Carotid artery intima-media thickness (CIMT) has been used as an early indicator of subclinical atherosclerosis. Multiple studies have identified significant associations between plasma total ...non-esterified fatty acid (NEFA) concentrations and risk factors associated with subclinical atherosclerosis. However, the relationship between CIMT and serum NEFA is less clear. We hypothesized fasting serum total, individual saturated, and trans NEFA are positively associated with, and individual monounsaturated, n-6 polyunsaturated (PUFA) and n-3 PUFA NEFA are inversely associated with, CIMT.
We investigated the associations between fasting serum NEFA, and CIMT assessed in 1998–1999 among Cardiovascular Health Study (CHS) participants (N = 1,569) not taking anti-diabetic medication. A total of 35 individual NEFAs were measured in stored specimens from 1996–1997 using gas chromatography. CIMT was determined using ultrasound images, and was defined as the sum of the maximum common CIMT at the far wall divided by its standard deviation (SD) and the maximum internal CIMT at the far wall divided by its SD. At baseline, mean age was 77.3 ± 4.2, body mass index (BMI) was 26.8 ± 4.3 and 64% were female. Associations were assessed by linear regression, with adjustments for other individual NEFAs, age, sex, race, field center, education, smoking, BMI, physical activity, alcohol consumption, eGFR, serum albumin, hyperglycemia, hypertension, use of anti-hypertensive, statin, and other lipid-lowering drugs.
In adjusted models per SD increment, linoelaidic acid (trans18:2) was positively associated with CIMT β (95% confidence interval): 10.4 (0.99, 19.8), P = 0.03, and α-linolenic acid (18:3n-3) was marginally associated with lower CIMT –21.2 (–42.6, 0.2), P = 0.05. No significant associations were observed between total NEFAs or any other individual NEFAs (SFA, MUFA, and n-6 PUFA) and CIMT.
In this large community-based cohort of older adults, higher concentration of linoelaidic acid was positively associated with CIMT, suggesting the importance of partially hydrogenated fat in the development of subclinical atherosclerosis in older adults. Overall, however, serum fasting NEFAs were largely unrelated to subclinical atherosclerosis in CHS participants.
NIH, NHLBI, USDA.
Aims/hypothesis
Elevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. ...Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies.
Methods
A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation.
Results
Previously reported SNP associations were significantly replicated (
p
≤ 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (
G6PC2
-rs477224 and
GCK-
rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in
G6PC2
tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at
SLC17A2
-rs75862513.
Conclusions/interpretation
These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries.
Data availability
The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here:
https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1
Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture ...using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β SE = 1.17 0.45 vs. 0.09 0.09 kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
Abstract Purpose Sudden cardiac death (SCD) is an important cause of mortality in the adult population. Height has been associated with cardiac hypertrophy and an increased risk of arrhythmias but ...also with decreased risk of coronary heart disease, suggesting a complex association with SCD. Methods We examined the association of adult height with the risk of physician-adjudicated SCD in two large population-based cohorts: the Cardiovascular Health Study and the Atherosclerosis Risk in Communities study. Results Over an average follow-up time of 11.7 years in Cardiovascular Health Study, there were 199 (3.6%) cases of SCD among 5556 participants. In Atherosclerosis Risk in Communities study, over 12.6 years, there were 227 (1.5%) cases of SCD among 15,633 participants. In both cohorts, there was a trend toward decreased SCD with taller height. In fixed effects meta-analysis, the pooled hazard ratio per 10 cm of height was 0.84; 95% confidence interval, 0.73–0.98; P = .03. The association of increased height with lower risk of SCD was slightly attenuated after inclusion of risk factors associated with height, such as hypertension and left ventricular hypertrophy. The association appeared stronger among men than women in both cohorts. Conclusions In two population-based prospective cohorts of different ages, greater height was associated with lower risk of SCD.
In longitudinal studies, observation times are often irregular and subject-specific. Frequently they are related to the outcome measure or other variables that are associated with the outcome measure ...but undesirable to condition upon in the model for outcome. Regression analyses that are unadjusted for outcome-dependent follow-up then yield biased estimates. The authors propose a class of inverse-intensity rate-ratio weighted estimators in generalized linear models that adjust for outcome-dependent follow-up. The estimators, based on estimating equations, are very simple and easily computed; they can be used under mixtures of continuous and discrete observation times. The predictors of observation times can be past observed outcomes, cumulative values of outcome-model covariates and other factors associated with the outcome. The authors validate their approach through simulations and they illustrate it using data from a supported housing program from the US federal government. /// Dans les études longitudinales, les temps d'observation sont souvent irréguliers et varient d'un individu à l'autre. Ils sont fréquemment liés à la variable d'intérêt ou à certaines covariables qu'on peut ne pas vouloir incorporer au modèle. Les analyses de régression qui font fi de l'influence des covariables sur le suivi produisent alors des estimations biaisées. Les auteurs proposent une classe d'estimateurs pondérés par l'inverse d'un rapport d'intensité pour des modèles linéaires généralisés adaptés à ces circonstances. Les estimateurs, déduits d'équations d'estimation, sont très simples et faciles à calculer; ils sont valides même en présence d'un mélange de temps d'observations discrets et continus. La prévision des temps d'observation peut s'appuyer sur des événements observés, des cumuls de covariables ou d'autres facteurs liés à la variable d'intérêt. Les auteurs valident leur approche par voie de simulations et ils l'illustrent au moyen de données portant sur un programme d'aide au logement du Gouvernement fédéral américain.
Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different ...populations has been largely unexplored.
Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein HDL, low density lipoprotein LDL, and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with corrected IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.
Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.
Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.
As part of the 'Population Architecture ...using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.
We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).
These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.
NCT00000611.
Nuclear factor-kappaB (NF-kappaB) has been shown to be abnormally activated in some human hepatocellular carcinomas (HCCs), but most studies of NF-kappaB in patient samples have focused on the p65 ...subunit. Recent information has implicated IkappaB family members (e.g. Bcl-3) as possible mediators of NF-kappaB activation. Therefore, we examined the expression of all NF-kappaB family members and downstream targets in HCC.
Archived HCCs from 30 patients were evaluated by immunohistochemistry for NF-kappaB family proteins, Bcl-3 and targets of NF-kappaB/IkappaB function. Results were validated by Western blotting in frozen paired HCC and adjacent normal tissue in a subset of cases.
NF-kappaB p50 and p52 subunits were frequently localized to tumor cell nuclei (40 and 48%), whereas p65 positivity was infrequent. Bcl-3 was overexpressed in 90% of tumor cell nuclei compared with 26% of adjacent non-neoplastic liver (p < 0.001).
Aberrant Bcl-3 nuclear expression occurs in the vast majority of HCCs compared with adjacent normal or cirrhotic liver tissue. Bcl-3 is known to interact with NF-kappaB p50 and p52 homodimers, and our study demonstrates very frequent nuclear colocalization of Bcl-3 and p50/p52, suggesting that the Bcl-3/p50 or Bcl-3/p52 interactions are important in HCC pathogenesis.
The relationship between hormonal contraceptive method use and sexually transmitted infections is not well understood. Studies that implement routine screening for STIs among different contraceptive ...users, such as the ASPIRE HIV-1 prevention trial, can be useful for identifying potential risk factors of STIs. However, the complex nature of non-random data can lead to challenges in estimation of associations for potential risk factors. In particular, if screening for the disease is not random (i. e. it is driven by symptoms or other clinical indicators), estimates of association can suffer from bias, often referred to as informative sampling bias. Time-varying predictors and potential stratification variables can further contribute to difficulty in obtaining unbiased estimates. In this paper, we estimate the association between time- varying contraceptive use and Sexually transmitted infections acquisition, in the presence of informative sampling, by extending the work Buzkova (2010). We use a two-step procedure to jointly model the non-random screening process and sexually transmitted infection risk. In the first step, inverse intensity rate ratios (IIRR) weights are estimated. In the second step, a weighted proportional rate model is fit to estimate the IIRR weighted hazard ratio. We apply the method to evaluate the relationship between hormonal contraception and risk of sexually transmitted infections among women participating in a biomedical HIV-1 prevention trial. We compare our results using the proposed weighted method to those generated using conventional approaches that do not account for potential informative sampling bias or do not use the full potential of the data. Using the IIRR weighted approach we found depot medroxyprogesterone acetate users have a significantly decreased hazard of
acquisition compared to IUD users (hazard ratio: 0.44, 95% CI: (0.25, 0.83)), which is consistent with the literature. We did not find significant increased or decreased hazard of other STIs for hormonal contraceptive users compared to non-hormonal IUD users.
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