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David P Strachan

Publications and source records attributed to David P Strachan.

At least 19 recordsLinked to original sources
PubMed2016

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Atlases as Topic↗
PubMed2007

50 years of asthma: UK trends from 1955 to 2004.

Trends in asthma indicators from population surveys (prevalence) and routine statistics (primary care, prescriptions, hospital admissions and mortality) in the UK were reviewed from 1955 to 2004. The prevalence of asthma increased in children by 2 to 3-fold, but may have flattened or even fallen recently. Current trends in adult prevalence are flat. The prevalence of a life-time diagnosis of asthma increased in all age groups. The incidence of new asthma episodes presenting to general practitioners increased in all ages to a plateau in the mid 1990s and has declined since. During the 1990s, the annual prevalence of new cases of asthma and of treated asthma in general practice showed no major change. Hospital admissions increased from the early 1960s, more so in children, until the late 1980s and have fallen since. Asthma mortality showed two waves, a shorter and more intense one in the mid 1960s and a longer and less intense one in the late 1970s and early 1980s. The relative roles of diagnostic transfer, coding changes, medical care and epidemiological factors are discussed.

Adolescent↗
PubMed2006

Childhood chest illness and the rate of decline of adult lung function between ages 35 and 45 years.

RATIONALE: There is an association between childhood chest illness and impairment of adult ventilatory function. It has not yet been established whether respiratory illness in childhood predisposes to chronic obstructive pulmonary disease by accelerating the decline in adult lung function. OBJECTIVES: To determine the effects of childhood chest illness and smoking on the rate of decline of adult ventilatory function from the age of 35 to 45 yr in a large, nationally representative sample of British adults. METHODS: Spirometry measurements were compared at 35 and 45 yr of age in 1,158 adults participating in the British 1958 Birth Cohort. Multiple regression analysis was used to measure the association between childhood chest illness and within-person change in spirometric volumes between age 35 and 45 yr, adjusting for potential confounding factors. MEASUREMENTS AND MAIN RESULTS: The mean reduction in FEV(1) between ages 35 and 45 yr was 35 ml/yr. Compared with subjects without the relevant respiratory history, the rate of decline was not significantly associated with pneumonia (mean difference, -0.2; 95% confidence interval, -6.1 to +5.8 ml/yr), whooping cough (0.7, -5.1 to +6.5 ml/yr), wheeze by age 7 yr (0.4, -5 to +5.9 ml/yr), or wheeze onset by age 8 to 16 yr (-3.4, -10.5 to +3.6 ml/yr). A similar pattern emerged for forced vital capacity. CONCLUSIONS: Childhood chest illness does not adversely affect the rate of decline of lung function in mid-adult life.

Adolescent↗
PubMed2006

Genetic variation in myosin IXB is associated with ulcerative colitis.

BACKGROUND & AIMS: Common germline genetic variation in the 3' region of myosin IXB (MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that MYO9B variants might influence intestinal permeability. These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease. METHODS: Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3' region of MYO9B. These included the strongest celiac disease-associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn's disease, 1520 with ulcerative colitis) and 4440 controls. RESULTS: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease. CONCLUSIONS: MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.

Adolescent↗
PubMed2006

Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys.

BACKGROUND: Data for trends in prevalence of asthma, allergic rhinoconjunctivitis, and eczema over time are scarce. We repeated the International Study of Asthma and Allergies in Childhood (ISAAC) at least 5 years after Phase One, to examine changes in the prevalence of symptoms of these disorders. METHODS: For the ISAAC Phase Three study, between 2002 and 2003, we did a cross-sectional questionnaire survey of 193,404 children aged 6-7 years from 66 centres in 37 countries, and 304,679 children aged 13-14 years from 106 centres in 56 countries, chosen from a random sample of schools in a defined geographical area. FINDINGS: Phase Three was completed a mean of 7 years after Phase One. Most centres showed a change in prevalence of 1 or more SE for at least one disorder, with increases being twice as common as decreases, and increases being more common in the 6-7 year age-group than in the 13-14 year age-group, and at most levels of mean prevalence. An exception was asthma symptoms in the older age-group, in which decreases were more common at high prevalence. For both age-groups, more centres showed increases in all three disorders more often than showing decreases, but most centres had mixed changes. INTERPRETATION: The rise in prevalence of symptoms in many centres is concerning, but the absence of increases in prevalence of asthma symptoms for centres with existing high prevalence in the older age-group is reassuring. The divergent trends in prevalence of symptoms of allergic diseases form the basis for further research into the causes of such disorders.

Adolescent↗
PubMed2006

Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study.

BACKGROUND: Functionally relevant polymorphisms of the beta2-adrenoceptor gene (ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the ADRB2 gene. METHODS: The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses. FINDINGS: Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36.3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44.6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16-Gln27 haplotype at these loci, 19.3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11.9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1.5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies. INTERPRETATION: ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population.

Adult↗
PubMed2006

Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial.

BACKGROUND: Epidemiological studies have shown inverse associations between geohelminth (intestinal helminth) infection and atopy, leading to the suggestion that geohelminths might protect against allergy. Periodic deworming of school children with anthelmintics is a widely implemented intervention and has raised concerns that such programmes could increase allergy. We investigated the effect of repeated anthelmintic treatments with albendazole over 12 months on the prevalence of atopy and clinical indices of allergy. METHODS: We did a cluster-randomised controlled trial in schoolchildren from 68 rural schools. Children were randomly assigned by school to either albendazole (34 schools, 1164 children) every 2 months for 12 months, or to no intervention (34 schools, 1209 children). The intervention schools received a total of seven albendazole treatments. The primary outcome was atopy at 12 months (allergen skin-test reactivity), and analysis was by intention-to-treat for whole-school analyses and per protocol for children. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN61195515. FINDINGS: Data for analysis were available for all schools and from 67.4% (784 of 1164) and 70.1% (848 of 1209) of children in albendazole and no-treatment groups, respectively. Albendazole treatment caused large reductions in geohelminth prevalence over the study period (adjusted odds ratio 0.13, 95% CI 0.09-0.19, p<0.001), but there was no evidence that treatment was associated with an increase in atopy prevalence (0.97, 0.68-1.39, p=0.862), or clinical allergy (wheeze, 1.07, 0.54-2.11, p=0.848) in the albendazole compared with the no-treatment group. INTERPRETATION: We saw no increase in the prevalence of atopy or clinical allergy associated with albendazole treatment. Deworming programmes for schoolchildren are unlikely to be accompanied by an increase in allergy.

Albendazole↗
PubMed2006

Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes.

BACKGROUND: Atopic illnesses, related to high circulating IgE levels, and the autoimmune disease type 1 diabetes, have been reported to be inversely associated. One possible explanation is that susceptibility alleles for one disease provide protection for the other. OBJECTIVE: Using the largest sample sizes reported so far for the identification of genetic determinants of circulating IgE levels, we investigated associations between total serum IgE (log-transformed) and single nucleotide polymorphisms in 8 genes that are candidate susceptibility loci for IgE levels/atopic illness (IL13, IL4, IL4RA, FCER1B, IL12B, TBET) and/or type 1 diabetes (CTLA4, PTPN22, IL2RA). METHODS: As many as 4570 DNA samples obtained from members of the British 1958 Birth Cohort were genotyped for 51 candidate variants, and the associations of alleles and genotypes with log-transformed serum IgE levels were evaluated by regression modeling. RESULTS: We obtained evidence of association between IL13 variants and total serum IgE levels (P = .00002, explaining 0.59% of phenotypic variance). However, there was no evidence of association of the confirmed type 1 diabetes susceptibility genes CTLA4 and PTPN22 and the candidate gene IL2RA with IgE levels. CONCLUSION: Allelic variation in the IL-13 gene is robustly confirmed as a contributor to the variance of IgE levels but has no detectable effect in type 1 diabetes. CLINICAL IMPLICATIONS: Although the allelic variation at the confirmed IL-13 locus explains too little of the between-individual variation of circulating IgE to be of use for clinical prediction on its own, the discovery of additional susceptibility loci in the future may aid in the stratification of atopic subjects and improve risk assessment.

Adolescent↗
PubMed2006

Which aspects of the farming lifestyle explain the inverse association with childhood allergy?

BACKGROUND: Farmers' children have a reduced prevalence of allergic disorders. The specific protective environmental factors responsible are not yet identified. OBJECTIVE: We sought to determine whether farmers' children in the rural county of Shropshire, England, have a reduced risk of atopy and, if so, to identify the factors responsible. METHODS: The Study of Asthma and Allergy in Shropshire was a 2-stage cross-sectional study. In stage 1 a questionnaire to elicit allergic status, diet, and farming exposure was completed by the parents of 4767 children. In stage 2 a stratified subsample of 879 children underwent skin prick testing and measurement of domestic endotoxin. RESULTS: Compared with rural nonfarming children, farmers' children had significantly less current asthma symptoms (adjusted odds ratio (OR), 0.67; 95% CI, 0.49-0.91; P = .01) and current seasonal allergic rhinitis (adjusted OR, 0.50; 95% CI, 0.33-0.77; P = .002) but not current eczema symptoms (adjusted OR, 0.91; 95% CI, 0.68-1.21; P = .53) or atopy (adjusted OR, 0.68; 95% CI, 0.40-1.16; P = .15). In contrast, current unpasteurized milk consumption was associated with significantly less current eczema symptoms (adjusted OR, 0.59; 95% CI, 0.40-0.87; P = .008) and a greater reduction in atopy (adjusted OR, 0.24; 95% CI, 0.10-0.53; P = .001). The effect was seen in all children, independent of farming status. Unpasteurized milk consumption was associated with a 59% reduction in total IgE levels (P < .001) and higher production of whole blood stimulated IFN-gamma (P = .02). CONCLUSION: Unpasteurized milk consumption was the exposure mediating the protective effect on skin prick test positivity. The effect was independent of farming status and present with consumption of infrequent amounts of unpasteurized milk. CLINICAL IMPLICATIONS: Unpasteurized milk might be a modifiable influence on allergic sensitization in children.

Agriculture↗
PubMed2006

The predictive value of early life total immunoglobulin E measurement in identifying atopic children in a population-based birth cohort study.

Atopy is common and the prevalence amongst children is rising. Measurements in early childhood that can predict subsequent development of atopy could be clinically useful for targeting preventive measures. We used the Children in Focus (CiF) subgroup of a large population-based birth cohort study (the Avon Longitudinal Study of Parents and Children) to investigate whether total immunoglobulin E (IgE) measured at 12 and 18 months could predict subsequent development of atopy at 5 yr of age. Atopy was determined by positive skin prick test (> or = 3 mm wheal) to one or more of 14 inhalant and food allergens. Prevalence of skin prick positivity to any allergen was 14.5% (104 of 715; 95% CI: 12.0-17.1%). Total IgE levels were significantly higher at 12 months of age (p < 0.0005) but not 18 months of age in those children subsequently atopic. The highest positive predictive value was 41% with an IgE measurement of >51 kU/l, with a sensitivity of 13.5% and a specificity of 95.8%. Although significant differences in early life IgE measurements were seen, the extent of overlap was great, such that the overall performance of IgE at 12 months as a screening test for atopy was poor.

Child, Preschool↗
PubMed2005

Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.

Case-Control Studies↗
PubMed2005

Relationship between travel time to the nearest hospital and survival from ruptured abdominal aortic aneurysms: record linkage study.

BACKGROUND: There is currently a trend in Britain to concentrate specialist services in a smaller number of hospitals in order to improve outcomes. However, for rapidly life-threatening conditions such as ruptured abdominal aortic aneurysms (RAAAs), the resulting increased travel time to hospital might adversely affect survival. This study aimed to evaluate the relationship between travel time to the nearest hospital and survival from RAAAs in West Sussex. METHODS: Information was collected regarding outcome, postcode, age, sex and diagnoses for all West Sussex residents who had a RAAA between January 1996 and September 1999, including admissions and deaths, wherever they occurred. Deprivation scores were calculated based on postcode. Potential travel time to the nearest hospital was calculated using "Microsoft AutoRoute Express" and its effect on outcome was analysed using multiple logistic regression. RESULTS: After adjusting for age, sex, Townsend deprivation score and nearest hospital, the odds ratio for survival associated with a 10 min increase in potential travel time to the nearest hospital was 0.97 (0.88 unadjusted) (95 percent confidence interval for adjusted odds ratio: 0.70 to 1.34; p = 0.86). CONCLUSION: Several previous studies suggested better survival with longer distances travelled. They are likely to be biased by omission of community deaths. This methodologically better study found no such relationship between RAAA survival and travelling time to hospital in West Sussex, although confidence intervals were wide. This is particularly pertinent while there is a push to centralize vascular and other services in the United Kingdom.

Aged↗
PubMed2005

Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes.

BACKGROUND: One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18). RESULTS: Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls. CONCLUSION: None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied.

Animals↗
PubMed2005

No evidence of association or interaction between the IL4RA, IL4, and IL13 genes in type 1 diabetes.

Attempts to identify susceptibility loci that, on their own, have marginal main effects by use of gene-gene interaction tests have increased in popularity. The results obtained from analyses of epistasis are, however, difficult to interpret. Gene-gene interaction, albeit only marginally significant, has recently been reported for the interleukin-4 and interleukin-13 genes (IL4 and IL13) with the interleukin-4 receptor A gene (IL4RA), contributing to the susceptibility of type 1 diabetes (T1D). We aimed to replicate these findings by genotyping both large family and case-control data sets and by using previously published data. Gene-gene interaction tests were performed using linear regression models in cases only. We did not find any single-locus associations with T1D and did not obtain evidence of gene-gene interaction. Additional support from independent samples will be even more important in the study of gene-gene interactions and other subgroup analyses.

Adolescent↗
PubMed2004

Developing a large electronic primary care database (Doctors' Independent Network) for research.

BACKGROUND AND OBJECTIVES: Primary care databases form a unique source of population-based clinical information on the prevalence and management of diagnosed disorders. Historically such databases have lacked individual level socio-economic markers. We describe the development of the Doctors' Independent Network (DIN) database for epidemiological and health services research. DIN includes a socio-economic marker (ACORN) based on postcode linkage at individual patient level. The validity of DIN is assessed against the General Practice Research Database (GPRD). METHODS: External validity is assessed by comparing the demographic structure and prevalence rates for treated ischemic heart disease (IHD) and treated hay fever with those from the GPRD. We assess the utility of a socio-economic measure (ACORN) based on postcode-linkage at individual patient level by examining the trend in prevalence rates of IHD and hay fever by ACORN index. RESULTS: 142 practices providing high quality data were selected, with 1827361 fully registered patients contributing data between 1992 and 2001, representing an identical age-sex structure to that for England & Wales and GPRD. Regionally adjusted prevalence of treated IHD (7.29 and 5.37%, respectively for men and women aged 35+ in 1998) in DIN was highly comparable to GPRD (7.27 and 5.42%). In DIN, the odds ratio of IHD was 1.37 (95% CI 1.30-1.44) in subjects living in "striving" compared to "thriving" areas. The prevalence of treated hay fever prevalence was similar across databases, with inverse associations seen with ACORN in DIN (higher rates in "thriving" areas). CONCLUSIONS: DIN provides comparable period prevalence rates to GPRD for two common conditions, with social trends as expected. Primary care databases such as these have the potential to replace the decennial national morbidity surveys carried out in UK general practices, with DIN having the important advantage of including a socio-economic index.

Adolescent↗
PubMed2004

The hygiene theory: fact or fiction?

PURPOSE OF REVIEW: The "hygiene hypothesis" offers a potentially credible and parsimonious explanation for the increasing prevalence of allergy noted in many westernized populations. The authors review recent evidence both for and against this hypothesis. RECENT FINDINGS: A strong body of epidemiologic evidence indicates that the original observations, namely of a birth order effect and increased risk of atopic disorders in those born into small, affluent households, are robust findings. Improved hygiene is believed to mediate its effect through decreased exposure to infectious agents in early life, and recent evidence has focused attention on the importance of the gastrointestinal microbial environment. In particular, infection with hepatitis A, Helicobacter pylori, and toxoplasma in those living in temperate climates, and geoheminths in those living in endemic areas, have been shown to be associated with reduced risk of atopic manifestations. It is postulated that these infections exert their effect through critically altering T-helper (Th)1/Th2 regulation, which is supported by the examination of the cytokine profiles of cord mononuclear cells when exposed to gastrointestinal flora and, furthermore, emerging evidence on the benefits of probiotics on symptoms of atopic dermatitis. Attempts to identify an inverse relation between Th1- and Th2-mediated disorders (as might be predicted by the Th1/Th2 paradigm) have, however, yielded conflicting results, raising the possibility that this model may be something of an oversimplification. SUMMARY: The hygiene hypothesis remains a credible but nonspecific explanation for observed variations over time, place and persons at risk for developing atopic allergic disorders. More prospective studies are needed to unravel which infectious agents exert a protective effect and the time period of importance for sensitization. The clinical implications of these advances in our understanding of the etiology of atopic allergic disorders are currently limited.

Adult↗