The CC Genotype of the Delta-Sarcoglycan Gene Polymorphism rs13170573 Is Associated with Obstructive Sleep Apnea in the Chinese Population

Obstructive sleep apnea (OSA) is a highly heterogeneous sleep disorder, and increasing evidence suggests that genetic factors play a role in the etiology of OSA. Airway muscle dysfunction might promote pharyngeal collapsibility, mutations or single nucleotide polymorphisms (SNPs) in the delta-sarcoglycan (SCGD) gene associated with muscle dysfunction. To evaluate if SCGD gene SNPs are associated with OSA, 101 individuals without OSA and 97 OSA patients were recruited randomly. The genotype distributions of SNPs (rs157350, rs7715464, rs32076, rs13170573 and rs1835919) in case and control populations were evaluated. The GG, GC and CC genotypes of rs13170573 in control and OSA groups were 51.5% and 37.1%, 36.6% and 35.1%, and 11.9% and 27.8%, respectively. Significantly fewer OSA patients possessed the GG genotype and significantly more possessed the CC genotype compared with controls. Further multivariate logistic regression analysis showed that the CC genotype was an independent risk factor for OSA, with an odds ratio (OR) of 2.17 (95% confidence interval [CI]: 1.19–6.01). Other factors, such as age ≥50 years, male gender, body mass index (BMI) ≥25 kg/m², low-density lipoprotein cholesterol (LDL-C) level ≥3.33 mg/dL, smoking and hypertension, were also independent risk factors for OSA in our multivariate logistic regression model.     

Shared genetic risk factors for obstructive sleep apnea and obesity.

Both obesity and obstructive sleep apnea (OSA) are complex disorders with multiple risk factors, which interact in a complicated fashion to determine the overall phenotype. In addition to environmental risk factors, each disorder has a strong genetic basis that is likely due to the summation of small to moderate effects from a large number of genetic loci. Obesity is a strong risk factor for sleep apnea, and there are some data to suggest sleep apnea may influence obesity. It is therefore not surprising that many susceptibility genes for obesity and OSA should be shared. Current research suggests that approximately half of the genetic variance in the apnea hypopnea index is shared with obesity phenotypes. Genetic polymorphisms that increase weight will also be risk factors for apnea. In addition, given the interrelated pathways regulating both weight and other intermediate phenotypes for sleep apnea such as ventilatory control, upper airway muscle function, and sleep characteristics, it is likely that there are genes with pleiotropic effects independently impacting obesity and OSA traits. Other genetic loci likely interact with obesity to influence development of OSA in a gene-by-environment type of effect. Conversely, environmental stressors such as intermittent hypoxia and sleep fragmentation produced by OSA may interact with obesity susceptibility genes to modulate the importance that these loci have on defining obesity-related traits.     

Cumulative Association of Obstructive Sleep Apnea Severity and Short Sleep Duration with the Risk for Hypertension

Obstructive sleep apnea (OSA) and short sleep duration are individually associated with an increased risk for hypertension (HTN). The aim of this multicenter cross-sectional study was to test the hypothesis of a cumulative association of OSA severity and short sleep duration with the risk for prevalent HTN. Among 1,499 patients undergoing polysomnography for suspected OSA, 410 (27.3%) previously diagnosed as hypertensive and taking antihypertensive medication were considered as having HTN. Patients with total sleep time (TST) <6 h were considered to be short sleepers. Logistic regression procedures were performed to determine the independent association of HTN with OSA and sleep duration. Considering normal sleepers (TST ≥6 h) without OSA as the reference group, the odds ratio (OR) (95% confidence intervals) for having HTN was 2.51 (1.35–4.68) in normal sleepers with OSA and 4.37 (2.18–8.78) in short sleepers with OSA after adjustment for age, gender, obesity, diabetes, depression, current smoking, use of thyroid hormones, daytime sleepiness, poor sleep complaint, time in bed, sleep architecture and fragmentation, and study site. The risk for HTN appeared to present a cumulative association with OSA severity and short sleep duration (p<0.0001 for linear trend). The higher risk for HTN was observed in short sleepers with severe OSA (AHI ≥30) (OR, 4.29 [2.03–9.07]). In patients investigated for suspected OSA, sleep-disordered breathing severity and short sleep duration have a cumulative association with the risk for prevalent HTN. Further studies are required to determine whether interventions to optimize sleep may contribute to lower BP in patients with OSA.     

Relationship between Obstructive Sleep Apnea Severity and Sleep,Depression and Anxiety Symptoms in Newly-Diagnosed Patients

Obstructive sleep apnea (OSA) occurs in at least 10% of the population, and leads to higher morbidity and mortality; however, relationships between OSA severity and sleep or psychological symptoms are unclear. Existing studies include samples with wide-ranging comorbidities, so we assessed relationships between severity of OSA and common sleep and psychological disturbances in recently diagnosed OSA patients with minimal co-morbidities. We studied 49 newly diagnosed, untreated OSA patients without major co-morbidities such as mental illness, cardiovascular disease, or stroke; subjects were not using psychoactive medications or tobacco (mean ± std age: 46.8±9.1 years; apnea/hyponea index [AHI]: 32.1±20.5 events/hour; female/male: 12/37; weight <125 kg). We evaluated relationships between the AHI and daytime sleepiness (Epworth Sleepiness Scale; ESS), sleep quality (Pittsburg Sleep Quality Index; PSQI), depressive symptoms (Beck Depression Inventory-II; BDI), and anxiety symptoms (Beck Anxiety Inventory; BAI), as well as sex and body mass index (BMI). AHI was similar in females and males. Mean levels of all symptoms were above normal thresholds, but AHI was not correlated with age, ESS, PSQI, BDI, or BAI; only BMI was correlated with OSA severity. No differences in mean AHI appeared when subjects were grouped by normal versus elevated values of ESS, PSQI, BDI, or BAI. Consistent with other studies, a strong link between OSA severity and psychological symptoms did not appear in these newly diagnosed patients, suggesting that mechanisms additional to the number and frequency of hypoxic events and arousals occurring with apneas contribute to adverse health effects in OSA. OSA patients presenting with mild or moderate severity, and no major co-morbidities will not necessarily have low levels of sleep or psychological disturbances.     

A whole-genome scan for obstructive sleep apnea and obesity

Obstructive sleep apnea (OSA) is a common, chronic, complex disease associated with serious cardiovascular and neuropsychological sequelae and with substantial social and economic costs. Along with male gender, obesity is the most characteristic feature of OSA in adults. To identify susceptibility loci for OSA, we undertook a 9-cM genome scan in 66 white pedigrees (n=349 subjects) ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and body mass index (BMI). Candidate regions on chromosomes 1p (LOD score 1.39), 2p (LOD score 1.64), 12p (LOD score 1.43), and 19p (LOD score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on chromosomes 2p (LOD score 3.08), 7p (LOD score 2.53), and 12p (LOD score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on chromosomes 2p (adjusted LOD score 1.33) and 19p (adjusted LOD score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels.     

A Genome-Wide Association Study of Optic Disc Parameters

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10⁻¹⁹) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10⁻³³) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10⁻¹¹) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10⁻¹⁰) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.     

The Potential Association between Obstructive Sleep Apnea and Diabetic Retinopathy in Severe Obesity—The Role of Hypoxemia

Background

Obstructive sleep apnea (OSA) is common in obese patients with type 2 diabetes mellitus (DM) and may contribute to diabetic microvascular complications.

Methods

To investigate the association between OSA, hypoxemia during sleep, and diabetic retinal complications in severe obesity. This was a prospective observational study of 93 obese patients mean (SD) age: 52(10) years; mean (SD) body mass index (BMI): 47.3(8.3) kg/m²) with DM undergoing retinal screening and respiratory monitoring during sleep. OSA was defined as apnea-hypopnea index (AHI) of ≥15 events/hour, resulting in two groups (OSA+ vs. OSA−).

Results

Forty-six patients were OSA+: median (95% CI) AHI = 37(23–74)/hour and 47 were OSA–ve (AHI = 7(4–11)/hour). Both groups were similar for ethnicity, BMI, cardiovascular co-morbidities, diabetes duration, HbA_1c, and insulin treatment (p>0.05). The OSA+ group was significantly more hypoxemic. There was no significant difference between OSA+ and OSA− groups for the presence of retinopathy (39% vs. 38%). More OSA+ subjects had maculopathy (22% vs. 13%), but this did not reach statistical significance. Logistic regression analyses showed that AHI was not significantly associated with the presence of retinopathy or maculopathy (p>0.05). Whilst minimum oxygen saturation was not significantly associated with retinopathy, it was an independent predictor for the presence of maculopathy OR = 0.79 (95% CI: 0.65–0.95; p<0.05), after adjustment.

Conclusions

The presence of OSA, as determined by AHI, was not associated with diabetic retinal complications. In contrast, severity of hypoxemia during sleep (minimum oxygen saturations) may be an important factor. The importance of hypoxia in the development of retinal complications in patients with OSA remains unclear and further studies assessing the pathogenesis of hypoxemia in patients with OSA and diabetic retinal disease are warranted.     

Impact of the AHI1 Gene on the Vulnerability to Schizophrenia: A Case-Control Association Study

Background

The Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany.

Methodology/Principal Findings

29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (280 patients with psychotic disorders; 348 controls) and Germany (247 patients with schizophrenic disorders; 360 controls). Allelic, genotypic and haplotype frequencies were compared between cases and controls in both samples separately, as well as in the combined sample. The effect of genotype on several psychopathological measures (BPRS, KGV, PANSS) assessed in a Spanish subsample was also evaluated. We found several significant associations in the Spanish sample. Particularly, rs7750586 and rs911507, both located upstream of the AHI1 coding region, were found to be associated with schizophrenia in the analysis of genotypic (p = 0.0033, and 0.031, respectively) and allelic frequencies (p = 0.001 in both cases). Moreover, several other risk and protective haplotypes were detected (0.006<p<0.036). Joint analysis also supported the association of rs7750586 and rs911507 with the risk for schizophrenia. The analysis of clinical measures also revealed an effect on symptom severity (minimum P value = 0.0037).

Conclusions/Significance

Our data support, in agreement with previous reports, an effect of AHI1 variation on the susceptibility to schizophrenia in central and southern European populations.     

Association between Obstructive Sleep Apnea and Community-Acquired Pneumonia

BackgroundWe hypothesized that obstructive sleep apnea (OSA) can predispose individuals to lower airway infections and community-acquired pneumonia (CAP) due to upper airway microaspiration. This study evaluated the association between OSA and CAP.MethodsWe performed a case-control study that included 82 patients with CAP and 41 patients with other infections (control group). The controls were matched according to age, sex and body mass index (BMI). A respiratory polygraph (RP) was performed upon admission for patients in both groups. The severity of pneumonia was assessed according to the Pneumonia Severity Index (PSI). The associations between CAP and the Epworth Sleepiness Scale (ESS), OSA, OSA severity and other sleep-related variables were evaluated using logistic regression models. The associations between OSA, OSA severity with CAP severity were evaluated with linear regression models and non-parametric tests.FindingsNo significant differences were found between CAP and control patients regarding anthropometric variables, toxic habits and risk factors for CAP. Patients with OSA, defined as individuals with an Apnea-Hypopnea Index (AHI) ≥10, showed an increased risk of CAP (OR = 2·86, 95%CI 1·29–6·44, p = 0·01). Patients with severe OSA (AHI≥30) also had a higher risk of CAP (OR = 3·18, 95%CI 1·11–11·56, p = 0·047). In addition, OSA severity, defined according to the AHI quartile, was also significantly associated with CAP (p = 0·007). Furthermore, OSA was significantly associated with CAP severity (p = 0·0002), and OSA severity was also associated with CAP severity (p = 0·0006).ConclusionsOSA and OSA severity are associated with CAP when compared to patients admitted to the hospital for non-respiratory infections. In addition, OSA and OSA severity are associated with CAP severity. These results support the potential role of OSA in the pathogenesis of CAP and could have clinical implications. This link between OSA and infection risk should be explored to investigate the relationships among gastroesophageal reflux, silent aspiration, laryngeal sensory dysfunction and CAP.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01071421","term_id":"NCT01071421"}}NCT01071421     

Sleepiness,inflammation and oxidative stress markers in middle-aged males with obstructive sleep apnea without metabolic syndrome: a cross-sectional study

Background

The simultaneous occurrence of metabolic syndrome and excessive daytime sleepiness are very common in obstructive sleep apnea (OSA) patients. Both conditions, if present in OSA, have been reported to be associated with inflammation and disruption of oxidative stress balance that impair the cardiovascular system. To verify the impact of daytime sleepiness on inflammatory and oxidative stress markers, we evaluated OSA patients without significant metabolic disturbance.

Methods

Thirty-five male subjects without diagnostic criteria for metabolic syndrome (Adult Treatment Panel III) were distributed into a control group (n = 10) (43 ± 10.56 years, apnea-hypopnea index - AHI 2.71 ± 1.48/hour), a non-sleepy OSA group (n = 11) (42.36 ± 9.48 years, AHI 29.48 ± 22.83/hour) and a sleepy OSA group (n = 14) (45.43 ± 10.06 years, AHI 38.20 ± 25.54/hour). Excessive daytime sleepiness was considered when Epworth sleepiness scale score was ≥ 10. Levels of high-sensitivity C-reactive protein, homocysteine and cysteine, and paraoxonase-1 activity and arylesterase activity of paraoxonase-1 were evaluated.

Results

Patients with OSA and excessive daytime sleepiness presented increased high-sensitivity C-reactive protein levels even after controlling for confounders. No significant differences were found among the groups in paraoxonase-1 activity nor arylesterase activity of paraoxonase-1. AHI was independently associated and excessive daytime sleepiness tended to have an association with high-sensitivity C-reactive protein.

Conclusions

In the absence of metabolic syndrome, increased inflammatory response was associated with AHI and daytime sleepiness, while OSA was not associated with abnormalities in oxidative stress markers.     

Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study

Recent epidemiological studies have indicated that baseline C-reactive protein (CRP) levels may have value in prediction of cardiovascular risk. Using six tag single-nucleotide polymorphisms (SNPs) selected from our complete list of SNPs on the CRP gene, we investigated the association of CRP genotypes with plasma CRP levels and cardiovascular risk in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study cohort (1,296 Caucasians, 48.5% male, 54.7 +/- 12.8 yr old). There was a significant trend toward association of CRP haplotypes with CRP levels (P = 0.045). SNP analysis indicated a highly significant association of SNP -757 (rs3093059, P = 0.0004) and SNP -286 (rs3091244, P = 0.0065) and a borderline association of SNP -7180 (rs1341665, P = 0.06) with CRP levels. Neither CRP haplotypes nor individual SNP genotypes were associated with intima-media thickness of the common carotid or internal carotid artery or the bifurcation of the carotid arteries. These results indicated a strong impact of local SNPs of the CRP gene on plasma CRP levels, but there was no direct evidence that these genetically controlled CRP elevations by local CRP SNPs contributed to cardiovascular disease phenotypes.     

T Regulatory Lymphocytes and Endothelial Function in Pediatric Obstructive Sleep Apnea

Background

Obstructive sleep apnea (OSA) is a low-grade inflammatory disease affecting the cardiovascular and metabolic systems. Increasing OSA severity reduces T-regulatory lymphocytes (Tregs) in OSA children. Since Tregs modulate endothelial activation, and attenuate insulin resistance, we hypothesized that Tregs are associated with endothelial and metabolic dysfunction in pediatric OSA.

Methods

50 consecutively recruited children (ages 4.8–12 years) underwent overnight polysomnography and fasting homeostatic model (HOMA) of insulin resistance was assessed. Percentage of Tregs using flow cytometry, and endothelial function, expressed as the time to peak occlusive hyperemia (Tmax), were examined. In a subgroup of children (n = 21), in vitro Treg suppression tests were performed.

Results

Circulating Tregs were not significantly associated with either BMI z score or HOMA. However, a significant inverse correlation between percentage of Tregs and Tmax emerged (p<0.0001, r = −0.56). A significant negative correlation between Tregs suppression and the sleep pressure score (SPS), a surrogate measure of sleep fragmentation emerged (p = 0.02, r = −0.51) emerged, but was not present with AHI.

Conclusions

Endothelial function, but not insulin resistance, in OSA children is strongly associated with circulating Tregs and their suppressive function, and appears to correlate with sleep fragmentation. Thus, alterations in T cell lymphocytes may contribute to cardiovascular morbidity in pediatric OSA.     

Plasma Levels of Adiponectin,a Novel Adipocyte‐Derived Hormone,in Sleep Apnea**

Objective: Obstructive sleep apnea (OSA) is associated with obesity, sympathetic activation, systemic inflammation, and cardiovascular morbidity. Obesity, β‐adrenergic agonists, and inflammation are linked to decreased expression and/or secretion of an adipose tissue‐derived antiatherogenic hormone, adiponectin. The purpose of the study was to investigate whether OSA affected plasma levels of adiponectin, which might help explain OSA‐associated cardiovascular morbidity. Research Methods and Procedures: We randomly selected 68 otherwise healthy male subjects, either with moderate/severe OSA [apnea‐hypopnea index (AHI) ≥ 20; n = 35] or without OSA (AHI ≤ 5; n = 33). The diagnosis of OSA was made based on prospective full polysomnography. Adiponectin was measured before polysomnography between 8 and 10 PM . Results: AHI was higher in the OSA group (49.5 ± 4.4 vs. 2.9 ± 0.4 events/h; p < 0.001). OSA subjects were also more obese, with greater BMI (33 ± 1 vs. 30 ± 1; p = 0.016) and percentage body fat (29 ± 1% vs. 26 ± 1%; p = 0.030). Adiponectin levels were 7.67 ± 0.73 and 6.33 ± 0.51 μg/mL in the OSA and non‐OSA groups, respectively, and this difference was significant in covariate analysis (taking into account age, hemodynamic characteristics, measures of body fat, and OSA severity) (p = 0.009). After excluding from both groups the subjects with extreme BMI, such that the OSA and non‐OSA study cohorts had similar BMI and percentage body fat, subjects with OSA had significantly higher plasma adiponectin (8.49 ± 0.92 vs. 6.32 ± 0.55 μg/mL; p = 0.042), differences also evident in covariate analysis (p = 0.017). Discussion: Plasma adiponectin levels are elevated in otherwise healthy subjects with OSA. Therefore, low adiponectin is unlikely to explain the association between OSA and cardiovascular disease.     

Genome-Wide Association Study for Levels of Total Serum IgE Identifies HLA-C in a Japanese Population

Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10⁻¹⁰). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.     

Genetic Loci for Retinal Arteriolar Microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10⁻⁸. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10⁻¹² in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.     

Association of Genetic Variants with Primary Angle Closure Glaucoma in Two Different Populations

Purpose

A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal.

Method

Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL.

Results

After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317.

Conclusion

The present results support the initial GWAS findings, and confirm the SNP’s contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.     

Association of mTOR Polymorphisms with Cancer Risk and Clinical Outcomes: A Meta-Analysis

Genetic polymorphisms in mTOR gene may be associated with cancer risk and clinical outcomes of cancer patients by affecting mTOR gene expression or its activation. However, inconsistent results have been reported. The aim of this study is to systematically evaluate the association between mTOR polymorphisms (rs2295080, rs2536 and rs11121704) and cancer risk as well as clinical outcome by a meta-analysis. We identified 10 eligible studies and extracted data by two investigators. Based on dominant and recessive models, odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by using Stata, version 11 to evaluate the association strength. Our meta-analysis results showed that the wild genotype TT of rs2295080 polymorphism was associated with increased cancer risk under dominant model (OR = 1.24, 95%CI: 1.12–1.36, p<0.0005) in Chinese but not with clinical outcome parameters, while the TT genotype of rs11121704 was associated with poor clinical outcome parameters (OR = 1.53, 95%CI: 1.01–2.32, p = 0.044), such as death, metastasis and resistance to chemotherapy. However, rs2536 may not influence cancer susceptibility. In conclusion, this meta-analysis indicated the common polymorphisms in mTOR gene might be genetic risk factors for the carcinogenesis and clinical outcomes of cancer patients. However, further investigation on large population and different ethnicities are warranted.     

Impact of obstructive sleep apnea on the occurrence of restenosis after elective percutaneous coronary intervention in ischemic heart disease

Rationale

There is growing evidence that obstructive sleep apnea is associated with coronary artery disease. However, there are no data on the course of coronary stenosis after percutaneous coronary intervention in patients with obstructive sleep apnea.

Objectives

To determine whether sleep apnea is associated with increased late lumen loss and restenosis after percutaneous coronary intervention.

Methods

78 patients with coronary artery disease who underwent elective percutaneous coronary intervention were divided in 2 groups: 43 patients with an apnea hypopnea – Index < 10/h (group I) and 35 pt. with obstructive sleep apnea and an AHI > 10/h (group II). Late lumen loss, a marker of restenosis, was determined using quantitative coronary angiography after 6.9 ± 3.1 months.

Main results

Angiographic restenosis (>50% luminal diameter), was present in 6 (14%) of group I and in 9 (25%) of group II (p = 0.11). Late lumen loss was significant higher in pt. with an AHI > 10/h (0.7 ± 0.69 mm vs. 0.38 ± 0.37 mm, p = 0.01). Among these 35 patients, 21(60%) used their CPAP devices regularly. There was a marginally lower late lumen loss in treated patients, nevertheless, this difference did not reach statistical significance (0.57 ± 0.47 mm vs. 0.99 ± 0.86 mm, p = 0.08). There was no difference in late lumen loss between treated patients and the group I (p = 0.206).

Conclusion

In summary, patients with OSA and coronary artery disease have a higher degree of late lumen loss, which is a marker of restenosis and vessel remodeling after elective percutaneous intervention.     

Longitudinal Genome-Wide Association of Cardiovascular Disease Risk Factors in the Bogalusa Heart Study

Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7×10⁻²⁴), and rs445925 at APOE with LDL levels (combined P = 8.7×10⁻¹⁹). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children.