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

ABSTRACT: Homozygosity for the SERPINA1 Z allele causes α₁-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory 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 the 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 nonrespiratory 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 (β=0.0031, p=1.22×10^-5) in nonsmokers, 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 nonrespiratory health-related traits and disease risk.

SUBMITTER: Fawcett KA

PROVIDER: S-EPMC8107350 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Fawcett Katherine A KA Song Kijoung K Qian Guoqing G Farmaki Aliki-Eleni AE Packer Richard R John Catherine C Shrine Nick N Granell Raquel R Ring Sue S Timpson Nicholas J NJ Yerges-Armstrong Laura M LM Eastell Richard R Wain Louise V LV Scott Robert A RA Tobin Martin D MD Hall Ian P IP

ERJ open research 20210401 2

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory 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 the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3 ...[more]

PMID: 33981765

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Project description:IntroductionRetinal vasculometry (RV) provides a neurovascular biomarker which may relate to cognitive status. However, the presence and form of association remains unclear and unexamined at scale.MethodsArtificial intelligence-enabled RV measures from 66,350 UK Biobank study participants were related to combined cognition scores. Differences in RV were examined per standard deviation (SD) increase in cognitive score, using multilevel linear regression, adjusted for age, sex, measurement center, ethnicity, and within-person RV clustering.ResultsOne hundred ten thousand two hundred eighty-two retinal images from 63,165 (95%) participants (mean age 56.6 years, 55.5% female) were analyzed. A one SD increase in cognition score was strongly associated with increased arteriolar width, arteriolar tortuosity, increased venular width particularly among those < 50 years and venular area among those > 50 years; also, inversely associated with venular tortuosity, and arteriolar and venular width variance.DiscussionThese easily accessible, affordable, and non-invasive RV measures should be evaluated further as an early predictor of future neurodegenerative disease.HighlightsHow cognitive status relates to retinal vasculometry (RV) measures remains uncertain and unexamined at scale.Using data from a large population-based study (UK Biobank) we show strong graded associations between cognitive status and RV, which contrast with some RV associations observed with aging. Specifically, increased arteriolar tortuosity, arteriolar and venular width (at younger ages), and area are positively associated, and venular tortuosity and arteriolar and venular width variability are inversely associated with higher cognitive status, all showing strong, graded, precise relationships. These associations appeared to be strongest for fluid intelligence and prospective memory tests.These easily accessible, non-invasive RV measures provide a neurovascular marker indicative of cognitive status, which should be evaluated as early predictors of neurodegenerative disease.

Project description:Later chronotype (i.e. evening preference) and later timing of sleep have been associated with greater morbidity, including higher rates of metabolic dysfunction and cardiovascular disease (CVD). However, no one has examined whether chronotype is associated with mortality risk to date. Our objective was to test the hypothesis that being an evening type is associated with increased mortality in a large cohort study, the UK Biobank. Our analysis included 433 268 adults aged 38-73 at the time of enrolment and an average 6.5-year follow-up. The primary exposure was chronotype, as assessed through a single self-reported question-defining participants as definite morning types, moderate morning types, moderate evening types or definite evening types. The primary outcomes were all-cause mortality and mortality due to CVD. Prevalent disease was also compared among the chronotype groups. Analyses were adjusted for age, sex, ethnicity, smoking, body mass index, sleep duration, socioeconomic status and comorbidities. Greater eveningness, particularly being a definite evening type, was significantly associated with a higher prevalence of all comorbidities. Comparing definite evening type to definite morning type, the associations were strongest for psychological disorders (OR 1.94, 95% CI 1.86-2.02, p = < 0.001), followed by diabetes (OR 1.30, 95% CI 1.24-1.36, p = < 0.001), neurological disorders (OR 1.25, 95% CI 1.20-1.30, p = < 0.001), gastrointestinal/abdominal disorders (OR 1.23, 95% CI 1.19-1.27, p = < 0.001) and respiratory disorders (OR 1.22, 95% CI 1.18-1.26, p = < 0.001). The total number of deaths was 10 534, out of which 2127 were due to CVD. Greater eveningness, based on chronotype as an ordinal variable, was associated with a small increased risk of all-cause mortality (HR 1.02, 95% CI 1.004-1.05, p = 0.017) and CVD mortality (HR 1.04, 95% CI 1.00-1.09, p = 0.06). Compared to definite morning types, definite evening types had significantly increased risk of all-cause mortality (HR 1.10, 95% CI 1.02-1.18, p = 0.012). This first report of increased mortality in evening types is consistent with previous reports of increased levels of cardiometabolic risk factors in this group. Mortality risk in evening types may be due to behavioural, psychological and physiological risk factors, many of which may be attributable to chronic misalignment between internal physiological timing and externally imposed timing of work and social activities. These findings suggest the need for researching possible interventions aimed at either modifying circadian rhythms in individuals or at allowing evening types greater working hour flexibility.

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

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Pleiotropic associations of heterozygosity for the <i>SERPINA1</i> Z allele in the UK Biobank.

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

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Pleiotropic associations of heterozygosity for the &lt;i&gt;SERPINA1&lt;/i&gt; Z allele in the UK Biobank.

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Pleiotropic associations of heterozygosity for the <i>SERPINA1</i> Z allele in the UK Biobank.