Person:

Redline, Susan

Background: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. Methodology/Principal Findings: We tested a set of (\sim)50,000 polymorphisms from (\sim)2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. Conclusions/Significance: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study. Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×(10^{−6}). Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts. Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.

Background: Obstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self‐reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association. Methods and Results: In the Multi‐Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002–2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010–2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA (“normal”). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow‐up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group. Conclusions: OSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.

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.

Background: Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. Methods and Results: We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community‐based study of existing (“parent”) cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12‐lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea‐hypopnea index (OAHI). CSA was defined by a central apnea index ≥5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow‐up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2‐ to 3‐fold increased odds of developing AF (central apnea index ≥5 odds ratio [OR], 3.00, 1.40–6.44; Cheyne–Stokes respiration OR, 1.83, 0.95–3.54; CSA or Cheyne–Stokes respiration OR, 2.00, 1.16–3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91–1.03; OAHI 5 to <15 OR, 0.84, 0.59–1.17; OAHI 15 to <30 OR, 0.93, 0.60–1.45; OAHI ≥30 OR, 0.76, 0.42–1.36). Conclusions: In a prospective, community‐based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors.