Madé Wenten

Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation.

RATIONALE Prenatal exposure to tobacco smoke increases the risk for diseases later in the childs life that may be mediated through alterations in DNA methylation. OBJECTIVES To demonstrate that differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations. METHODS Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and pyrosequencing in buccal cells of 348 children participating in the Childrens Health Study. Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 participants in the Childrens Health Study children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by pyrosequencing. Estimates were standardized across loci using a Z score to enable cross-comparison of results. MEASUREMENTS AND MAIN RESULTS DNA methylation patterns were associated with in utero exposure to maternal smoking. Exposed children had significantly lower methylation of AluYb8 (beta, -0.31; P = 0.03). Differences in smoking-related effects on LINE1 methylation were observed in children with the common GSTM1 null genotype. Differential methylation of CpG loci in eight genes was identified through the screen. Two genes, AXL and PTPRO, were validated by pyrosequencing and showed significant increases in methylation of 0.37 (P = 0.005) and 0.34 (P = 0.02) in exposed children. The associations with maternal smoking varied by a common GSTP1 haplotype. CONCLUSIONS Life-long effects of in utero exposures may be mediated through alterations in DNA methylation. Variants in detoxification genes may modulate the effects of in utero exposure through epigenetic mechanisms.

Turnover intention in new graduate nurses: a multivariate analysis

Title Turnover intention in new graduate nurses: a multivariate analysis Aim This paper is a report of a study to determine the relationship of new nurse turnover intent with individual characteristics, work environment variables and organizational factors and to compare new nurse turnover with actual turnover in the 18 months of employment following completion of a residency. Background Because of their influence on patient safety and health outcomes nurse turnover and turnover intent have received considerable attention worldwide. When nurse staffing is inadequate, especially during nursing shortages, unfavourable clinical outcomes have been documented. Method Prospective data collection took place from 1999 to 2006 with 889 new paediatric nurses who completed the same residency. Scores on study instruments were related to likelihood of turnover intent using logistic regression analysis models. Relationships between turnover intent and actual turnover were compared using Kaplan–Meier survivorship. Results The final model demonstrated that older respondents were more likely to have turnover intent if they did not get their ward choice. Also higher scores on work environment and organizational characteristics contributed to likelihood that the new nurse would not be in the turnover intent group. These factors distinguish a new nurse with turnover intent from one without 79% of the time. Increased seeking of social support was related to turnover intent and older new graduates were more likely to be in the turnover intent group if they did not get their ward choice. Conclusion When new graduate nurses are satisfied with their jobs and pay and feel committed to the organization, the odds against turnover intent decrease. What is already known about this topic There is concern in many countries about nurse turnover and the resulting effects on patient safety and quality of care. Decreasing ability to recruit experienced nurses has increased the emphasis on recruitment of new graduate nurses, particularly in the United States of America. Historically, new graduate nurses have a high turnover rate within the first year of employment. What this paper adds When new graduate nurses are satisfied with their jobs and pay and feel committed to the organization, the odds of turnover intent decrease. Increased seeking social support to cope with the transition from student to competent Registered Nurse is related to turnover intent. Older graduates (>30) are 4·5 times more likely to have turnover intent if they do not get their ward of choice.

Associations of Weight, Weight Change, and Body Mass with Breast Cancer Risk in Hispanic and Non-Hispanic White Women

PURPOSE A wealth of studies have examined the effects of weight, weight gain, and obesity on breast cancer risk; however, few have examined this relationship in Hispanic white women, a population with the highest rate of obesity in the U.S. METHODS A population-based case-control study was conducted in New Mexico of Hispanic (n = 694) and non-Hispanic (n = 813) white women with incident breast cancer during the period of January 1, 1992 through December 31, 1994. Conditional logistic regression models were fitted to estimate the relative risk of breast cancer for levels of weight, weight change, and body mass index (BMI) and to assess differences in the effects by ethnicity, menopausal status, early life BMI, and estrogen receptor/progesterone receptor (ER/PR) expression in tumors. RESULTS Weight change from age 18 to usual adult weight was associated with increased risk of breast cancer among Hispanics [4th quartile vs. baseline, odds ratio (OR): 2.41; 95% confidence interval (CI): 1.45-4.03] with no substantial variation by menopausal status. In non-Hispanic white women, weight change was a risk factor for those in the post-menopausal group (4th quartile vs. baseline, OR: 2.27; 95% CI: 1.09-4.73). The effect of usual BMI (test for interaction p = 0.04) and weight change (test for interaction p = 0.03) differed by ethnicity. Increased risk from weight gain was largely restricted to women who were lean at age 18 and those with ER(+)/PR(+) tumors. Height, weight at age 18, and BMI at age 18 were not associated with risk in either ethnic group. CONCLUSIONS Weight change and obesity are risk factors for breast cancer in both Hispanic and non-Hispanic white women. However, the risk for Hispanic women is evident independent of menopausal status, while the risk for non-Hispanics is apparent in post-menopausal women. Due to the increasing prevalence of adult obesity, particularly among Hispanic women, adult weight gain may be an important modifiable risk factor for the primary prevention of breast cancer among Hispanic populations.

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

OBJECTIVE. Associations between single-nucleotide polymorphisms in the β2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects β2-adrenergic receptor gene expression and associations of β2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of β2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Childrens Health Study. METHODS. We fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes. RESULTS. Exposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism–specific results. No associations were found for Glu27Gln. CONCLUSIONS. Both in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16–Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of β2-adrenergic receptor gene variants on respiratory health outcomes.

Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

RATIONALE The glutathione S-transferases (GSTs) are important detoxification enzymes. OBJECTIVES To investigate effects of variants in GST mu genes on lung function and assess their interactions with tobacco smoke exposure. METHODS In this prospective study, 14,836 lung function measurements were collected from 2,108 children who participated in two Southern California cohorts. For each child, tagging single nucleotide polymorphisms in GSTM2, GSTM3, GSTM4, and GSTM5 loci were genotyped. Using principal components and haplotype analyses, the significance of each locus in relation to level and growth of FEV1, maximum midexpiratory flow rate (MMEF), and FVC was evaluated. Interactions between loci and tobacco smoke on lung function were also investigated. MEASUREMENTS AND MAIN RESULTS Variation in the GST mu family locus was associated with lower FEV1 (P = 0.01) and MMEF (0.04). Two haplotypes of GSTM2 were associated with FEV1 and MMEF, with effect estimates in opposite directions. One haplotype in GSTM3 showed a decrease in growth for MMEF (-164.9 ml/s) compared with individuals with other haplotypes. One haplotype in GSTM4 showed significantly decreased growth in FEV1 (-51.3 ml), MMEF (-69.1 ml/s), and FVC (-44.4 ml), compared with all other haplotypes. These results were consistent across two independent cohorts. Variation in GSTM2 was particularly important for FVC and FEV(1) among children whose mothers smoked during pregnancy. CONCLUSIONS Genetic variation across the GST mu locus is associated with 8-year lung function growth. Children of mothers who smoked during pregnancy and had variation in GSTM2 had lower lung function growth.

Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions

The individual effect of functional single nucleotide polymorphisms within the catalase and myeloperoxidase genes (CAT and MPO) has been studied in relation to asthma; however, their interrelationship with ambient air pollution exposures has yet to be determined. The authors investigated the interrelationships between variants in CAT and MPO, ambient air pollutants, and acute respiratory illness. Health information, air pollution, and incident respiratory-related school absences were ascertained in January-June 1996 for 1,136 Hispanic and non-Hispanic white US elementary schoolchildren as part of the prospective Childrens Health Study. Functional and tagging single nucleotide polymorphisms for the CAT and MPO loci were genotyped. The authors found epistasis between functional polymorphisms in the CAT/MPO loci, which differed by levels of oxidant-stress-producing air pollutants. Risk of respiratory-related school absences was elevated for children with the CAT (G/G) and MPO (G/A or A/A) genes (relative risk = 1.35, 95% confidence interval: 1.03, 1.77; P-interaction = 0.005). The epistatic effect of CAT and MPO variants was most evident in communities exhibiting high ambient ozone levels (P-interaction = 0.03). The association of respiratory-illness absences with functional variants in CAT and MPO that differ by air pollution levels illustrates the need to consider genetic epistasis in assessing gene-environment interactions.

Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence

Background Inducible nitric oxide (NO) synthase (iNOS, encoded by NOS2A) produces NO in response to environmental stimuli, which can result in nitrosative stress. Because nitrosative stress affects respiratory health, it was hypothesised that variants in NOS2A are associated with asthma incidence and lung function growth during adolescence. Methods In this prospective study, spirometric testing was performed at school and a presence or absence of asthma was ascertained annually by questionnaire among children participating in the Southern California Childrens Health Study. 24 single nucleotide polymorphisms (SNPs) of the NOS2A region (with seven promoter SNPs in one haplotype block), spanning 20 kb upstream and 10 kb downstream were genotyped. Association between the NOS2A region and asthma or lung function growth was tested using genetic block-specific principal component and haplotype analyses. This study was restricted to children with Latino and Caucasian ancestry for analyses of both asthma (n=1596) and lung function growth (n=2108). Result A pair of “yin–yang” haplotypes in the promoter region showed strong association with new-onset asthma and lung function growth. The “yin” haplotype (h0111101) was associated with 44% increased asthma risk (p=0.003) and reduced forced expiratory volume in 1 s (FEV1) growth from 10 to 18 years of age (−29.46 ml, p=0.07), whereas the “yang”(h1000010) haplotype was associated with 23% reduced asthma risk (p=0.13) and better FEV1 growth (43.84 ml, p=0.01). Furthermore, the increased asthma risk associated with h0111101 was restricted to children with the GSTM1 “null” genotype (interaction p=0.002, HR 1.89, 95% CI 1.34 to 2.60). Conclusion Common haplotypes in the NOS2A promoter are associated with new-onset asthma and lung function growth. These effects are stronger in adolescents with the GSTM1 “null” genotype.

In Utero Smoke Exposure, Glutathione S-Transferase P1 Haplotypes, and Respiratory Illness-Related Absence Among Schoolchildren

BACKGROUND. The GSTP1 Ile105Val variant and secondhand tobacco smoke exposure have been independently associated with acute respiratory illness; however, susceptibility to in utero and secondhand tobacco smoke has yet to be examined in relation to variation across the GSTP1 locus. OBJECTIVE. The purpose of this work was to determine whether variation across the GSTP1 locus is associated with respiratory illness–related school absences and to determine whether this relationship varies by in utero and secondhand tobacco smoke exposure. METHODS. Tobacco smoke exposure status, incident respiratory-related school absence records, and DNA samples was ascertained for 1132 Hispanic and non-Hispanic white elementary school children as part of the Childrens Health Study. RESULTS. Four GSTP1 single-nucleotide polymorphisms were selected that accounted for 93% of the variation across the locus. Individual single-nucleotide polymorphism analyses showed a protective effect for the minor alleles in single-nucleotide polymorphisms 1 (rs6591255), 3 (GSTP1 Ile105Val: rs1695), and 4 (rs749174) for respiratory illness. The haplotype, which includes a minor allele for single-nucleotide polymorphisms 1, 3, and 4 (h1011), was associated with a decreased risk of respiratory illness. The protective effect of GSTP1 variants was lost among individuals exposed to in utero and secondhand tobacco smoke. CONCLUSIONS. A common GSTP1 haplotype, which includes the functional Ile105Val polymorphism, was associated with respiratory-related school absences. The protection afforded by this haplotype was lost in children exposed to involuntary tobacco smoke. The paradigm of loss of genetic protection among those exposed to tobacco smoke has clinical and public health implications that warrant broader consideration in research and practice.