesity were not risk factors for congenital anomalies. For 18% of mothers, their partners were their first cousins. Fewer than 1% of babies of white British origin were the offspring of first-cousin unions compared with 38% of those in the Pakistani subgroup and 5% of those in the other subgroup. Anomalies were present in 6% of offspring of first-cousin unions and 5% of those of more distantly related parents. Mothers in first-cousin unions were more than twice as likely to have a baby with an anomaly than were mothers in nonconsanguineous unions; rates for nonconsanguineous unions did not differ significantly among ethnic groups. No significant effect was seen for the interaction between deprivation and consanguinity on risk of congenital anomaly (interaction RR, 0.99; 95% confidence interval, 0.97–1.01). For the offspring of first-cousin parents in the Pakistani population, the population attributable risk was 30.7%, and the RR was 2.18.These results indicate that consanguinity is a major risk factor for congenital anomalies. Antenatal counseling covers the risks associated with advanced maternal age, medications, and alcohol consumption, but should also include advice about the risks associated with consanguinity. Culturally sensitive information about the risks of consanguineous unions and congenital anomalies should be available and communicated to couples and local communities. Health professionals should be aware of the increased risks because these risks will result in an increased need for antenatal, pediatric, and genetic services.
Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The ...objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151)). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. ...About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.
Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically ...determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV
) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV
changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10
; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10
, replication p=5.9×10
) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV
decline in patients taking ICS (C allele β 56.36 mL·year
, 95% CI 29.96-82.76 mL·year
) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β -27.57 mL·year
, 95% CI -53.27- -1.87 mL·year
).The study uncovered genetic factors associated with FEV
changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.
Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, ...centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.
Genome-wide mRNA profiling in lung tissue from human and animal models can provide novel insights into the pathogenesis of chronic obstructive pulmonary disease (COPD). While 6 months of smoke ...exposure are widely used, shorter durations were also reported. The overlap of short term and long-term smoke exposure in mice is currently not well understood, and their representation of the human condition is uncertain. Lung tissue gene expression profiles of six murine smoking experiments (n = 48) were obtained from the Gene Expression Omnibus (GEO) and analyzed to identify the murine smoking signature. The "human smoking" gene signature containing 386 genes was previously published in the lung eQTL study (n = 1,111). A signature of mild COPD containing 7 genes was also identified in the same study. The lung tissue gene signature of "severe COPD" (n = 70) contained 4,071 genes and was previously published. We detected 3,723 differentially expressed genes in the 6 month-exposure mice datasets (FDR <0.1). Of those, 184 genes (representing 48% of human smoking) and 1,003 (representing 27% of human COPD) were shared with the human smoking-related genes and the COPD severity-related genes, respectively. There was 4-fold over-representation of human and murine smoking-related genes (P = 6.7 × 10
) and a 1.4 fold in the severe COPD -related genes (P = 2.3 × 10
). There was no significant enrichment of the mice and human smoking-related genes in mild COPD signature. These data suggest that murine smoke models are strongly representative of molecular processes of human smoking but less of COPD.
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