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Alpha-1 antitrypsin deficiency: From the lung to the heart?


Abstract

BACKGROUND AND AIMS Alpha-1 antitrypsin (A1AT) is the most abundant serine protease inhibitor in human blood and exerts important anti-inflammatory and immune-modulatory effects. In combination with smoking or other long-term noxious exposures such as occupational dust and fumes, genetic A1AT deficiency can cause chronic obstructive pulmonary disease, a condition with elevated cardiovascular risk. The effects of A1AT deficiency on cardiovascular risk have hardly been studied today. METHODS Using data from 2614 adults from the population-based SAPALDIA cohort, we tested associations of serum A1AT and SERPINA1 mutations with carotid intima-media thickness (CIMT, measured by B-mode ultrasonography) or self-reported arterial hypertension or cardiovascular disease in multiple regression models using a Mendelian Randomization like analysis design. Mutations Pi-S and Pi-Z were coded as ordinal genotype score (MM, MS, MZ/SS, SZ and ZZ), according to their progressive biological impact. RESULTS Serum A1AT concentration presented a u-shaped association with CIMT. At the lower end of the A1AT distribution, an analogous, linear association between SERPINA1 score and higher CIMT was observed, resulting in an estimated 1.2% (95%-confidence interval -0.1-2.5) increase in CIMT per unit (p = 0.060). Genotype score was significantly associated with arterial hypertension with an odds ratio (OR) of 1.2 (1.0-1.5) per unit (p = 0.028). The association with cardiovascular disease was not significant (OR 1.3 (0.9-1.9)). CONCLUSIONS Our results support a possible causal relationship between genetic A1AT deficiency and increased cardiovascular risk, which needs to be better taken into account for the management of affected patients and first-degree relatives.

Abstract

BACKGROUND AND AIMS Alpha-1 antitrypsin (A1AT) is the most abundant serine protease inhibitor in human blood and exerts important anti-inflammatory and immune-modulatory effects. In combination with smoking or other long-term noxious exposures such as occupational dust and fumes, genetic A1AT deficiency can cause chronic obstructive pulmonary disease, a condition with elevated cardiovascular risk. The effects of A1AT deficiency on cardiovascular risk have hardly been studied today. METHODS Using data from 2614 adults from the population-based SAPALDIA cohort, we tested associations of serum A1AT and SERPINA1 mutations with carotid intima-media thickness (CIMT, measured by B-mode ultrasonography) or self-reported arterial hypertension or cardiovascular disease in multiple regression models using a Mendelian Randomization like analysis design. Mutations Pi-S and Pi-Z were coded as ordinal genotype score (MM, MS, MZ/SS, SZ and ZZ), according to their progressive biological impact. RESULTS Serum A1AT concentration presented a u-shaped association with CIMT. At the lower end of the A1AT distribution, an analogous, linear association between SERPINA1 score and higher CIMT was observed, resulting in an estimated 1.2% (95%-confidence interval -0.1-2.5) increase in CIMT per unit (p = 0.060). Genotype score was significantly associated with arterial hypertension with an odds ratio (OR) of 1.2 (1.0-1.5) per unit (p = 0.028). The association with cardiovascular disease was not significant (OR 1.3 (0.9-1.9)). CONCLUSIONS Our results support a possible causal relationship between genetic A1AT deficiency and increased cardiovascular risk, which needs to be better taken into account for the management of affected patients and first-degree relatives.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Uncontrolled Keywords:Cardiology and Cardiovascular Medicine
Language:English
Date:March 2018
Deposited On:19 Jun 2018 11:15
Last Modified:24 Sep 2019 23:31
Publisher:Elsevier
ISSN:0021-9150
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.atherosclerosis.2018.01.042
PubMed ID:29432934
Project Information:
  • : FunderSNSF
  • : Grant ID4026-028099
  • : Project TitleSwiss study on air pollution and lung diseases in adults (SAPALDIA study)
  • : FunderSNSF
  • : Grant ID324730_135673
  • : Project TitleAir Pollution Exposure Assessment in Eight Swiss Areas
  • : FunderSNSF
  • : Grant ID3200-042532
  • : Project TitleSwiss Study on Air Pollution and Lung Diseases in Adults: Participants'Follow-up and Further Analysis.
  • : FunderSNSF
  • : Grant ID3247-065896
  • : Project TitleThe SAPALDIA II Cohort Study:Impact of environmental and personalrisk factors on the occurrence, course, remission and progressionof respiratory diseases in the Swiss population.
  • : FunderSNSF
  • : Grant ID3100-059302
  • : Project TitleThe SAPALDIA II Cohort Study:Impact of environmental and personalrisk factors on the occurrence, course, remission and progressionof respiratory diseases in the Swiss population.
  • : FunderSNSF
  • : Grant ID3200-052720
  • : Project TitleSwiss Study on Air Pollution and Lung Diseases in Adults: Mortality follow-up extension.

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