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On page 1 showing 1 ~ 7 papers out of 7 papers

The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study.

  • Jaime Ramos-Cejudo‎ et al.
  • Frontiers in aging neuroscience‎
  • 2021‎

Objective: Active neutrophils are important contributors to Alzheimer's disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia. Methods: We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk. Results: The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline. Conclusion: Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted.


Platelet Function Is Associated With Dementia Risk in the Framingham Heart Study.

  • Jaime Ramos-Cejudo‎ et al.
  • Journal of the American Heart Association‎
  • 2022‎

Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.


Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.

  • Han Chen‎ et al.
  • American journal of human genetics‎
  • 2019‎

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.


Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

  • Yao Hu‎ et al.
  • American journal of human genetics‎
  • 2021‎

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.


Genome-wide association and functional follow-up reveals new loci for kidney function.

  • Cristian Pattaro‎ et al.
  • PLoS genetics‎
  • 2012‎

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.


Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

  • Anna V Mikhaylova‎ et al.
  • American journal of human genetics‎
  • 2021‎

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.


Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

  • Ron Do‎ et al.
  • Nature‎
  • 2015‎

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.


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