scholarly journals Novel Genetic and Cognitive Findings From the Long Life Family Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 582-582
Author(s):  
Mary Wojczynski ◽  
Nancy W Glynn ◽  
Evan Hadley
Keyword(s):  
Candidate Genes ◽  
Healthy Aging ◽  
Family Study ◽  
Collaborative Study ◽  
Genetic Interactions ◽  
Cognitive Tests ◽  
Blood Draw ◽  
Future Directions ◽  
Long Life ◽  
International Collaborative Study

Abstract The Long Life Family Study (LLFS), funded by the National Institute on Aging, is an international collaborative study of the genetics and familial components of exceptional longevity and healthy aging. We phenotyped 4,953 individuals from 539 two-generational families (1,727 proband; 3,226 offspring) at baseline (2006-2009). A second visit (2014-2017) was conducted for 2,904 (478 proband; 2,426 offspring) participants. The longitudinal, comprehensive in-person visits measured domains of healthy aging, including physical performance, cognition, and blood markers. Extensive genetic analyses were performed using the baseline blood draw, including genotyping with the Illumina 2.5M Human Omni array, linkage analyses with the families, whole genome sequencing using the TopMED protocol, and metabolomic assays. Collectively, this symposium will present novel findings that elucidate new potential genes and genetic interactions, investigate metabolomics profiles among APOE4 carriers, and refine phenotypic cognition definitions. Specifically, Dr. Santanasto will share results flanking the mesothelin gene associated with longitudinal gait speed. Then, Dr. An will share his findings of a new intronic variant in PKD1L2 gene associated with adiponectin, a marker of insulin resistance. Next, Dr. Arbeev will discuss genetic interactions between candidate genes for physiologic dysregulation and candidate genes for Alzheimer’s disease (AD, UNC5C gene). Ms. Yao will examine metabolomic profile differences between APOE4 carriers who develop AD and those who do not. Lastly, Mr. Xiang will introduce a method for combining multiple cognitive tests into a more sensitive overall cognitive score. As Discussant, Dr. Evan Hadley will share insights and propose future directions for LLFS.

scholarly journals Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Todd E. Druley ◽  
Lihua Wang ◽  
Shiow J. Lin ◽  
Joseph H. Lee ◽  
Qunyuan Zhang ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Healthy Aging ◽  
Family Study ◽  
Long Life

scholarly journals Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study

2021 ◽  
Vol 79 (1) ◽  
pp. 117-125
Author(s):  
Mengtian Du ◽  
Stacy L. Andersen ◽  
Nicole Schupf ◽  
Mary F. Feitosa ◽  
Megan S. Barker ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Function ◽  
Test Scores ◽  
Healthy Aging ◽  
Family Study ◽  
Apoe Genotype ◽  
Cognitive Test ◽  
Cross Sectional ◽  
Long Life ◽  
E4 Allele

Background: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. Objective: To test whether APOE genotype is associated with change of cognitive function in older adults. Methods: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ɛ2 or ɛ4 alleles. Results: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE ɛ4 allele on Logical Memory. Participants carrying at least one copy of the ɛ4 allele had lower scores in both immediate (–0.31 points, 95% CI: –0.57, –0.05) and delayed (–0.37 points, 95% CI: –0.64, –0.10) recall comparing to non-ɛ4 allele carriers. We did not detect any significant longitudinal effect of the ɛ4 allele. There was no cross-sectional or longitudinal effect of the ɛ2 allele. Conclusion: The APOE ɛ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE ɛ2 allele was not significantly associated with any of the cognitive test scores.

scholarly journals Linkage Guided Sequence Analysis Revealed a Novel Gene PKD1L2 for Adiponectin: The Long Life Family Study (LLFS)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 582-583
Author(s):  
Joseph Lee ◽  
Jason Anema ◽  
Lihua Wang ◽  
Warwick Daw ◽  
Kaare Christensen ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Healthy Aging ◽  
Family Study ◽  
Sequence Data ◽  
Receptor Gene ◽  
Linkage Peak ◽  
European Ancestry ◽  
Functional Variants ◽  
Novel Variants ◽  
Long Life

Abstract Adiponectin is involved in regulating insulin resistance (IR) and is a potential regulator of healthy aging and lifespan. To identify novel variants associated with adiponectin, we further assessed our previously identified linkage peak on 16q23.2 (LODs=3.8). We used sequence data of 632 participants (age, 24-110 years) from 47 families of European ancestry in the Long Life Family Study, a study with familial clustering of exceptional longevity in the US and Denmark. Adiponectin levels were log-transformed, and adjusted for age, sex, sites, and PCs for ancestry. We found a variant in the PKD1L2 (rs527459046, p=2e-8, MAF=3%, r2=1.5%, accounting for linkage=28%). The PKD1L2, 1.4 Mb upstream of the CDH13 (adiponectin receptor gene) is expressed in heart, liver, and adipocytes, known to function as an ion-channel regulator or a GPCR regulator for aging-related lipolysis, IR, and adiponectin/leptin secretion. Haplotyping, epistatic and bioinformatic analyses will be engaged to capture additional/functional variants and regulatory networks.

scholarly journals Role of Genetic Interactions in Alzheimer’s Disease: Lessons from Long Life Family Study (LLFS)

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 491-491
Author(s):  
Anatoliy Yashin ◽  
Dequing Wu ◽  
Konstantin Arbeev ◽  
Eric Stallard ◽  
Qihua Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Family Study ◽  
Interaction Analysis ◽  
Specific Interaction ◽  
Interaction Effects ◽  
Genetic Interactions ◽  
Risk Scores ◽  
Long Life

Abstract Experimental and clinical studies of Alzheimer’s disease (AD) provide plentiful evidence of AD heterogeneity and involvement of many interacting genes and pathways in regulation of AD-related traits. However, detailed mechanisms of genetic interactions (GxG) involved in AD remain largely unknown. Uncovering hidden patterns of such interactions from human data will help better understand the nature of AD heterogeneity and find new targets for AD prevention. In this paper, we applied a newly developed method of evaluating joint GxG effects on AD to analysis of the Long Life Family Study data. The analysis included several steps: (i) selecting candidate genes from stress response pathways that are thought to be involved in AD; (ii) estimating interaction effects of SNP-pairs on AD risk, and selecting the top interacting SNPs; (iii) running GWAS-like interaction analysis for SNP-pairs, with one SNP fixed; (iv) using characteristics of the detected SNP-pairs interactions to construct the SNP-specific Interaction Polygenic Risk Scores (IPRS); and (v) evaluating the effects of IPRSs on AD. We found that SNP-specific IPRS have highly significant effects on AD risk. For most SNPs involved in the significant interaction effects on AD, their individual effects were statistically not significant. Male and female analyses yielded different subsets of the top interacting SNPs. These results support major role of genetic interactions in heterogeneity of AD, and indicate that AD mechanisms can involve different combinations of the interacting genetic variants in males and females, which may point to different pathways of resistance/response to stressors in two genders.

A Collaborative Study to Establish the Second International Standard for Streptokinase

1990 ◽  
Vol 64 (02) ◽  
pp. 267-269 ◽  
Author(s):  
A B Heath ◽  
P J Gaffney
Keyword(s):  
High Purity ◽  
Collaborative Study ◽  
World Health Organisation ◽  
World Health ◽  
Clot Lysis ◽  
Current Standard ◽  
International Standard ◽  
Accelerated Degradation ◽  
The World ◽  
International Collaborative Study

SummaryAn International Standard for Streptokinase - Streptodomase (62/7) has been used to calibrate high purity clinical batches of SK since 1965. An international collaborative study, involving six laboratories, was undertaken to replace this standard with a high purity standard for SK. Two candidate preparations (88/826 and 88/824) were compared by a clot lysis assay with the current standard (62/7). Potencies of 671 i.u. and 461 i.u. were established for preparations A (88/826) and B (88/824), respectively.Either preparation appeared suitable to serve as a standard for SK. However, each ampoule of preparation A (88/826) contains a more appropriate amount of SK activity for potency testing, and is therefore preferred. Accelerated degradation tests indicate that preparation A (88/826) is very stable.The high purity streptokinase preparation, coded 88/826, has been established by the World Health Organisation as the 2nd International Standard for Streptokinase, with an assigned potency of 700 i.u. per ampoule.

An International Collaborative Study to Investigate Standardisation of Hirudin Potency

1993 ◽  
Vol 69 (05) ◽  
pp. 430-435 ◽  
Author(s):  
Colin Longstaff ◽  
Man-Yu Wong ◽  
Patrick J Gaffney
Keyword(s):  
Specific Activity ◽  
Collaborative Study ◽  
Residual Activity ◽  
Quality Standard ◽  
Upper Limit ◽  
Assay Procedure ◽  
Specific Activities ◽  
International Collaborative ◽  
Range Of Values ◽  
International Collaborative Study

SummaryAn international collaborative study has been carried out to investigate the reproducibility of hirudin assays in 13 laboratories using four recombinant hirudins and one natural, sulphated product. A simple assay procedure was proposed involving the titration of α-thrombin with inhibitor and measurement of residual activity using a chromogenic substrate. A standard α-thrombin preparation was supplied to ensure that this reagent was of uniform quality throughout the study. The method appeared to present no difficulties and laboratories reported similar potencies for the 5 hirudin samples, in line with expected values. This gave 200–222 Thrombin Inhibitory Units/ampoule (TIU/ampoule) of lyophilised hirudin, with geometric coefficient of variation (gcv) values ranging from 10.15–15.97%. This corresponds to specific activities of approximately 14,300–15,900 TIU/mg protein. This is close to the upper limit of previously reported values of specific activity. We conclude that the precision of this determination compared with the wider range of values in the literature (8,000–16,000 thrombin inhibitory units [TIU]/mg) results from the use of good quality standard α-thrombin by all laboratories. This study has important implications for hirudin standardisation.

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