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1.  Common variants in DRD2 are associated with sleep duration: the CARe consortium 
Human Molecular Genetics  2015;25(1):167-179.
Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10−7). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.
doi:10.1093/hmg/ddv434
PMCID: PMC4690488  PMID: 26464489
2.  Eating behavior by sleep duration in the Hispanic Community Health Study/Study of Latinos 
Appetite  2015;95:275-284.
Sleep is an important pillar of health and a modifiable risk factor for diabetes, stroke and obesity. Little is known of diet and sleep patterns of Hispanics/Latinos in the US. Here we examine eating behavior as a function of sleep duration in a sub-sample of 11,888 participants from the Hispanic Community Health Study/Study of Latinos, a community-based cohort study of Hispanics aged 18–74 years in four US cities. Using a cross-sectional probability sample with self-report data on habitual sleep duration and up to two 24-hour dietary recalls, we quantified the Alternative Healthy Eating Index (AHEI-2010) score, a measure of diet quality, and intake of selected nutrients related to cardiovascular health. Linear regression models were fit to estimate least-square means of usual nutrient intake of saturated fats, potassium density, fiber, calcium, caffeine and the AHEI-2010 score by sleep duration adjusting for age, sex, Hispanic/Latino background, income, employment status, education, depressive symptomology, and years lived in the US. Distribution of calories over the day and association with sleep duration and BMI were also examined.
Short sleepers (≤ 6 hr) had significantly lower intake of potassium, fiber and calcium and long sleepers (≥9 hr) had significantly lower intake of caffeine compared to others sleepers after adjusting for covariates. However no difference in the AHEI-2010 score was seen by sleep duration. Significantly more long sleepers, compared to intermediate and short sleepers, reported having ≥30% total daily calories before bedtime. Not consuming a snack or meal within three hours before bedtime was associated with higher AHEI-2010 scores. These findings identify novel differences in dietary patterns by sleep duration in a Hispanic/Latino population in the U.S.
doi:10.1016/j.appet.2015.07.014
PMCID: PMC4589504  PMID: 26189885
3.  Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study 
Diabetes Care  2015;38(11):2050-2058.
OBJECTIVE
We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults.
RESEARCH DESIGN AND METHODS
Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants ≥65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989–1994. In 1989–1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989–1990 and again in 1992–1993, 1994–1995, 1996–1997, and 1998–1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history.
RESULTS
Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19–2.86]), snoring (HR 1.27 [95% CI 0.95–1.71]), and daytime sleepiness (HR 1.54 [95% CI 1.13–2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes.
CONCLUSIONS
Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.
doi:10.2337/dc15-0137
PMCID: PMC4613916  PMID: 26384390
4.  Associations between Obstructive Sleep Apnea, Sleep Duration, and Abnormal Fasting Glucose. The Multi-Ethnic Study of Atherosclerosis 
Rationale: No data exist as to the role of ethnicity in the associations between obstructive sleep apnea (OSA), sleep duration, and metabolic dysfunction.
Objectives: To examine links between OSA, objectively measured habitual sleep duration, and fasting glucose in U.S. ethnic groups.
Methods: The Multi-Ethnic Study of Atherosclerosis is a multisite community-based study that conducted polysomnography and wrist actigraphy. In 2,151 subjects (1,839 in fully adjusted models), the apnea–hypopnea index was used to classify OSA as none (0–4.9/h), mild (5–14.9/h), or moderate to severe (≥15/h). Actigraphic sleep duration was classified as short (≤5 h/night), intermediate (>5 and <8 h/night), or long (≥8 h/night). Subjects were classified as having normal fasting glucose (<100 mg/dl and no hypoglycemic medication use) or abnormal fasting glucose (≥100 mg/dl and/or hypoglycemic medication use).
Measurements and Main Results: The sample was 45.8% male, age 68.5 ± 9.2 (mean ± SD) years, and 27.3% African American, 37.2% white, 11.8% Chinese, and 23.8% Hispanic. The prevalence of abnormal fasting glucose was 40.2%. Relative to subjects without apnea, moderate-to-severe OSA was significantly associated with abnormal fasting glucose in African Americans (odds ratio, 2.14; 95% confidence interval, 1.12–4.08) and white participants (odds ratio, 2.85; 95% confidence interval, 1.20–6.75), but not among Chinese or Hispanic subjects, after adjusting for site, age, sex, waist circumference, and sleep duration (P = 0.06 for ethnicity-by-OSA severity interaction). In contrast, sleep duration was not significantly associated with abnormal fasting glucose after considering the influence of OSA.
Conclusions: This large multiethnic study confirmed previous reports of an independent association between OSA and metabolic dysfunction, and suggested that this association may vary by ethnicity.
doi:10.1164/rccm.201502-0366OC
PMCID: PMC4595677  PMID: 26084035
obstructive sleep apnea; type 2 diabetes mellitus; insulin resistance; ethnicity
5.  Joint associations of insomnia and sleep duration with prevalent diabetes: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) 
Journal of diabetes  2015;8(3):387-397.
Background
Inadequate sleep quantity and quality are associated with a higher risk of type 2 diabetes. This relationship is not well-examined in US Hispanics/Latinos, and prior analyses may be confounded by sleep apnea. This cross-sectional study examined joint associations of sleep duration and insomnia with diabetes among diverse US Hispanic/Latinos.
Methods
Baseline data on sleep quantity and quality were obtained from 15227 participants (mean age 41; range 18–74 years) from the Hispanic Community Health Study/Study of Latinos. Complex survey multinomial logistic regression was used to examine associations between prevalent diabetes and six phenotypes defined by cross-classifying sleep duration (short ≤6 h, average >6–9 h, long >9 h) and insomnia, adjusting for sex, age, site and Hispanic/Latino background interaction, education, physical activity, diet quality, and sleep apnea.
Results
In the weighted population, 14% had diabetes, 28% had insomnia, 9% were short sleepers, and 19% were long sleepers. Compared with those with average sleep and no insomnia, those with short sleep and insomnia were more likely to have diabetes (odds ratio [OR] 1.46; 95% confidence interval [CI] 1.02, 2.11). Average sleepers with insomnia (1.28; 95% CI 1.02, 1.61) and long sleepers without insomnia (1.33; 95% CI 1.07, 1.65) also had elevated odds of diabetes. Further adjustment for body mass index attenuated associations, except with long sleep without insomnia.
Conclusions
Both decreased quantity and quality of sleep are associated with diabetes in Hispanic/Latinos, with the greatest odds among those with short sleep duration and insomnia. The association is largely explained by obesity.
doi:10.1111/1753-0407.12308
PMCID: PMC5021506  PMID: 25952169
acculturation; Hispanic Americans; insomnia; sleep; type 2 diabetes mellitus
6.  Interest in Bariatric Surgery Among Obese Patients with Obstructive Sleep Apnea 
Background
Standard obstructive sleep apnea (OSA) therapies are poorly tolerated. Bariatric surgery is a potential alternative but the level of interest in this intervention among OSA patients is unknown.
Objectives
Determine the proportion of OSA patients who would be interested in bariatric surgery.
Setting
Sleep clinics, United States.
Methods
Consecutive adult patients with untreated severe OSA and a body mass index of 35–45 kg/m2 were approached. Patients at low peri-operative risk and no urgent indication for OSA treatment were invited to a separate informational visit about bariatric surgery as primary treatment for OSA.
Results
Of 767 eligible patients, 230 (30.0%) were not at low peri-operative risk, 49 (6.4%) had drowsy driving, and 16 (2.1%) had no insurance coverage for bariatric surgery. Of the remaining 482 patients, over one-third (35.5%) were interested in bariatric surgery. Surgical interest was 47.2% in women vs. 27.6% in men (p <0.01) and 67.3% in diabetics vs. 31.0% in non-diabetics (p<0.01). In multivariable adjusted models, female gender (odds ratio 1.89, 95% CI [1.10–3.25]) and diabetes (odds ratio 3.97, 95% CI [1.97–8.01]) remained highly predictive of bariatric surgery interest.
Conclusions
Nearly two-thirds of obese patients with severe OSA are good candidates for bariatric surgery. Among candidates, over one-third are interested in this treatment. Interest rates are highest among women and diabetics, indicating that metabolic improvements continue to be a major driver of surgery even in patients with severe OSA. Given patient interest, the role of bariatric surgery should be routinely discussed with obese OSA patients.
doi:10.1016/j.soard.2015.01.006
PMCID: PMC4501907  PMID: 25892349
Obstructive sleep apnea; bariatric surgery; obesity; diabetes; peri-operative risk
7.  The Association between Sleep Patterns and Obesity in Older Adults 
Background
Reduced sleep duration has been increasingly reported to predict obesity. However, timing and regularity of sleep may also be important. In this study, the cross-sectional association between objectively measured sleep patterns and obesity was assessed in two large cohorts of older individuals.
Methods
Wrist actigraphy was performed in 3053 men (mean age: 76.4 years) participating in the Osteoporotic Fractures in Men Study (MrOS) and 2985 women (mean age: 83.5 years) participating in the Study of Osteoporotic Fractures (SOF). Timing and regularity of sleep patterns were assessed across nights, as well as daytime napping.
Results
Greater night-to-night variability in sleep duration and daytime napping were associated with obesity independent of mean nocturnal sleep duration in both men and women. Each 1 hour increase in the variability of nocturnal sleep duration increased the odds of obesity 1.63-fold (95% CI [1.31-2.02]) among men and 1.22-fold (95% CI [1.01-1.47]) among women. Each 1 hour increase in napping increased the odds of obesity 1.23-fold (95%CI [1.12-1.37]) in men and 1.29-fold (95%CI [1.17-1.41]) in women. In contrast, associations between later sleep timing and night-to-night variability in sleep timing with obesity were less consistent.
Conclusions
In both older men and women, variability in nightly sleep duration and daytime napping were associated with obesity independent of mean sleep duration. These findings suggest that characteristics of sleep beyond mean sleep duration may play a role in weight homeostasis, highlighting the complex relationship between sleep and metabolism.
doi:10.1038/ijo.2014.13
PMCID: PMC4110191  PMID: 24458262
sleep duration; sleep pattern; napping; variability; obesity; geriatrics
8.  Sex‐Specific Association of Obstructive Sleep Apnea With Retinal Microvascular Signs: The Multi‐Ethnic Study of Atherosclerosis 
Background
Obstructive sleep apnea (OSA) is a common condition affecting more men than women. The relationship of OSA with microvascular disease is unclear, complicated by possible sex difference. Assessment of the relationship of OSA with retinal microvascular signs in men and women may provide insights into such a relationship.
Methods and Results
We examined the sex‐specific cross‐sectional association of OSA severity with retinal vascular calibers in 1808 participants, and with specific retinopathy signs in 1831 participants from a sample of 2060 participants aged 54 to 93 years who underwent successful polysomnography in the Multi‐Ethnic Study of Atherosclerosis, 2010–2012. OSA severity was defined by the apnea–hypopnea index (events/h) as none (<5), mild (5–14.9), moderate (15–29.9), and severe (≥30). As compared to no OSA, moderate/severe OSA in men was associated with retinal arteriolar narrowing (odds ratio [OR] and 95% CI for the narrowest quartile: 1.65 [1.00–2.71]) and retinal venular widening (1.80 [1.07–3.04] for the widest quartile), but not in women (odds ratio: 1.10 [0.67–1.81] and 0.91 [0.58–1.43], respectively) after adjusting for age, race/ethnicity, body mass index, pack‐years of cigarette smoking, alcohol intake, hypertension duration, diabetes mellitus duration, HbA1c levels, lipid profile, micro‐/macroalbuminuria, estimated glomerular filtration rate, β‐blockers use, antihypertensive therapy, and lipid‐lowering therapy. In contrast, severe OSA was associated with retinal microaneurysms in women, but not in men (odds ratio: 3.22 [1.16–8.97] and 0.59 [0.27–1.30], respectively).
Conclusions
The associations of OSA severity with retinal microvascular signs may differ by sex. Whether these findings were related to sex differences in OSA exposure needs further investigation.
doi:10.1161/JAHA.116.003598
PMCID: PMC5015394  PMID: 27451457
apnea‐hypopnea index; epidemiology; microvascular dysfunction; obstructive sleep apnea; retinal vascular calibers; retinopathy; sex‐specific; Epidemiology; Lifestyle; Primary Prevention; Risk Factors
9.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study 
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35–80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 ×10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
10.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study 
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35-80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
11.  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.
Design
Cross-sectional epidemiologic survey.
Participants
Middle-aged women (n = 60,028) participating in the Nurses Health Study II who reported a habitual sleep duration of 7 hours or more.
Results
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.
Conclusion
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
12.  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.
doi:10.1093/aje/kwj280
PMCID: PMC3496783  PMID: 16914506
obesity; sleep deprivation; weight gain; women
13.  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.
doi:10.1183/09031936.00029808
PMCID: PMC2655306  PMID: 18579548
sleep apnea; upper airway; oropharynx; pharyngometry; genetic epidemiology; heritability
14.  Short sleep duration and weight gain: a systematic review 
Obesity (Silver Spring, Md.)  2008;16(3):643-653.
Objective
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.
Methods
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.
Results
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.
Discussion
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.
doi:10.1038/oby.2007.118
PMCID: PMC2723045  PMID: 18239586
sleep; sleep duration; sleep deprivation; risk factor; weight
15.  The Association between Sleep Duration and Obesity in Older Adults 
Background
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.
Methods
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.
Results
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.
Conclusions
In older men and women, actigraphy-ascertained reduced sleep durations are strongly associated with greater adiposity.
doi:10.1038/ijo.2008.198
PMCID: PMC2605208  PMID: 18936766
sleep duration; sleep deprivation; obesity; central obesity; geriatrics; insomnia; sleepiness
16.  Shared Genetic Basis for Obstructive Sleep Apnea and Adiposity Measures 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1038/sj.ijo.0803803
PMCID: PMC2672200  PMID: 18209735
obesity; sleep apnea; genetics; heritability; genetic correlation
17.  New developments in the use of positive airway pressure for obstructive sleep apnea 
Journal of Thoracic Disease  2015;7(8):1323-1342.
Obstructive sleep apnea (OSA) is a disorder which afflicts a large number of individuals around the world. OSA causes sleepiness and is a major cardiovascular risk factor. Since its inception in the early 1980’s, continuous positive airway pressure (CPAP) has emerged as the major treatment of OSA, and it has been shown to improve sleepiness, hypertension, and a number of cardiovascular indices. Despite its successes, adherence with treatment remains a major limitation. Herein we will review the evidence behind the use of positive airway pressure (PAP) therapy, its various modes, and the methods employed to improve adherence. We will also discuss the future of PAP therapy in OSA and personalization of care.
doi:10.3978/j.issn.2072-1439.2015.07.30
PMCID: PMC4561253  PMID: 26380760
Obstructive sleep apnea (OSA); positive airway pressure (PAP); treatment adherence
18.  Effects of physical activity on melatonin levels in previously sedentary men and women 
Background
The inverse association between physical activity and cancer risk may be mediated by higher melatonin levels. However,few studies have examined the effect of increased physical activity on melatonin levels.
Methods
The parent study was a randomized controlled trial (RCT) which randomized 51 men and 49 women to a 12-month moderate-to-vigorous aerobic exercise intervention (‘exercisers’) and 51 men and 51 women to a stretching control (‘controls’). Participants were aged 40-75 years, and previously sedentary. Levels of the principal urinary metabolite of melatonin 6-sulphatoxymelatonin (aMT6s), corrected for creatinine levels, were measured in spot morning urine samples by immunoassay at baseline and 12-months. Changes in levels between exercisers and controls were compared using generalized estimating equations for linear regression.
Results
We observed no statistically significant difference in the change in aMT6s levels from baseline to 12-months in exercisers compared with controls (change in aMT6s levels: exercisers, +6.5%; controls, +13%; P=0.66). There was no evidence of effect modification by age, sex or body mass index.
Conclusions
A 12-month moderate-intensity exercise intervention did not affect levels of aMT6s.
Impact
Further research needs to focus on other potential mechanisms through which physical activity may reduce the risk of cancer.
doi:10.1158/1055-9965.EPI-14-0299
PMCID: PMC4119501  PMID: 24859868
aMT6s; cancer; exercise; sedentary; sex hormones
19.  Association of Sleep Habits With Accidents and Near Misses in United States Transportation Operators 
Objective
To explore sleep risk factors and their association with adverse events in transportation operators.
Methods
Self-reported sleep-related behaviors were analyzed in transportation operators (drivers, pilots, and rail operators) aged 26 to 78 years who completed the National Sleep Foundation’s 2012 “Planes, Trains, Automobiles, and Sleep” survey. Regression analyses were used to assess the associations of various sleep-related variables with the combined outcome of self-reported accidents and near misses.
Results
Age- and body mass–adjusted predictors of accidents/near misses included an accident while commuting (odds ratio [OR] = 4.6; confidence interval [CI], 2.1 to 9.8), driving drowsy (OR = 4.1; CI, 2.5 to 6.7), and Sheehan Disability Scale score greater than 15 (OR = 3.5; CI, 2.2 to 5.5). Sleeping more than 7 hours nightly was protective for accident/near misses (OR = 0.6; CI, 0.4 to 0.9).
Conclusion
Recognized risk factors for poor sleep or excessive daytime sleepiness were significantly associated with self-reported near misses and/or accidents in transportation operators.
doi:10.1097/JOM.0000000000000132
PMCID: PMC4340239  PMID: 24806564
20.  A pilot study investigating the effects of continuous positive airway pressure treatment and weight-loss surgery on autonomic activity in obese obstructive sleep apnea patients☆, ☆☆ 
Journal of electrocardiology  2014;47(3):364-373.
Background
We have previously demonstrated that severity of obstructive sleep apnea (OSA) as measured by the apnea–hypopnea index (AHI) is a significant independent predictor of readily-computed time-domain metrics of short-term heart rate variability (HRV).
Methods
We aimed to assess time-domain HRV measured over 5-min while awake in a trial of obese subjects undergoing one of two OSA therapies: weight-loss surgery (n = 12, 2 males, median and interquartile range (IQR) for BMI 43.7 [42.0, 51.4] kg/m2, and AHI 18.1 [16.3, 67.5] events/h) or continuous positive airway pressure (CPAP) (n = 15, 11 males, median BMI 33.8 [31.3, 37.9] kg/m2, and AHI 36.5 [24.7, 77.3] events/h). Polysomnography was followed by electrocardiography during wakefulness; measurements were repeated at 6 and 12–18 months post-intervention.
Results
Despite similar measurements at baseline, subjects who underwent surgery exhibited greater improvement in short-term HRV than those who underwent CPAP (p = 0.04).
Conclusions
Our data suggest a possible divergence in autonomic function between the effects of weight loss resulting from bariatric surgery, and the amelioration of obstructive respiratory events resulting from CPAP treatment. Randomized studies are necessary before clinical recommendations can be made.
doi:10.1016/j.jelectrocard.2014.02.008
PMCID: PMC4340702  PMID: 24636793
Obstructive sleep apnea; Heart rate variability; Weight-loss surgery; Continuous positive airway pressure
21.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Summary
Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.
doi:10.1016/S0140-6736(14)61183-1
PMCID: PMC4322187  PMID: 25262344
22.  CPAP versus Oxygen in Obstructive Sleep Apnea 
The New England journal of medicine  2014;370(24):2276-2285.
Background
Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.
Methods
We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea–hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.
Results
Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (−2.4 mm Hg; 95% confidence interval [CI], −4.7 to −0.1; P = 0.04) or the group receiving supplemental oxygen (−2.8 mm Hg; 95% CI, −5.1 to −0.5; P = 0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.
Conclusions
In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800.)
doi:10.1056/NEJMoa1306766
PMCID: PMC4172401  PMID: 24918372
23.  No effect of exercise on urinary 6-sulfatoxymelatonin and catecholamines in young women participating in a 16-week randomized controlled trial 
Background
Women with breast cancer have decreased levels of melatonin or its metabolite in plasma and/or urine.
Methods
We measured serum melatonin, urinary 6-sulfatoxymelatonin, catecholamines and cortisol in 141 sedentary young female participants in a clinical trial comparing 150 min/wk aerobic exercise for 4 months to no-exercise controls. Demographics, health surveys, body composition, sleep quality, fitness levels, blood and urine samples were obtained at baseline and 16 weeks.
Results
There were no differences between groups at baseline in demographics, exercise, sleep habits, or study hormones. There were also no significant differences between groups in any of the hormones at 16 weeks.
Conclusion
Sixteen weeks of exercise had minimal effects on melatonin secretion of young women.
Impact
There is convincing evidence that exercise protects against breast cancer, but this does not appear to occur through changes in melatonin secretion.
doi:10.1158/1055-9965.EPI-13-0583
PMCID: PMC3769436  PMID: 23861293
6-sulfatoxymelatonin; cortisol; epinephrine; exercise; randomized controlled trial
24.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
doi:10.1371/journal.pgen.1004517
PMCID: PMC4125087  PMID: 25102180
Journal of sleep research  2013;22(4):443-451.
Summary
The objective of the study is to examine whether increasing OSA severity is associated with worsening endothelial function.
The design is a cross-sectional examination of the baseline assessment of a multicenter randomized controlled clinical trial examining the effects of oxygen, CPAP therapy, or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an Apnea Hypopnea Index (AHI) of 15 to 50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included.
OSA severity indices (oxygen desaturation index [ODI], AHI, and percent sleep time below 90% oxygen saturation [TST<90]) and a measure of endothelium mediated vasodilatation (Framingham Reactive Hyperemia Index, F-RHI derived from peripheral arterial tonometry, PAT) were assessed.
The sample included 267 individuals with a mean AHI of 25.0 ± 8.5 (SD) and mean F-RHI 0.44 ± 0.38. In adjusted models, the slope of the relationship between ODI and F-RHI differed above and below an ODI of 24.6 (p=0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% (95% CI: (0%, 5%); p=0.05) while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: (0%, 27%); p=0.05) per 5-unit increase in ODI. A similar pattern was observed between AHI and F-RHI. No relation was noted with TST<90 and F-RHI.
There was evidence of a graded decline in endothelial function in association withn higher levels of intermittent hypoxemia.
doi:10.1111/jsr.12026
PMCID: PMC4011016  PMID: 23331757
Sleep apnea; Cardiovascular disease; Endothelial dysfunction

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