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1.  Synthesis, Antimalarial, Antileishmanial, Antimicrobial, Cytotoxicity and Methemoglobin (MetHb) Formation Activities of New 8-Quinolinamines 
Bioorganic & medicinal chemistry  2006;15(2):915-930.
We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties) and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21–33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51–63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against P. falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices vs. mammalian cells. The most promising analogs (21–24) also displayed potent antimalarial activity in vivo in a P. berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against L. donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21–24, 26–32 and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.
PMCID: PMC4045844  PMID: 17084633
2.  Obstructive sleep apnea and psychomotor vigilance task performance 
Obstructive sleep apnea (OSA) is a highly prevalent disorder with considerable morbidity and mortality. Vigilance and attentiveness are often impaired in OSA patients. In occupational medicine settings, subjective reports of sleepiness are notoriously inaccurate, making the identification of objective measures of vigilance potentially important for risk assessments of fitness for duty. In order to evaluate the effects of OSA on attentiveness and vigilance, we conducted a cross-sectional study to examine the association between OSA and psychomotor vigilance task (PVT) performance.
Patients attending sleep clinics for evaluation of possible sleep apnea were recruited. The subjects underwent either a standard overnight laboratory polysomnography or home sleep study. Subjective daytime sleepiness was assessed by Epworth sleepiness scale, and vigilance was tested using a portable device. The participants were asked to respond to the PVT signals using their dominant hand. Each PVT administration lasted 10 minutes, with stimuli signals appearing randomly at variable intervals of 2–10 seconds.
Mean age of the participants was 46±15 years, and mean body mass index was 34.3±9.8 kg/m2. Participants with higher Epworth scores had worse PVT performance (P<0.05). In multivariate analyses, age, body mass index, and poor sleep efficiency (measured by Pittsburgh sleep quality index score) were associated with worse PVT performance (P<0.05). In contrast, PVT performance did not differ significantly across categories of apnea hypopnea index severity. Subgroup analysis demonstrated that women had worse performance on all PVT measures (P<0.05).
PVT performance can be utilized for risk assessments of sleepiness and may be particularly useful among populations where subjective reports are unreliable.
PMCID: PMC4043718  PMID: 24920941
obstructive sleep apnea; psychomotor vigilance test; sleepiness
3.  Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans 
Diabetes  2013;62(3):965-976.
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10−8). Locus-wide analysis demonstrated significant associations (Pemp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
PMCID: PMC3581206  PMID: 23193183
4.  Pathophysiology & genetics of obstructive sleep apnoea 
Obstructive sleep apnoea (OSA) is a highly prevalent condition with proven neurocognitive and cardiovascular consequences. OSA patients experience repetitive narrowing or collapse of the pharyngeal airway during sleep. Multiple factors likely underlie the pathophysiology of this condition with considerable inter-individual variation. Important risk factors for OSA include obesity, male gender, and ageing. However, the mechanisms underlying these major risk factors are not well understood. We briefly review the state-of-the-art knowledge regarding OSA pathogenesis in adults and highlight the potential role of genetics in influencing key OSA pathophysiological traits.
PMCID: PMC3858846  PMID: 20308743
Arousal; genioglossus; lung; obstructive sleep apnoea; upper airway; ventilatory control stability
5.  Clinical Presentation of Shift Workers to a Sleep Clinic 
Sleep & breathing = Schlaf & Atmung  2011;16(2):10.1007/s11325-011-0540-y.
To assess the relationship between shift work (SW) history and symptom severity in a sleep clinic population.
A retrospective chart review of 1,275 employed adult patients referred to a sleep disorders clinic was performed. Patients were categorized as working day shift, fixed evening or night shift, or rotating shifts. Sleep related symptoms were assessed across three domains – sleepiness, insomnia, and apnea-related symptoms.
The distribution of work shift was 69% day shift, 8% fixed evening or night shift and 23% rotating shifts. In general, sleepiness and insomnia symptoms were greatest in fixed shift workers. In analyses adjusted for age, sex, education, race, BMI, habitual sleep duration, marital status, education level, alcohol intake, and smoking history, fixed shift workers were 4.8 times (95% CI: 1.9-12.5) more likely to report sleep onset difficulties, 3.3 times (95% CI: 1.2-9.1) more likely to report excessive caffeine intake and 1.8 times (95% CI: 1.1-3.0) more likely to report drowsy driving as compared to day shift workers. In contrast rotating shift workers reported more difficulty with sleep onset (OR 2.7; 95% CI: 1.3-5.6) relative to day shift workers. No relationship between work shift and apnea-related symptoms was identified.
Among patients referred to a sleep disorders clinic, shift workers and in particular fixed shift workers, have greater difficulties with sleep onset, drowsy driving and excessive caffeine intake. Given the presence of effective treatments for SW related sleep symptoms, these findings suggest an under-utilization of sleep medicine specialists for the care of patients with symptoms related to SW.
PMCID: PMC3843959  PMID: 21720936
shift work; sleep disorder; insomnia; excessive sleepiness
6.  Heritability of Upper Airway Dimensions Derived Using Acoustic Pharyngometry 
Acoustic pharyngometry represents a simple, quick, non-invasive method for measuring upper airway dimensions which are predictive of sleep apnea risk. In this study we sought to assess the genetic basis for upper airway size as obtained by pharyngometry.
Participants over age 14 y in the Cleveland Family Study underwent three acoustic pharyngometry measurements. Variance component models adjusted for age and sex were used to estimate heritability of pharyngometry-derived airway measures.
A total of 568 of 655 subjects (87%) provided quality pharyngometry curves. Although African-Americans tended to have narrower airways compared to Caucasians, heritability patterns were similar in these two groups. Minimum cross-sectional area had a heritability of 0.34 (p=0.004) in Caucasians and 0.39 (p<0.001) in African-Americans, suggesting that 30-40% of the total variance in this measure is explained by shared familial factors. Estimates were unchanged after adjustment for body mass index or neck circumference. In contrast, oropharyngeal length did not have significant heritability in either ethnic group.
The minimum cross-sectional area in the oropharynx is a highly heritable trait suggesting the presence of an underlying genetic basis. These findings demonstrate the potential utility of acoustic pharyngometry in dissecting the genetic basis of sleep apnea.
PMCID: PMC2655306  PMID: 18579548
sleep apnea; upper airway; oropharynx; pharyngometry; genetic epidemiology; heritability
7.  Mechanical Ventilation and Air Leaks After Lung Biopsy for Acute Respiratory Distress Syndrome 
The Annals of thoracic surgery  2006;82(1):10.1016/j.athoracsur.2006.02.022.
Open lung biopsy in acute respiratory distress syndrome (ARDS) may provide a specific etiology and change clinical management, yet concerns about complications remain. Persistent air leak is the most common postoperative complication. Risk factors in this setting are not known.
We performed a retrospective analysis of 53 patients who underwent open lung biopsy for clinical ARDS (based on American European Consensus Conference criteria) between 1989 and 2000.
Sixteen patients (30.2%) developed an air leak lasting more than 7 days or died with an air leak. Univariate analyses showed no significant correlation with age, gender, sex, corticosteroid use, diabetes, immunocompromised status, or pathologic diagnosis. A lower risk of air leak was associated with lower peak airway pressure and tidal volume, use of pressure-cycled ventilation, and use of an endoscopic stapling device. In multivariate analyses, only peak airway pressure remained a significant predictor. The risk of prolonged air leak was reduced by 42% (95% confidence interval [CI: 17% to 60%]) for every 5 cm H2O reduction in peak airway pressure.
The use of a lung-protective ventilatory strategy that limits peak airway pressures is strongly associated with a reduced risk of postoperative air leak after open lung biopsy in ARDS. Using such a strategy may allow physicians to obtain information from open lung biopsy to make therapeutic decisions without undue harm to ARDS patients.
PMCID: PMC3822769  PMID: 16798226
8.  Short sleep duration and weight gain: a systematic review 
Obesity (Silver Spring, Md.)  2008;16(3):643-653.
The recent obesity epidemic has been accompanied by a parallel growth in chronic sleep deprivation. Physiologic studies suggest sleep deprivation may influence weight through effects on appetite, physical activity, and/or thermoregulation. This work reviews the literature regarding short sleep duration as an independent risk factor for obesity and weight gain.
A literature search was conducted for all articles published between 1966 and January 2007 using the search “sleep” AND (“duration” OR “hour” OR “hours”) AND (“obesity” OR “weight) in the MEDLINE database. Additional references were identified by reviewing bibliographies and contacting experts in the field. Studies reporting the association between sleep duration and at least one measure of weight were included.
Thirty-six publications (31 cross-sectional, 5 prospective, and 0 experimental) were identified. Findings in both cross-sectional and cohort studies of children suggested short sleep duration is strongly and consistently associated with concurrent and future obesity. Results from adult cross-sectional analyses were more mixed with 17 of 23 studies supporting an independent association between short sleep duration and increased weight. In contrast, all 3 longitudinal studies in adults found a positive association between short sleep duration and future weight. This relationship appeared to wane with age.
Short sleep duration appears independently associated with weight gain, particularly in younger age groups. However, major study design limitations preclude definitive conclusions. Further research with objective measures of sleep duration, repeated assessments of both sleep and weight and experimental study designs that manipulate sleep are needed to better define the causal relationship of sleep deprivation on obesity.
PMCID: PMC2723045  PMID: 18239586
sleep; sleep duration; sleep deprivation; risk factor; weight
9.  Shared Genetic Basis for Obstructive Sleep Apnea and Adiposity Measures 
Obesity and obstructive sleep apnea each have a substantial genetic basis and commonly co-exist in individuals. The degree to which the genetic underpinnings for these disorders overlap has not been previously quantified.
A total of 1802 individuals from 310 families in the Cleveland Family Study underwent home sleep studies as well as standardized assessment of body mass index and circumferences at the waist, hip, and neck. In 713 participants with laboratory sleep studies, fasting blood samples were assayed for leptin, adiponectin, and resistin. Variance component models were used to estimate heritability and genetic correlations.
The heritability of the apnea hypopnea index was 0.37 ± 0.04 and 0.33 ± 0.07 for home and laboratory sleep studies respectively. The genetic correlations between apnea hypopnea index and anthropomorphic adiposity measures ranged from 0.57 to 0.61 suggesting obesity can explain nearly 40% of the genetic variance in sleep apnea. The magnitude of the genetic correlations between apnea severity and adipokine levels was substantially less than those with anthropomorphic measures, ranging from 0.11–0.46. After adjusting for body mass index, no significant genetic correlation with apnea severity was observed for any of the other adiposity measures.
Substantial but not complete overlap in genetic bases exist between sleep apnea and anthropomorphic indices of adiposity, and this overlap accounts for more than one third of the genetic variance in apnea severity. These findings suggest that genetic polymorphisms exist that importantly influence sleep apnea susceptibility through both obesity-dependent and obesity-independent pathways.
PMCID: PMC2672200  PMID: 18209735
obesity; sleep apnea; genetics; heritability; genetic correlation
10.  Relation Between Sleep Duration and BMI Varies by Age and Sex in Youth Age 8–19 
Pediatric Obesity  2011;7(1):53-64.
The objectives of this study were to 1) compare the strength of associations between sleep duration and BMI in middle childhood, early and late adolescence; 2) determine whether sleep duration in middle childhood predicts BMI in early or late adolescence; 3) examine the consistency of these associations by sex.
Subjects included 313 children/adolescents aged 8–19 participating in a longitudinal cohort study on sleep and health. Participants were assessed at three time points approximately 4 years apart: ages 8–11, 12–15 and 16–19. BMI z-score (BMIz) was calculated using age and sex normative data from the Centers for Disease Control. Sleep duration was reported by the parent (ages 8–15) or the adolescent (ages 16–19).
Half of the participants were male and 79% were Caucasian. Sleep duration had a negative linear association with BMIz for boys but not girls, and the magnitude of this association decreased with age. Sleep duration at age 8–11 predicted BMIz in early and late adolescence for boys but not girls, and associations were largely attenuated after adjusting for BMIz at age 8–11. The strongest predictor of adolescent BMIz was BMIz at age 8–11 for both boys and girls.
We conclude that the association between sleep duration and BMIz varies by sex and age, with stronger associations in boys and in middle childhood compared to adolescence.
PMCID: PMC3313079  PMID: 22434739
Adolescents; BMI; Children; Obesity; Sleep
11.  Postural Effects on Pharyngeal Protective Reflex Mechanisms 
Sleep  2004;27(6):1105-1112.
Study Objectives
Pharyngeal muscle dilators are important in obstructive sleep apnea pathogenesis because the failure of protective reflexes involving these muscles yields pharyngeal collapse. Conflicting results exist in the literature regarding the responsiveness of these muscles during stable non-rapid eye movement sleep. However, variations in posture in previous studies may have influenced these findings. We hypothesized that tongue protruder muscles are maximally responsive to negative pressure pulses during supine sleep, when posterior tongue displacement yields pharyngeal occlusion.
We studied all subjects in the supine and lateral postures during wakefulness and stable non-rapid eye movement sleep by measuring genioglossus and tensor palatini electromyograms during basal breathing and following negative pressure pulses.
Upper-airway physiology laboratory of Sleep Medicine Division, Brigham and Women’s Hospital.
17 normal subjects.
Measurements and Results
We observed an increase in genioglossal responsiveness to negative pressure pulses in sleep as compared to wakefulness in supine subjects (3.9 percentage of maximum [%max] ± 1.1 vs 4.4 %max ± 1.0) but a decrease in the lateral decubitus position (4.1 %max ± 1.0 vs 1.5 %max ± 0.4), the interaction effect being significant. Despite this augmented reflex, collapsibility, as measured during negative pressure pulses, increased more while subjects were in the supine position as compared with the lateral decubitus position. While the interaction between wake-sleep state and position was also significant for the tensor palatini, the effect was weaker than for genioglossus, although, for tensor palatini, baseline activity was markedly reduced during non-rapid eye movement sleep as compared with wakefulness.
We conclude that body posture does have an important impact on genioglossal responsiveness to negative pressure pulses during non-rapid eye movement sleep. We speculate that this mechanism works to prevent pharyngeal occlusion when the upper airway is most vulnerable to collapse eg, during supine sleep.
PMCID: PMC3504469  PMID: 15532204
pharynx; posture; sleep; breathing; genioglossus; lung; tensor palatini; respiration; upper airway; vestibular
12.  Correlates of Long Sleep Duration 
Sleep  2006;29(7):881-889.
Study Objective
Sleeping more than 7 to 8 hours per day has been consistently associated with increased mortality. Whether this association is causal and what pathways explain this association are unknown. We sought to identify factors that could potentially explain the association between long sleep and mortality.
Cross-sectional epidemiologic survey.
Middle-aged women (n = 60,028) participating in the Nurses Health Study II who reported a habitual sleep duration of 7 hours or more.
Multiple sclerosis (odds ratio [OR] = 3.7, 95% confidence interval [3.0–4.5]), antidepressant use (OR = 3.1, [2.9–3.3]), benzodiazepine use (OR = 3.0 [2.6–3.3]), and systemic lupus erythematosus (OR = 2.9, [2.3–3.6]) were the factors most strongly associated with prolonged sleep. Combining these data with prevalence information and a range of plausible associations with mortality, the confounding rate ratio was estimated. This parameter is the ratio of the unadjusted long sleep–mortality rate ratio to the rate ratio adjusted for the factor and measures the extent that the factor can alter the long sleep—mortality association, either through confounding or as a causal intermediate. Based on this parameter, psychiatric and socioeconomic factors have the greatest potential to influence the long sleep–mortality relationship. Assuming each factor doubles mortality risk, the confounding rate ratios for depression, antidepressant use, and unemployment were 1.10, 1.18, and 1.12. Lesser influential factors were benzodiazepine use, poverty, low societal status, sedentary lifestyle, and obesity.
Depression and low socioeconomic status are strong candidates for producing the statistical association between long sleep and mortality, either as confounders or as causal intermediates. Future causal research on the effects of long sleep should include a detailed assessment of psychiatric disease and socioeconomic status.
PMCID: PMC3500381  PMID: 16895254
Sleep duration; long sleep; depression
13.  Association between Reduced Sleep and Weight Gain in Women 
American journal of epidemiology  2006;164(10):947-954.
Physiologic studies suggest that sleep restriction has metabolic effects that predispose to weight gain. The authors investigated the association between self-reported usual sleep duration and subsequent weight gain in the Nurses’ Health Study. The 68,183 women who reported habitual sleep duration in 1986 were followed for 16 years. In analyses adjusted for age and body mass index, women sleeping 5 hours or less gained 1.14 kg (95% confidence interval (CI): 0.49, 1.79) more than did those sleeping 7 hours over 16 years, and women sleeping 6 hours gained 0.71 kg (95% CI: 0.41, 1.00) more. The relative risks of a 15-kg weight gain were 1.32 (95% CI: 1.19, 1.47) and 1.12 (95% CI: 1.06, 1.19) for those sleeping 5 and 6 hours, respectively. The relative risks for incident obesity (body mass index: >30 kg/m2) were 1.15 (95% CI: 1.04, 1.26) and 1.06 (95% CI: 1.01, 1.11). These associations remained significant after inclusion of important covariates and were not affected by adjustment for physical activity or dietary consumption. These data suggest that short sleep duration is associated with a modest increase in future weight gain and incident obesity. Further research is needed to understand the mechanisms by which sleep duration may affect weight.
PMCID: PMC3496783  PMID: 16914506
obesity; sleep deprivation; weight gain; women
14.  Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea 
Obstructive sleep apnea (OSA) is two to three times more common in men as in women. The mechanisms leading to this difference are currently unclear but could include gender differences in respiratory stability [loop gain (LG)] or upper airway collapsibility [pharyngeal critical closing pressure (Pcrit)]. The aim of this study was to compare LG and Pcrit between men and women with OSA to determine whether the factors contributing to apnea are similar between genders. The first group of 11 men and 11 women were matched for OSA severity (mean ± SE apnea-hypopnea index = 43.8 ± 6.1 and 44.1 ± 6.6 events/h). The second group of 12 men and 12 women were matched for body mass index (BMI; 31.6 ± 1.9 and 31.3 ± 1.8 kg/m2, respectively). All measurements were made during stable supine non-rapid eye movement sleep. LG was determined using a proportional assist ventilator. Pcrit was measured by progressively dropping the continuous positive airway pressure level for three to five breaths until airway collapse. Apnea-hypopnea index-matched women had a higher BMI than men (38.0 ± 2.4 vs. 30.0 ± 1.9 kg/m2; P = 0.03), but LG and Pcrit were similar between men and women (LG: 0.37 ± 0.02 and 0.37 ± 0.02, respectively, P = 0.92; Pcrit: 0.35 ± 0.62 and –0.18 ± 0.87, respectively, P = 0.63). In the BMI-matched subgroup, women had less severe OSA during non-rapid eye movement sleep (30.9 ± 7.4 vs. 52.5 ± 8.1 events/h; P = 0.04) and lower Pcrit (–2.01 ± 0.62 vs. 1.16 ± 0.83 cmH2O; P = 0.005). However, LG was not significantly different between genders (0.38 ± 0.02 vs. 0.33 ± 0.03; P = 0.14). These results suggest that women may be protected from developing OSA by having a less collapsible upper airway for any given degree of obesity.
PMCID: PMC3496786  PMID: 15994243
pharyngeal critical closing pressure; loop gain; gender
15.  Oxygen saturation/FiO2 ratio is a simple predictor of noninvasive positive pressure ventilation failure in critically ill patients 
Journal of critical care  2010;26(5):510-516.
Noninvasive positive pressure ventilation (NPPV) can improve outcomes of critically ill patients. Early and simple predictors of NPPV outcome could improve clinical management of patients with respiratory failure.
Materials and Methods
A prospective observational study was conducted in a medical intensive care unit (ICU) of a tertiary medical center. Patients requiring NPPV were included and followed. Clinical data including respiratory mechanics at the time of NPPV initiation, and clinical outcomes were recorded. Data were analyzed to identify variables that distinguished NPPV success or failure.
A total of 133 patients were included in the study. NPPV success rate was 41%. Patients diagnosed with malignancy had only 29% NPPV success rate. Among patients without malignancy, higher oxygen saturation, oxygen saturation/FiO2 (SF) ratios, and SF/minute ventilation (MV) ratios were associated with NPPV success. Receiver operating curve analyses identify SF < 98.5 to be a specific (89% specificity, P=0.013) predictor of NPPV failure. Furthermore, for patients requiring at least 24hr of NPPV support, tidal volume (TV)/predicted body weight (PBW) ratio inversely correlated with respiratory improvement.
For patients without malignancy, SF ratios at the time of NPPV initiation discriminated NPPV success and failure, and could be used to help guide the management of critically ill patients who require ventilatory support.
PMCID: PMC3117064  PMID: 21036535
Mechanical ventilation; Respiratory Insufficiency; Non-Invasive Positive-Pressure Ventilation; Clinical Markers; Hypoxemia; Critical Care
16.  A Study of the Relationship between the Interleukin-6 Gene and Obstructive Sleep Apnea 
Because obstructive sleep apnea (OSA) is associated with increased levels of inflammatory cytokines, we examined the relationship between OSA and polymorphisms for interleukin-6 (IL-6).
6 single nucleotide polymorphisms (SNPs) within IL-6 were genotyped in 259 African-Americans from the Cleveland Family Study with replication conducted in the Cardiovascular Health Study (n=124). OSA was dichotomized into apnea hypopnea index (AHI)>15 or on treatment vs. absent: AHI<5. Logistic regression was conducted, adjusting for age and sex in models with and without body mass index (BMI).
SNP IL6-6021 was associated with a decreased risk of OSA after adjusting for BMI (Odds Ratio for T allele 0.24; 95%CI [0.09–0.67]; p=0.006; q=0.07) under an additive model. This same allele was associated with increased BMI. The results from the replication sample were consistent in direction though not statistically significant (p=0.23). The SNPs were studied in European-Americans, although the minor allele frequency in IL6-6021 was too low (4%) for meaningful comparisons.
A synonymous SNP within the IL-6 coding region was protective of OSA in African-Americans; with qualitatively similar findings observed in another cohort. This suggests that variants in IL-6 may influence the risk of OSA in a pathway that is not explained by obesity.
PMCID: PMC3078635  PMID: 21207764
17.  A Candidate Gene Study of Obstructive Sleep Apnea in European Americans and African Americans 
Rationale: Obstructive sleep apnea (OSA) is hypothesized to be influenced by genes within pathways involved with obesity, craniofacial development, inflammation, and ventilatory control.
Objectives: We conducted the first candidate gene study of OSA using family data from European Americans and African Americans, selecting biologically plausible genes from within these pathways.
Methods: A total of 1,080 single nucleotide polymorphisms (SNPs) were genotyped in 729 African Americans and 505 SNPs were genotyped in 694 European Americans. Coding for SNPs additively, association testing on the apnea-hypopnea index (AHI) as a continuous trait, and OSA as a dichotomous trait (AHI ≥15) was conducted using methods that account for familial correlations in models adjusted for age, age-squared, and sex, with and without body mass index.
Measurements and Main Results: In European Americans, variants within C-reactive protein (CRP) and glial cell line–derived neurotrophic factor (GDNF) were associated with AHI (CRP: β = 4.6; SE = 1.1; P = 0.0000402) (GDNF: β = 4.3; SE = 1; P = 0.0000201) and with the dichotomous OSA trait (CRP: odds ratio = 2.4; 95% confidence interval, 1.5–3.9; P = 0.000170) (GDNF: odds ratio = 2; 95% confidence interval, 1.4–2.89; P = 0.0000433). In African Americans, rs9526240 within serotonin receptor 2a (HTR2A: odds ratio = 2.1; 95% confidence interval, 1.5–2.9; P = 0.00005233) was associated with OSA.
Conclusions: This candidate gene analysis identified the potential role of genes operating through intermediate disease pathways to influence sleep apnea phenotypes, providing a framework for focusing future replication studies.
PMCID: PMC2970865  PMID: 20538960
sleep apnea; body mass index; genetics; candidate gene study
18.  Sleep-disordered Breathing and Prothrombotic Biomarkers 
Rationale: Individuals with sleep-disordered breathing (SDB) are at increased cardiovascular risk, possibly due to SDB-related stresses contributing to atherosclerosis.
Objectives: We postulate that pathways associated with a prothrombotic potential are up-regulated in SDB.
Methods: Morning and evening plasminogen activator inhibitor-1 (PAI-1), morning fibrinogen, and morning D-dimer were measured in 537 Cleveland Family Study adults. Piecewise multivariable linear mixed models estimated relative mean change or mean change in the biomarker per 5-unit increase in apnea-hypopnea index (AHI) in two groups: AHI less than 15 and AHI greater than or equal to 15, and hypoxia defined as percentage of sleep time with SaO2 less than 90% (< 2%, ≥ 2%).
Measurements and Main Results: Nonlinear associations were demonstrated: morning and evening PAI-1 increased by 12% (95% confidence interval [CI], 5–20%; P < 0.001) and 11% (95% CI, 2–20%; P = 0.01), respectively per 5-unit AHI increase until an AHI of 15, when no further increase in PAI-1 was demonstrated. The association between AHI and morning PAI-1 remained significant after adjusting for evening PAI-1 level (10%; 95% CI, 3–17%; P < 0.01). Morning fibrinogen increased on average by 8.4 mg/dl (95% CI, 3.12–13.65; P = 0.002) per five-unit AHI increase until an AHI of 15. There was no association between AHI and morning D-dimer. Hypoxia severity was not associated with thrombotic marker levels.
Conclusions: PAI-1 and fibrinogen levels increase monotonically with AHI at degrees of SDB considered mildly to moderately abnormal, suggesting that even mild SDB levels may increase prothrombotic processes. There may be a plateau in this effect, occurring at levels considered to reflect only moderate SDB severity. These relationships with mild-to-moderate SDB were not observed with D-dimer.
PMCID: PMC2949407  PMID: 20508215
sleep apnea; thrombosis; cardiovascular disease
19.  A Measure of Ventilatory Variability at Wake-Sleep Transition Predicts Sleep Apnea Severity 
Chest  2008;134(1):73-78.
Increased variability in ventilation may contribute to the pathogenesis of obstructive sleep apnea (OSA) by promoting ventilatory instability, fluctuations of neuromuscular output to the upper airway, and pharyngeal collapsibility. We assessed the association of a measure of ventilatory variability measured at the wake-sleep transition with OSA and associated covariates.
485 participants in the Cleveland Family Study underwent overnight polysomnography with independent derivation of the Ventilatory Variability Index and the Apnea Hypopnea Index. The Ventilatory Variability Index was calculated from the variability in the power spectrum of the abdominal inductance signal over a 2-minute period beginning at sleep onset.
The Ventilatory Variability Index was strongly correlated with the Apnea Hypopnea Index (r=0.43, p<0.001). After adjusting for age, body mass index, sex, and race, the Ventilatory Variability Index remained significantly associated with Apnea Hypopnea Index (p<0.001). The adjusted odds ratio for obstructive sleep apnea (Apnea Hypopnea Index ≥ 15) with each half standard deviation increase in Ventilatory Variability Index was 1.41 [1.25–1.59]. In a subgroup analysis of obese snorers, to limit analyses to those with a presumed anatomic predisposition for apnea, Ventilatory Variability Index remained associated with an elevated Apnea Hypopnea Index.
Increased ventilatory variability may be a useful phenotype in characterizing obstructive sleep apnea.
PMCID: PMC2672201  PMID: 18347208
Sleep apnea syndromes; sleep disordered breathing; polysomnography; apnea
20.  The Association between Sleep Duration and Obesity in Older Adults 
Reduced sleep has been reported to predict obesity in children and young adults. However, studies based on self-report have been unable to identify an association in older populations. In this study, the cross-sectional associations between sleep duration measured objectively and measures of weight and body composition were assessed in two cohorts of older adults.
Wrist actigraphy was performed for a mean (SD) of 5.2 (0.9) nights in 3055 men (age: 67–96 years) participating in the Osteoporotic Fractures in Men Study (MrOS) and 4.1 (0.8) nights in 3052 women (age: 70–99 years) participating in the Study of Osteoporotic Fractures (SOF). A subgroup of 2862 men and 455 women also underwent polysomnography to measure sleep apnea severity.
Compared to those sleeping an average of 7–8 hours per night, and after adjusting for multiple risk factors and medical conditions, a sleep duration of less than 5 hours was associated with a body mass index (BMI) that was on average 2.5 kg/m2 (95% CI: 2.0–2.9) greater in men and 1.8 kg/m2 (95%CI: 1.1–2.4) greater in women. The odds of obesity (BMI ≥ 30 kg/m2) was 3.7-fold greater (95% CI: 2.7–5.0) in men and 2.3-fold greater in women (95% CI: 1.6–3.1) who slept less than 5 hours. Short sleep was also associated with central body fat distribution and increased percent body fat. These associations persisted after adjusting for sleep apnea, insomnia, and daytime sleepiness.
In older men and women, actigraphy-ascertained reduced sleep durations are strongly associated with greater adiposity.
PMCID: PMC2605208  PMID: 18936766
sleep duration; sleep deprivation; obesity; central obesity; geriatrics; insomnia; sleepiness
21.  Genome-wide Linkage Screen for Stature and Body-mass Index in 3.032 Families - Evidence for Sex- and Population-specific Genetic Effects 
Stature (adult body height), and body mass index (BMI) have a strong genetic component explaining observed variation in human populations, however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population-and sex-specific analyses as well. For stature we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23 as well as 15q26 and 19q13 which have not been linked to stature previously. For BMI we found evidence for two loci: one on 7q35 and another on 11q22 both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of 1) combining data to maximize the sample size and 2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
PMCID: PMC2628452  PMID: 18781184
Body Height; Body Mass Index; Linkage mapping; Quantitative Trait Loci
22.  Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex- and population-specific genetic effects 
Stature (adult body height) and body mass index (BMI) have a strong genetic component explaining observed variation in human populations; however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population- and sex-specific analyses as well. For stature, we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23, as well as 15q26 and 19q13, which have not been linked to stature previously. For BMI, we found evidence for two loci: one on 7q35 and another on 11q22, both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of (1) combining data to maximize the sample size and (2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
PMCID: PMC2628452  PMID: 18781184
body height; body mass index; linkage mapping; quantitative trait loci
23.  Plasma Gelsolin Depletion and Circulating Actin in Sepsis—A Pilot Study 
PLoS ONE  2008;3(11):e3712.
Depletion of the circulating actin-binding protein, plasma gelsolin (pGSN) has been described in septic patients and animals. We hypothesized that the extent of pGSN reduction correlates with outcomes of septic patients and that circulating actin is a manifestation of sepsis.
Methodology/Principal Findings
We assayed pGSN in plasma samples from non-surgical septic patients identified from a pre-existing database which prospectively enrolled patients admitted to adult intensive care units at an academic hospital. We identified 21 non-surgical septic patients for the study. Actinemia was detected in 17 of the 21 patients, suggesting actin released into circulation from injured tissues is a manifestation of sepsis. Furthermore, we documented the depletion of pGSN in human clinical sepsis, and that the survivors had significantly higher pGSN levels than the non-survivors (163±47 mg/L vs. 89±48 mg/L, p = 0.01). pGSN levels were more strongly predictive of 28-day mortality than APACHE III scores. For every quartile reduction in pGSN, the odds of death increased 3.4-fold.
We conclude that circulating actin and pGSN deficiency are associated with early sepsis. The degree of pGSN deficiency correlates with sepsis mortality. Reversing pGSN deficiency may be an effective treatment for sepsis.
PMCID: PMC2577888  PMID: 19002257
24.  Lung Volume and Continuous Positive Airway Pressure Requirements in Obstructive Sleep Apnea 
Previous studies have demonstrated that lung volume during wakefulness influences upper airway size and resistance, particularly in patients with sleep apnea. We sought to determine the influence of lung volume on the level of continuous positive airway pressure (CPAP) required to prevent flow limitation during non-REM sleep in subjects with sleep apnea. Seventeen subjects (apnea–hypopnea index, 42.6 ± 6.2 [SEM]) were studied during stable non-REM sleep in a rigid head-out shell equipped with a positive/negative pressure attachment for manipulation of extrathoracic pressure. An epiglottic pressure catheter plus a mask/pneumotachometer were used to assess flow limitation. When lung volume was increased by 1,035 ± 22 ml, the CPAP level could be decreased from 11.9 ± 0.7 to 4.8 ± 0.7 cm H2O (p < 0.001) without flow limitation. The decreased CPAP at the same negative extrathoracic pressure yielded a final lung volume increase of 421 ± 36 ml above the initial value. Conversely, when lung volume was reduced by 732 ± 74 ml (n = 8), the CPAP level had to be increased from 11.9 ± 0.7 to 17.1 ± 1.0 cm H2O (p < 0.001) to prevent flow limitation, with a final lung volume decrease of 567 ± 78 ml. These results demonstrate that relatively small changes in lung volume have an important effect on the upper airway in subjects with sleep apnea during non-REM sleep.
PMCID: PMC2718445  PMID: 15817803
airflow limitation; continuous positive airway pressure; lung volume; sleep apnea; upper airway
25.  Genome-wide linkage analysis of longitudinal phenotypes using σ2A random effects (SSARs) fitted by Gibbs sampling 
BMC Genetics  2003;4(Suppl 1):S12.
The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time. We used Gibbs sampling to derive sigma-squared-A-random-effects (SSARs) for the longitudinal phenotype, and then used these as a new phenotype in subsequent genome-wide linkage analyses.
Additive genetic effects (σ2A.time) were estimated to account for ~9.2% of the variance in the rate of change of SBP with age, while additive genetic effects (σ2A) were estimated to account for ~43.9% of the variance in SBP at the mean age. The linkage results suggested that one or more major loci regulating change in SBP over time may localize to chromosomes 2, 3, 4, 6, 10, 11, 17, and 19. The results also suggested that one or more major loci regulating level of SBP may localize to chromosomes 3, 8, and 14.
Our results support a genetic component to both SBP and change in SBP with age, and are consistent with a complex, multifactorial susceptibility to the development of hypertension. The use of SSARs derived from quantitative traits as input to a conventional linkage analysis appears to be valuable in the linkage analysis of genetically complex traits. We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data.
PMCID: PMC1866446  PMID: 14975080

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