Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population.

The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors multiple genes that have been suggested to play a role in lipid metabolism and previous studies indicated the presence of a quantitative trait locus (QTL) for cholesterol levels in genetic isolates.

Two-locus linkage analysis applied to putative quantitative trait loci for lipoprotein(a) levels.

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.

A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer.

Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. A common Ala(222)/Val variant in the methylenetetrahydrofolate reductase (MTHFR) gene leads to a disturbed folate metabolism and is associated with decreased genomic DNA methylation. We previously reported that the MTHFR Val/Val genotype was associated with increased cancer mortality in men from a population-based cohort of subjects ages > or = 85 years.

No increase in mortality and morbidity among carriers of the C282Y mutation of the hereditary haemochromatosis gene in the oldest old: the Leiden 85-plus study.

Background: The C282Y mutation in the gene for haemochromatosis (HFE) has been associated with various diseases at middle age. However, recent studies indicate that penetrance of the C282Y mutation is low. We explored the association between the C282Y mutation, iron metabolism, and morbidity and mortality in participants of the Leiden 85-plus.

Organisation of the human genome and our tools for identifying disease genes.

Determination of the sequence of the human genome has been a major undertaking. It provided powerful tools to explore the genetic component in complex diseases. To fully understand the genetic pathways contributing to complex disease traits, we must not only reveal the genomic locus of all genes involved, but also delineate the functionally relevant allelic variation in such genes and understand the patterns of gene expression leading up to the actual disease trait.

Association of the tumour necrosis factor alpha -308G/A polymorphism with the risk of diabetes in an elderly population-based cohort.

Ample evidence supports a role for tumour necrosis factor alpha (TNFalpha) in the development of type 2 diabetes and cardiovascular disease. TNFalpha expression was found to be influenced by a -308G/A polymorphism in the promoter of the gene encoding TNFalpha (TNF). We investigated the contribution of this polymorphism to diabetes and cardiovascular mortality in a population-based cohort of 664 subjects aged 85 years and over (Leiden 85-plus Study).

Heritabilities of apolipoprotein and lipid levels in three countries.

This study investigated the influence of genes and environment on the variation of apolipoprotein and lipid levels, which are important intermediate phenotypes in the pathways toward cardiovascular disease. Heritability estimates are presented, including those for apolipoprotein E and AII levels which have rarely been reported before. We studied twin samples from the Netherlands (two cohorts; n = 160 pairs, aged 13-22 and n = 204 pairs, aged 34-62), Australia (n = 1362 pairs, aged 28-92) and Sweden (n = 302 pairs, aged 42-88).

Association of APOE epsilon2/epsilon3/epsilon4 and promoter gene variants with dementia but not cardiovascular mortality in old age.

The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study).

Netherlands twin family study of anxious depression (NETSAD).

In a longitudinal study of Dutch adolescent and young adult twins, their parents and their siblings, questionnaire data were collected on depression, anxiety and correlated personality traits, such as neuroticism. Data were collected by mailed surveys in 1991, 1993, 1995 and 1997. A total of 13,717 individuals from 3344 families were included in the study.

A powerful and rapid approach to human genome scanning using small quantities of genomic DNA.

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 intermarker distance that still allows for sufficient power.

Detection of sequence variability of the collagen type IIalpha 1 3' variable number of tandem repeat.

The variable number of tandem repeat (VNTR) 3' of the collagen type II (COL2A1) gene has been shown to be highly variable with a complex molecular structure. In a previous pilot experiment we observed discordance between methods to genotype this informative marker. To further investigate the extent and molecular nature of this discordance, we genotyped a random sample of 207 Caucasian individuals with two genotyping methods and sequenced new alleles.

Common gene variants, mortality and extreme longevity in humans.

Genetic factors influence variation in human life span. The fast technological advancements in genome research and the methodology for statistical analysis of complex traits provided new tools to unravel these genetic influences. Most of the genetic epidemiology and quantitative genetics is focused on the dissection of the genetic component of specific diseases rather than of human life span.

Zygosity diagnosis in young twins by parental report.

This study reports on zygosity determination in twins of childhood age. Parents responded to questionnaire items dealing with twin similarity in physical characteristics and frequency of mistaking one twin for another by parents, relatives and strangers. The accuracy of zygosity diagnosis was evaluated across twins aged 6, 8, and 10 and across parents.

Genetics of human aging. The search for genes contributing to human longevity and diseases of the old.

An aging population of humans reflects early-onset morbidity and mortality as well as late-onset disease in the phase when the mortality rate doubles and, finally, longevity of extremely long-lived subjects. Genetic influences have been reported to be relevant for each of these three phases. A growing field in genetic research is aimed at the identification of genes involved in multifactorial diseases of the old and in longevity.

Haplotype analysis of three polymorphisms of the COL2A1 gene and associations with generalised radiological osteoarthritis.

It was investigated whether radiographic osteoarthritis (ROA) is associated with specific haplotypes of the COL2A1 gene. Radiographs of knees, hips, hands, and spine were scored for the presence of ROA in subjects of 55-70 years from a population-based cohort study, the Rotterdam study. Cases had ROA in 3 or more joint groups; controls, from the same population, had ROA in less than 3 joint groups.

Common paraoxonase gene variants, mortality risk and fatal cardiovascular events in elderly subjects.

Recent studies indicate that the enzyme paraoxonase may be an important modulator of cardiovascular disease risk because of its ability to protect LDL from oxidation. We tested for association between two functional variants of the paraoxonase gene (Met-55/Leu and Gln-192/Arg) and both all-cause mortality and fatal cardiovascular disease. This was done within a population-based study among subjects aged 85 years and over in a cross-sectional and a prospective design.

Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort.

Objectives: We studied the contribution of putative risk genotypes at the angiotensin I-converting enzyme inhibitor (ACE D/D) and plasminogen activator inhibitor-1 (PAI-1 4G/4G) loci to all-cause and cardiovascular mortality in a population-based cohort.

Background: The ACE D/D and PAI-1 4G/4G genotypes have been consistently associated with elevated plasma activities of the gene products. Their role in cardiovascular disease, although explored intensively, is still equivocal.

Thermolabile methylenetetrahydrofolate reductase gene and the risk of cognitive impairment in those over 85.

Objectives: Previous reports have shown raised plasma concentrations of homocysteine in older persons with cognitive impairment. This may be caused by environmental and genetic factors. The relation between cognitive function and a common ala/val mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was studied in those over 85.

Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock.

Background: Some patients infected with Neisseria meningitidis develop septic shock accompanied by fibrin deposition and microthrombus formation in various organs, whereas others develop bacteraemia or meningitis without septic shock. We investigated whether genetic differences in the fibrinolytic system influence the development of meningococcal septic shock.

Methods: We investigated 50 patients who survived meningococcal infection, and 131 controls from the same geographical region.

Heritabilities of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine.

Objective: To estimate the genetic influence on the occurrence of radiologic osteoarthritis (ROA) in the knees, hips, and hands and disc degeneration of the spine in the general population.

Methods: A random sample of 1,583 individuals was drawn to estimate the prevalence of ROA and disc degeneration in the general population. Of 118 probands with multiple affected joint sites who were derived from this sample, we were able to recruit 257 siblings.

Response to activated protein C in subjects with and without dementia. The Dutch Vascular Factors in Dementia Study.

We performed a cross-sectional case-control study among 295 subjects with dementia and 406 control subjects drawn from participants of the Rotterdam Study, a population-based cohort study among subjects aged 55 years or over, and from participants of the Rotterdam Stroke Databank, a hospital-based stroke registry, to evaluate the association of the factor V Leiden mutation and activated protein C (APC) response with dementia and its subtypes. The risk of dementia was 2.11-fold increased among carriers of factor V Leiden mutation relative to subjects lacking factor V Leiden mutation (95% confidence interval, CI, 0.

The risk of mortality and the factor V Leiden mutation in a population-based cohort.

The factor V Leiden mutation (conferring resistance to activated protein C) has been implicated in the risk of arterial thrombosis and is a well-established risk factor for venous thrombosis especially in the elderly. We studied whether the disease association of the factor V mutation is reflected in an increased all-cause and cause-specific mortality. First, the prevalence of the factor V Leiden mutation was determined in a population-based study among subjects aged 85 years and over (4.

A genetic association study of the IGF-1 gene and radiological osteoarthritis in a population-based cohort study (the Rotterdam Study).

Objective: A genetic association study was performed to investigate whether radiographical osteoarthritis (ROA) was associated with specific genotypes of the insulin-like growth factor I (IGF-1) gene.

Methods: Subjects aged 55-65 years were selected from a population-based study of which ROA at the knee, hip, spine, and hand was assessed. Genotypes were determined of a polymorphism in the promoter region of the IGF-1 gene.

Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia.

The role of various gene loci was investigated in a family in which familial osteoarthritis (FOA), with onset at an early age, is transmitted as an autosomal dominant mendelian trait. The absence of clinical and radiographic signs of dysplasia and calcium pyrophosphate deposition disease (CPDD) indicates that the basic disease process in this family is osteoarthritis (OA). Genetic linkage analysis of 14 candidate genes resulted in the exclusion of 10 important genes (COL2A1, COL9A1, COL9A2, COL11A1, COL11A2, COMP, the CPDD region, CRTL-1, CRTM, and MMP3).

Investigation of the association of the CRTM and CRTL1 genes with radiographically evident osteoarthritis in subjects from the Rotterdam study.

Objective: To investigate whether radiographically evident osteoarthritis (ROA) in 55-65-year-old men and women is associated with specific alleles or genotypes of the cartilage matrix protein (CRTM) and cartilage link protein (CRTL1) genes.

Methods: Cases were selected from a population-based study on the presence of ROA of the knee or hip. Further radiographic analysis included scoring for spine and hand ROA.