scholarly journals Pleiotropic effects of heterozygosity for the SERPINA1 Z allele in the UK Biobank

2020 ◽  
Author(s):  
Katherine A Fawcett ◽  
Kijoung Song ◽  
Guoqing Qian ◽  
Aliki-Eleni Farmaki ◽  
Richard Packer ◽  
...  
Keyword(s):  
Lung Function ◽  
Rare Condition ◽  
Population Based ◽  
Uk Biobank ◽  
Mineral Density ◽  
Increased Risk ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
The Uk ◽  
Reduced Risk

Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear. We conducted the largest population-based study to date to determine Z allele effects on >2,400 phenotypes using the UK Biobank study (N>303,353). We detected strong associations between heterozygosity and non-respiratory phenotypes including increased height, increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher lung function in non-smokers, but smoking appears to abolish this protective effect. Individuals heterozygous for the Z allele may therefore have altered risk of smoking-induced lung disease and other, non-respiratory conditions.

scholarly journals Pleiotropic associations of heterozygosity for the SERPINA1 Z allele in the UK Biobank

2021 ◽  
pp. 00049-2021
Author(s):  
Katherine A. Fawcett ◽  
Kijoung Song ◽  
Guoqing Qian ◽  
Aliki-Eleni Farmaki ◽  
Richard Packer ◽  
...  
Keyword(s):  
Lung Function ◽  
Disease Risk ◽  
Large Population ◽  
Rare Condition ◽  
Forced Expiratory Volume ◽  
Uk Biobank ◽  
Mineral Density ◽  
Increased Risk ◽  
The Uk ◽  
Reduced Risk

Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear.We conducted a large population-based study to determine Z allele effects on >2400 phenotypes in UK Biobank (N>303 353).Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other non-respiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (FEV1/FVC) (β=0.0031, p=1.22×10−5) in non-smokers, whereas in smokers this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function.We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with non-respiratory health-related traits and disease risk.

scholarly journals Lifetime depression and age-related changes in body composition, cardiovascular function, grip strength and lung function: sex-specific analyses in the UK Biobank

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S44-S44
Author(s):  
Julian Mutz ◽  
Cathryn M Lewis
Keyword(s):  
Body Composition ◽  
Lung Function ◽  
Cardiovascular Function ◽  
Healthy Controls ◽  
Physiological Measures ◽  
Uk Biobank ◽  
Mineral Density ◽  
Age Related ◽  
The Uk ◽  
Age Related Changes

AimsIndividuals with mental disorders, on average, die prematurely, have higher levels of physical comorbidities and may experience accelerated ageing. In individuals with lifetime depression and healthy controls, we examined associations between age and multiple physiological measures.MethodThe UK Biobank study recruited >500,000 participants, aged 37–73 years, between 2006–2010. Generalised additive models were used to examine associations between age and grip strength, cardiovascular function, body composition, lung function and bone mineral density. Analyses were conducted separately in males and females with depression compared to healthy controls.ResultAnalytical samples included up to 342,393 adults (mean age = 55.87 years; 52.61% females). We found statistically significant differences between individuals with depression and healthy controls for most physiological measures, with standardised mean differences between -0.145 and 0.156. There was some evidence that age-related changes in body composition, cardiovascular function, lung function and heel bone mineral density followed different trajectories in individuals with depression. These differences did not uniformly narrow or widen with age. For example, BMI in female cases was 1.1 kg/m2 higher at age 40 and this difference narrowed to 0.4 kg/m2 at age 70. In males, systolic blood pressure was 1 mmHg lower in cases at age 45 and this difference widened to 2.5 mmHg at age 65.ConclusionIndividuals with depression differed from healthy controls across a broad range of physiological measures. Differences in ageing trajectories differed by sex and were not uniform across physiological measures, with evidence of both age-related narrowing and widening of case-control differences.

scholarly journals Altered Cortical Brain Structure and Increased Risk for Disease Seen Decades After Perinatal Exposure to Maternal Smoking: A Study of 9000 Adults in the UK Biobank

2019 ◽  
Vol 29 (12) ◽  
pp. 5217-5233 ◽  
Author(s):  
Lauren E Salminen ◽  
Rand R Wilcox ◽  
Alyssa H Zhu ◽  
Brandalyn C Riedel ◽  
Christopher R K Ching ◽  
...  
Keyword(s):  
Brain Structure ◽  
Brain Mri ◽  
Population Based ◽  
Smoke Exposure ◽  
Sensitivity Analyses ◽  
Uk Biobank ◽  
Increased Risk ◽  
Increase Risk ◽  
Sensory Cortices ◽  
The Uk

Abstract Secondhand smoke exposure is a major public health risk that is especially harmful to the developing brain, but it is unclear if early exposure affects brain structure during middle age and older adulthood. Here we analyzed brain MRI data from the UK Biobank in a population-based sample of individuals (ages 44–80) who were exposed (n = 2510) or unexposed (n = 6079) to smoking around birth. We used robust statistical models, including quantile regressions, to test the effect of perinatal smoke exposure (PSE) on cortical surface area (SA), thickness, and subcortical volumes. We hypothesized that PSE would be associated with cortical disruption in primary sensory areas compared to unexposed (PSE−) adults. After adjusting for multiple comparisons, SA was significantly lower in the pericalcarine (PCAL), inferior parietal (IPL), and regions of the temporal and frontal cortex of PSE+ adults; these abnormalities were associated with increased risk for several diseases, including circulatory and endocrine conditions. Sensitivity analyses conducted in a hold-out group of healthy participants (exposed, n = 109, unexposed, n = 315) replicated the effect of PSE on SA in the PCAL and IPL. Collectively our results show a negative, long term effect of PSE on sensory cortices that may increase risk for disease later in life.

scholarly journals COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

2017 ◽  
Vol 26 (146) ◽  
pp. 170068 ◽  
Author(s):  
Haitham S. Al Ashry ◽  
Charlie Strange
Keyword(s):  
General Population ◽  
Population Based ◽  
Rapid Decline ◽  
Augmentation Therapy ◽  
Ongoing Debate ◽  
Increased Risk ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Study Designs

Since the discovery of severe alpha-1 antitrypsin deficiency as a genetic risk factor for emphysema, there has been ongoing debate over whether individuals with intermediate deficiency with one protease inhibitor Z allele (PiMZ, or MZ) are at some risk for emphysema. This is important, because MZ individuals comprise 2–5% of the general population. In this review we summarise the evidence about the risks of the MZ population to develop emphysema or asthma. We discuss the different study designs that have tried to answer this question. The risk of emphysema is more pronounced in case–control than in population-based studies, perhaps due to inadequate power. Carefully designed family studies show an increased risk of emphysema in MZ smokers. This is supported by the rapid decline in lung function of MZ individuals when compared to the general population after massive environmental exposures. The risk of asthma in MZ subjects is less studied, and more literature is needed before firm conclusions can be made. Augmentation therapy in MZ individuals is not supported by any objective studies. MZ smokers are at increased risk for emphysema that is more pronounced when other environmental challenges are present.

scholarly journals Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis of the UK Biobank

2020 ◽  
Author(s):  
Ruth K Topless ◽  
Amanda Phipps-Green ◽  
Megan Leask ◽  
Nicola Dalbeth ◽  
Lisa K Stamp ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Population Based ◽  
Data Sets ◽  
Uk Biobank ◽  
Control Cohort ◽  
Risk Of Death ◽  
Increased Risk ◽  
Adjusted Logistic Regression ◽  
The Uk

AbstractObjectiveTo assess whether gout and / or rheumatoid arthritis (RA) are risk factors for coronavirus disease 19 (COVID-19) diagnosis. To assess whether gout and / or RA are risk factors for death from COVID-19.MethodsWe used data from the UK Biobank. Multivariate-adjusted logistic regression was employed in the following analyses. Analysis A: to test for association between gout or RA and COVID-19 diagnosis in a population-based cohort (n=473,139). Analysis B: to test for association between gout or RA and death from COVID-19 in a case-control cohort of people who died or survived with COVID-19 (n=2,073). Analysis C: to test for association with gout or RA and death from COVID-19 in a population-based cohort (n=473,139)ResultsNeither RA nor gout associated with COVID-19 diagnosis in analysis A, nor did RA or gout associate with risk of death in the COVID-19-diagnosed group in analysis B. However RA associated with risk of death from COVID-19 using the population-based cohort in analysis C independent of comorbidities and other measured risk factors (OR=1.8 [95% CI 1.2 ; 2.7]). Gout was not associated with death from COVID-19 in the same population-based analysis (OR=1.2 [95% CI 0.9 ; 1.7]).ConclusionsRA and gout are not risk factors for COVID-19-diagnosis. However RA, but not gout, is a risk factor for death from COVID-19 in a population-based analysis using the UK Biobank. These findings require replication in larger data sets that also allow inclusion of a wider range of factors.Key messagesWhat is already known?Information on the risk of death from COVID-19 for people with gout and rheumatoid arthritis is scarce.What does this study add?In a population-based analysis there is an increased risk of death by COVID-19 for people with rheumatoid arthritis independent of co-morbidities, but not gout.The findings need to be replicated in other datasets where the influence of therapies for RA can be tested.How might this impact on clinical practice?Improved clinical management and treatment for RA patients with COVID-19.

scholarly journals Altered cortical brain structure and increased risk for disease seen decades after perinatal exposure to maternal smoking: A study of 9,000 adults in the UK Biobank

2018 ◽  
Author(s):  
Lauren E. Salminen ◽  
Rand R. Wilcox ◽  
Alyssa H. Zhu ◽  
Brandalyn C. Riedel ◽  
Christopher R. K. Ching ◽  
...  
Keyword(s):  
Brain Structure ◽  
Brain Mri ◽  
Population Based ◽  
Smoke Exposure ◽  
Sensitivity Analyses ◽  
Uk Biobank ◽  
Increased Risk ◽  
Increase Risk ◽  
Sensory Cortices ◽  
The Uk

AbstractSecondhand smoke exposure is a major public health risk that is especially harmful to the developing brain, but it is unclear if early exposure affects brain structure during middle age and older adulthood. Here we analyzed brain MRI data from the UK Biobank in a population-based sample of individuals (ages 44-80) who were exposed (n=2,510) or unexposed (n=6,079) to smoking around birth. We used robust statistical models, including quantile regressions, to test the effect of perinatal smoke exposure (PSE) on cortical surface area (SA), thickness, and subcortical volume. We hypothesized that PSE would be associated with cortical disruption in primary sensory areas compared to unexposed (PSE-) adults. After adjusting for multiple comparisons, SA was significantly lower in the pericalcarine (PCAL), inferior parietal (IPL), and regions of the temporal and frontal cortex of PSE+adults; these abnormalities were associated with increased risk for several diseases, including circulatory and endocrine conditions. Sensitivity analyses conducted in a hold-out group of healthy participants (exposed, n=109, unexposed, n=315) replicated the effect of PSE on SA in the PCAL and IPL. Collectively our results show a negative, long term effect of PSE on sensory cortices that may increase risk for disease later in life.

scholarly journals Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽  
2021 ◽  
pp. n214
Author(s):  
Weedon MN ◽  
Jackson L ◽  
Harrison JW ◽  
Ruth KS ◽  
Tyrrell J ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Predictive Value ◽  
Population Based ◽  
Genome Project ◽  
Personal Genome ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Snp Chip ◽  
Pathogenic Variants ◽  
The Uk

Abstract Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

scholarly journals Air Trapping Is Associated with Heterozygosity for Alpha-1 Antitrypsin Mutations in Patients with Asthma

Respiration ◽  
2021 ◽  
pp. 1-10
Author(s):  
Marina Aiello ◽  
Marianna Ghirardini ◽  
Laura Marchi ◽  
Annalisa Frizzelli ◽  
Roberta Pisi ◽  
...  
Keyword(s):  
Lung Function ◽  
Serum Concentration ◽  
Forced Expiratory Volume ◽  
Small Airway ◽  
University Hospital ◽  
Air Trapping ◽  
Asthmatic Patients ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Few Data

<b><i>Background:</i></b> Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder involving lungs, characterized by low serum concentration of the protein alpha-1 antitrypsin (AAT) also called proteinase inhibitor (PI). Asthma is common in AATD patients, but there are only few data on respiratory function in asthmatic patients with AATD. <b><i>Objectives:</i></b> The aim of the study was to evaluate lung function in asthmatic outpatients with mutation in the <i>SERPINA1</i> gene coding for AAT versus asthmatic subjects without mutation. <b><i>Methods:</i></b> We performed the quantitative analysis of the serum concentration of AAT in 600 outpatients affected by mild to moderate asthma from the University Hospital of Parma, Italy. Fifty-seven of them underwent the genetic analysis subsequently; they were subdivided into mutated and non-mutated subjects. All the mutated patients had a heterozygous genotype, except 1 (PI*SS). We assessed the lung function through a flow-sensing spirometer and the small airway parameters through an impulse oscillometry system. <b><i>Results:</i></b> The values of forced vital capacity (% predicted) and those of the residual volume to total lung capacity ratio (%) were, respectively, lower and higher in patients mutated versus patients without mutation, showing a significantly greater air trapping (<i>p =</i> 0.014 and <i>p =</i> 0.017, respectively). Moreover, patients with mutation in comparison to patients without mutation showed lower forced expiratory volume in 3 s (% predicted) and forced expiratory volume in 6 s (L) spirometric values, reflecting a smaller airways contribution. <b><i>Conclusions:</i></b> In asthmatic patients, heterozygosity for AAT with PI*MZ and PI*MS genotypes was associated with small airway dysfunction and with lung air trapping.

scholarly journals Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1514
Author(s):  
Shing Fung Lee ◽  
Maja Nikšić ◽  
Bernard Rachet ◽  
Maria-Jose Sanchez ◽  
Miguel Angel Luque-Fernandez
Keyword(s):  
Cancer Patients ◽  
Socioeconomic Inequalities ◽  
Uk Biobank ◽  
Incident Cancer ◽  
Increased Risk ◽  
Exposure Variable ◽  
Independent Risk Factors ◽  
The Uk ◽  
Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

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