Relationship of genetic determinants of height with cardiometabolic and pulmonary traits in the Hispanic Community Health Study/Study of Latinos.

Background: Associations of adult height with cardiometabolic and pulmonary traits have been studied in majority European ancestry populations using Mendelian randomization and polygenic risk score (PRS) analysis. The standard PRS approach entails creating a PRS for height using variants identified in prior genome-wide association studies (GWAS). It is unclear how well the standard PRS approach performs in non-European populations and whether height-trait associations observed in Europeans are also observed in other populations. Methods: In the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we used: (i) the standard approach to create a PRS for height (PRS1) and (ii) a novel approach to optimize the selection of variants from previously established height association loci to better explain height in HCHS/SOL (PRS2). We also estimated the extent to which PRS-trait associations were independent or mediated by the PRS effect on height. Results: In 7539 women and 5245 men, PRS1 and PRS2 explained 9 and 29% of the variance in measured height, respectively. Both PRS1 and PRS2 were associated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/ FVC ratio, total cholesterol and 2-hour oral glucose-tolerance test insulin levels. Additionally, PRS2 was associated with estimated glomerular filtration rate and ankle brachial index. Both PRS1 and PRS2 had pleiotropic associations with FEV1/ FVC ratio in mediation analyses. Conclusions: Associations of polygenic scores of height with measures of lung function and cholesterol were consistent with those observed in prior studies of majority European ancestry populations. Mediation analysis may augment standard PRS approaches to disentangle pleiotropic and mediated effects.

Variants in the 15q24/25 locus associate with lung function decline in active smokers.

Genetic variation in nicotinic acetylcholine receptor subunit genes (nAChRs) is associated with lung function level and chronic obstructive pulmonary disease (COPD). It is unknown whether these variants also predispose to an accelerated lung function decline. We investigated the association of nAChR susceptibility variants with lung function decline and COPD severity. The rs1051730 and rs8034191 variants were genotyped in a population-based cohort of 1,226 heavy smokers (COPACETIC) and in an independent cohort of 883 heavy smokers, of which 653 with COPD of varying severity (LEUVEN). Participants underwent pulmonary function tests at baseline. Lung function decline was assessed over a median follow-up of 3 years in COPACETIC. Current smokers homozygous for the rs1051730 A-allele or rs8034191 G-allele had significantly greater FEV(1)/FVC decline than homozygous carriers of wild-type alleles (3.3% and 4.3%, p = 0.026 and p = 0.009, respectively). In the LEUVEN cohort, rs1051730 AA-carriers and rs8034191 GG-carriers had a two-fold increased risk to suffer from COPD GOLD IV (OR 2.29, 95% confidence interval [CI] = 1.11-4.75; p = 0.025 and OR = 2.42, 95% [CI] = 1.18-4.95; p = 0.016, respectively). The same risk alleles conferred, respectively, a five- and four-fold increased risk to be referred for lung transplantation because of end-stage COPD (OR = 5.0, 95% [CI] = 1.68-14.89; p = 0.004 and OR = 4.06, 95% [CI] = 1.39-11.88; p = 0.010). In Europeans, variants in nAChRs associate with an accelerated lung function decline in current smokers and with clinically relevant COPD.

Genetic variation in the glutathione synthesis pathway, air pollution, and children's lung function growth.

RATIONALE: Glutathione plays an important role in antioxidant and inflammatory processes in the lung. Alterations in glutathione metabolism are a central feature of several chronic lung diseases. OBJECTIVES: To determine whether sequence variation in genes in the glutathione synthesis pathway alters susceptibility to air pollution effects on lung function. METHODS: In this prospective study, 14,821 lung function measurements were taken on 2,106 children from 12 Southern California cities. Tagging single-nucleotide polymorphisms in glutathione metabolism pathway genes GSS, GSR, GCLM, and GCLC were genotyped by GoldenGate assay (Illumina, San Diego, CA). Mixed regression models were used to determine whether particular haplotypes were associated with FEV(1), maximal mid-expiratory flow rate, and FVC and whether any of the genetic associations varied with levels of exposure to air pollutants. MEASUREMENTS AND MAIN RESULTS: We found that variation in the GSS locus was associated with differences in susceptibility of children for lung function growth deficits associated with NO(2), PM(10), PM(2.5), elemental carbon, organic carbon, and O(3). The negative effects of air pollutants were largely observed within participants who had a particular GSS haplotype. The effects ranged from -124.2 to -149.1 for FEV(1), from -92.9 to -126.7 for FVC, and from -193.9 to -277.9 for maximal mid-expiratory flow rate for all pollutants except O(3), which showed a larger decrease in lung function in children without this haplotype. CONCLUSIONS: Variation in GSS was associated with differences in susceptibility to adverse effects of pollutants on lung function growth.

Passive smoking and lung function in alpha(1)-antitrypsin heterozygote schoolchildren.

BACKGROUND: A study was performed to determine whether Pi heterozygotes exposed to smoking have a higher risk of reduced lung function than Pi M homozygotes. METHODS: The effect of passive smoking on lung function was investigated in a cross sectional study of 997 primary and secondary schoolchildren aged 11-13 years categorised by Pi phenotype as either PiM homozygotes or Pi heterozygotes. Data on respiratory health and risk factors were collected by questionnaire, lung function was measured by spirometric tests, bronchial hyperresponsiveness was evaluated by methacholine test, atopic status was evaluated by skin prick testing, and a blood sample was collected to determine Pi phenotype. Urinary cotinine and creatinine concentrations were determined and assessment of exposure was made from questionnaire data and urinary cotinine concentrations. The results were analysed by multiple regression analysis. RESULTS: Sixty one subjects (6.1%) were found to be Pi heterozygotes. Lung function did not differ between homozygotes and heterozygotes. There was a reduction in lung function in subjects exposed to parental smoking in the overall sample: FEV(1)/FVC ratio (-0.78%), FEF(25-75) (-0.11 litres), and FEF(75) (-0.13 litres). Interaction terms between parental smoking and Pi status were significant with regard to FEV(1)/FVC ratio (p=0.035) and FEF(50) (p=0.023). In subjects exposed to parental smoking the decrement in lung function in Pi heterozygotes tended to be greater (FEV(1)/FVC ratio = -2.57, FEF(25-75) = -0.30, FEF(50) = -0.43, and FEF(75) = -0.29) than in PiM homozygotes. These results did not change significantly when the urinary cotinine concentration was used as an exposure variable. CONCLUSIONS: The detrimental effect of environmental tobacco smoke on lung function in schoolchildren is confirmed. This harmful effect is greater in Pi heterozygotes than in PiM homozygotes.