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In this study we examined the genetic architecture of variation in the pro-inflammatory state, using an extended twin-family design. Within the Netherlands Twin Register Biobank, fasting Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), C-Reactive Protein (CRP), and fibrinogen levels were available for 3,534 twins, 1,568 of their non-twin siblings, and 2,227 parents from 3,095 families. Heritability analyses took into account the effects of current and recent illness, anti-inflammatory medication, female sex hormone status, age, sex, body mass index, smoking status, month of data collection, and batch processing. Moderate broad-sense heritability was found for all inflammatory parameters (39%, 21%, 45%, and 46% for TNF-α, IL-6, CRP and fibrinogen, respectively). For all parameters, the remaining variance was explained by unique environmental influences and not by environment shared by family members. There was no resemblance between spouses for any of the inflammatory parameters, except for fibrinogen. Also, there was no evidence for twin-specific effects. A considerable part of genetic variation was explained by non-additive genetic effects for TNF-α, CRP, and fibrinogen. For IL-6, all genetic variance was additive. This study may have implications for future genome-wide association studies by setting a clear numerical target for genome-wide screens that aim to find genetic variants regulating the levels of these pro-inflammatory markers.
Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.
Plasma levels of lipoprotein(a) — Lp(a) — are associated with cardiovascular risk (Danesh et al., 2000) and were long believed to be influenced by the LPA locus on chromosome 6q27 only. However, a recent report of Broeckel et al. (2002) suggested the presence of a second quantitative trait locus on chromosome 1 influencing Lp(a) levels. Using a two-locus model, we found no evidence for an additional Lp(a) locus on chromosome 1 in a linkage study among 483 dizygotic twin pairs.
To locate the genes that make a substantial contribution to variation in natural dizygotic twinning in humans, large-scale studies are needed. New studies should not stop at DNA genotyping, but collect material that allow gene-expression analysis, transcriptomics, proteomics and endocrinology. In this article we describe a pilot study to examine the feasibility, effectiveness and logistics of large-scale nationwide sample collection in Dutch families in which two or more sisters have given birth to spontaneous dizygotic twins. Pedigree data and addresses from family members of proband mothers were collected by telephone. Blood and urine samples were collected during a home visit, and handled in the afternoon. All participants were bled between 7 a.m. and 10 a.m. after overnight fasting. Blood samples of fertile women with a natural cycle were collected on the second, third or fourth day of their menstrual cycle. The effects of transportation and storage on blood quality, lipids, RNA with and without challenge, lymphocytes and other parameters were examined. Genomic DNA was isolated from blood and cells were immortalized using Epstein–Barr virus. In 78.6% of the women with a natural cycle blood samples were collected on the second, third or fourth day of the menstrual cycle. This percentage is likely to increase with the more dense geographical distribution of participants in the larger population. We conclude that the pilot study demonstrated the feasibility of this protocol to collect good quality of plasma, DNA, RNA and lymphocyte samples by home visits.
Dense maps of short-tandem-repeat polymorphisms (STRPs) have allowed genome-wide searches
for genes involved in a great variety of diseases with genetic influences, including common complex
diseases. Generally for this purpose, marker sets with a 10 cM spacing are genotyped in hundreds
of individuals. We have performed power simulations to estimate the maximum possible inter-marker distance that still allows for sufficient power. In this paper we further report on
modifications of previously published protocols, resulting in a powerful screening set containing
229 STRPs with an average spacing of 18·3 cM. A complete genome scan using our protocol
requires only 80 multiplex PCR reactions which are all carried out using one set of conditions and
which do not contain overlapping marker allele sizes. The multiplex PCR reactions are grouped by
sets of chromosomes, which enables on-line statistical analysis of a set of chromosomes, as sets of
chromosomes are being genotyped. A genome scan following this modified protocol can be
performed using a maximum amount of 2·5 μg of genomic DNA per individual, isolated from
either blood or from mouth swabs.
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