Statistical Investigation of the Immune Response in Non-Human Primate Models

The human immunodeficiency virus (HIV) was first detected more than 30 years ago. Since then, intensive research has been done to develop a broadly protective vaccine, though without success. Our goal is to unveil some features of the protective immunity in non-human primate lentiviral infections in order to emulate HIV-infection. Two primate species have been studied, rhesus macaques (Rh) (Macaca mulatta) and African green monkeys (Ag) (Chlorocebus spp.). Simian immunodeficiency virus (SIV) infection is non-pathogenic to Ag while Rh develop an AIDS-like illness. In this study, peripheral blood mononuclear cells (PBMC) from 8 Ag and 27 Rh were stimulated with phorbol merystate acetate and ionomycin to activate lymphocytes regardless of their specificity. We hypothesize that the immune response of the two species is fundamentally different resulting in the different reactions to SIV infection. CD4+ and CD8+ T-cells were investigated with respect to multiple surface markers and production of gamma-interferon (IFN), tumor necrosis factor alpha (TNF) and interleukin two (IL2). Additionally to principal component analysis, we tried a new approach by using exploratory factor analysis to reveal latent influences. We found differing relations for both Ag and Rh especially among cytokine secretion patterns. Based on our results, it is assumable that, besides their clear biological interaction, the TNF and IL2 are dependent on a latent factor in the Ag. However, this strong relation could not be found in Rh. Instead, TNF and IL2 seem to oppose each other for Rh because they are assigned to different latent factors

Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment

Author Correction: Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

In the originally published version of this Article, financial support was not fully acknowledged. The sentence “KS was supported by the ‘Biomedical Research Program’ funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation” has been added to the acknowledgement section in both the PDF and HTML versions of the Article

Association of adiponectin and leptin with relative telomere length in seven independent cohorts including 11,448 participants.

Oxidative stress and inflammation are major contributors to accelerated age-related relative telomere length (RTL) shortening. Both conditions are strongly linked to leptin and adiponectin, the most prominent adipocyte-derived protein hormones. As high leptin levels and low levels of adiponectin have been implicated in inflammation, one expects adiponectin to be positively associated with RTL while leptin should be negatively associated. Within the ENGAGE consortium, we investigated the association of RTL with adiponectin and leptin in seven independent cohorts with a total of 11,448 participants. We performed partial correlation analysis on Z-transformed RTL and LN-transformed leptin/adiponectin, adjusting for age and sex. In extended models we adjusted for body mass index (BMI) and C-reactive protein (CRP). Adiponectin showed a borderline significant association with RTL. This appeared to be determined by a single study and when the outlier study was removed, this association disappeared. The association between RTL and leptin was highly significant (r = -0.05; p = 1.81 × 10-7). Additional adjustment for BMI or CRP did not change the results. Sex-stratified analysis revealed no difference between men and women. Our study suggests that high leptin levels are associated with short RTL

Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study

AbstractBackgroundAlthough epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain.ObjectivesThrough a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF).MethodsThis study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls.ResultsSerum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations.ConclusionsEvidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions