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The APOE ?4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study.

ABSTRACT: INTRODUCTION:Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function. OBJECTIVES:We assessed whether an association exists between the polymorphic human APOE ?2, ?3, and ?4 alleles and pulmonary function among participants in the Long Life Family Study. METHODS:Data from 4,468 Caucasian subjects who had genotyping performed for the APOE ?2, ?3, and ?4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the ?2 allele, defined as ?2/2 or ?2/3 genotypes, and the ?4 allele, defined as ?3/4 or ?4/4 genotypes, which were compared to the ?3/3 genotype. RESULTS:The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the ?4 allele as compared to women with the ?3/3 genotype or the ?2 allele. Carriage of the APOE ?4 allele was associated with FEV1/FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease. CONCLUSIONS:This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE ?4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals.

SUBMITTER: Kulminski AM

PROVIDER: S-EPMC6226172 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The APOE ε4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study.

Kulminski Alexander M AM Barochia Amisha V AV Loika Yury Y Raghavachari Nalini N Arbeev Konstantin G KG Wojczynski Mary K MK Thyagarajan Bharat B Vardarajan Badri N BN Christensen Kaare K Yashin Anatoliy I AI Levine Stewart J SJ

PloS one 20181109 11

<h4>Introduction</h4>Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function.<h4>Objectives</h4>We assessed whether an association exists between the polymorphic human APOE ε2, ε3, and ε4 alleles and pulmonary function among participants in the Long Life Family Study.<h4>Methods</h4>Data from 4,468 Caucasian subjects who had ge ...[more]

PMID: 30412599

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Project description:BackgroundThe apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer's disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility.Methods and findingsThis rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018).ConclusionsContrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.

Project description:BACKGROUND:Adipose tissue produces leptin, which is pro-inflammatory, and adiponectin, which has anti-inflammatory properties. Participants with chronic spinal cord injury (SCI) have increased body fat and are at increased risk for respiratory illness. OBJECTIVE:To assess the associations between leptin and adiponectin with pulmonary function in a chronic SCI cohort. DESIGN:Cross-sectional study. SETTING:Veterans Affairs Medical Center. PARTICIPANTS:A total of 285 participants (237 men and 48 women) with chronic SCI with mean (standard deviation) injury duration 17.8 (13.2) years from the VA Boston and the community participating in an epidemiologic study assessing factors associated with respiratory health. METHODS:Participants (24.6% cervical American Spinal Injury Association Impairment Scale (AIS) level A, B, and C; 33.6% other AIS A, B, and C; 41.8% AIS D) provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma leptin and adiponectin with spirometric measures of pulmonary function adjusted for age, race, gender, and height. Level and severity of SCI, mobility mode, body mass index, smoking, chronic obstructive pulmonary disease, asthma, chest injury history, laboratory batch, and other potential confounders were also considered. MAIN OUTCOME MEASUREMENTS:forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS:There was a statistically significant inverse relationship between plasma leptin assessed in quartiles or as a continuous covariate with FEV1 and FVC. In fully adjusted models, each interquartile range (16,214 pg/mL) increase in leptin was associated with a significant decrease in FEV1 (-93.1 mL; 95% confidence interval = -166.2, -20.0) and decrease in FVC (-130.7 mL; 95% confidence interval = -219.4, -42.0). There were no significant associations between leptin and FEV1/FVC or between plasma adiponectin with FEV1, FVC, or FEV1/FVC. CONCLUSION:Plasma leptin in individuals with chronic SCI is inversely associated with FEV1 and FVC, independently of SCI level and severity and other covariates. This finding suggests that plasma leptin may contribute to reduced pulmonary function in chronic SCI. LEVEL OF EVIDENCE:II.

Project description:ImportanceAccording to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.ObjectiveTo determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.Design, setting, and participantsThe National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.ExposuresPresence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).Main outcomes and measuresThe primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.ResultsAmong 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.Conclusions and relevanceDefining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

Dataset Information

The APOE ?4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study.

Publications

The APOE ε4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study.

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