Dataset Information

Cell-free DNA levels of twins and sibling pairs indicate individuality and possible use as a personalized biomarker.

ABSTRACT: Cell-free DNA (cfDNA) in the human blood circulation has been under investigation since its initial observation in 1948. Plasma cfDNA is known to be significantly elevated in diseased people. Due to possible variation in the population, evaluating cfDNA as a non-invasive biomarker at disease onset alone may not be sensitive enough to accurately diagnose diseases, particularly early stage cancers on a personal level. To understand the factors that define the cfDNA levels on the personal level and for better use as a non-invasive biomarker, we isolated cfDNA from the plasma of healthy individuals with varying degrees of genetic and/or environmental similarities (monozygotic twins, dizygotic twins, sibling pairs, and unrelated individuals) as well as from patients with varying stages of breast and ovarian cancer undergoing treatment. Cell-free DNA levels were quantified by a fluorometer (ng/ml) and/or real-time PCR (copies/ml). The associations between individuals with various degrees of genetic and/or environmental similarities and their plasma cfDNA levels were evaluated. The ACE model (A = additive genetic, C = common environment, and E = specific environmental factors) was used to determine the proportion of each factor on the cfDNA levels. We found a high correlation (r = 0.77; p < 0.0001) in plasma cfDNA levels between monozygotic twins (n = 39). However, the correlation was gradually reduced to moderate (r = 0.47; p = 0.016) between dizygotic twins (n = 13) and low correlation (r = 0.28; p = 0.043) between sibling pairs (n = 26). The ACE model analysis showed that the plasma cfDNA level of a given healthy individual is influenced both by genetic and the environmental components in similar proportions (53% and 47%, respectively; A = 53%, C = 22.5%, E = 24.5%). Moreover, while age had no effect, gender significantly influenced the individual's plasma cfDNA level. As expected, cfDNA levels were significantly higher in both breast (n = 26) (p<0.0001) and ovarian (n = 64) (p<0.0001) cancer patients compared to the healthy individuals. Our study demonstrated that both genome and environmental factors modulate the individual's cfDNA level suggesting that its diagnostic sensitivity may be improved only if the person's cfDNA level is known prior to disease presentation.

SUBMITTER: Alghofaili L

PROVIDER: S-EPMC6786590 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cell-free DNA levels of twins and sibling pairs indicate individuality and possible use as a personalized biomarker.

Alghofaili Lamyaa L Almubarak Hannah H Gassem Khawlah K Islam Syed S SS Coskun Serdar S Kaya Namik N Karakas Bedri B

PloS one 20191010 10

Cell-free DNA (cfDNA) in the human blood circulation has been under investigation since its initial observation in 1948. Plasma cfDNA is known to be significantly elevated in diseased people. Due to possible variation in the population, evaluating cfDNA as a non-invasive biomarker at disease onset alone may not be sensitive enough to accurately diagnose diseases, particularly early stage cancers on a personal level. To understand the factors that define the cfDNA levels on the personal level and ...[more]

PMID: 31600277

Similar Datasets

Project description:ObjectiveConverging lines of evidence point to the existence of immune dysfunction in autism spectrum disorder (ASD), which could directly affect several key neurodevelopmental processes. Previous studies have shown higher cytokine levels in patients with autism compared with matched controls or subjects with other developmental disorders. In the current study, we used plasma-cytokine profiling for 25 discordant sibling pairs to evaluate whether these alterations occur within families with ASD.MethodsPlasma-cytokine profiling was conducted using an array-based multiplex sandwich ELISA for simultaneous quantitative measurement of 40 unique targets. We also analyzed the correlations between cytokine levels and clinically relevant quantitative traits (Vineland Adaptive Behavior Scale in Autism (VABS) composite score, Social Responsiveness Scale (SRS) total T score, head circumference, and full intelligence quotient (IQ)). In addition, because of the high phenotypic heterogeneity of ASD, we defined four subgroups of subjects (those who were non-verbal, those with gastrointestinal issues, those with regressive autism, and those with a history of allergies), which encompass common and/or recurrent endophenotypes in ASD, and tested the cytokine levels in each group.ResultsNone of the measured parameters showed significant differences between children with ASD and their related typically developing siblings. However, specific target levels did correlate with quantitative clinical traits, and these were significantly different when the ASD subgroups were analyzed. It is notable that these differences seem to be attributable to a predisposing immunogenetic background, as no other significant differences were noticed between discordant sibling pairs. Interleukin-1β appears to be the cytokine most involved in quantitative traits and clinical subgroups of ASD.ConclusionsIn the present study, we found a lack of significant differences in plasma-cytokine levels between children with ASD and in their related non-autistic siblings. Thus, our results support the evidence that the immune profiles of children with autism do not differ from their typically developing siblings. However, the significant association of cytokine levels with the quantitative traits and the clinical subgroups analyzed suggests that altered immune responses may affect core feature of ASD.

Project description:Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to their children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at individual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset conditions, can be estimated at individual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating "virtual" mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We apply our approach to 19066 sibling pairs from the UK Biobank and show that a polygenic score consisting of imputed parental educational attainment SNP dosages is strongly related to offspring educational attainment even after correcting for offspring genotype at the same loci. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH (IMputing Parental genotypes In Siblings and Half Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.

Dataset Information

Cell-free DNA levels of twins and sibling pairs indicate individuality and possible use as a personalized biomarker.

Publications

Cell-free DNA levels of twins and sibling pairs indicate individuality and possible use as a personalized biomarker.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets