Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease.

Several studies have reported an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (LOAD). Here we report on the relationship between APOE*4 and early-onset Alzheimer's disease (EOAD) in a Dutch population-based study. The frequency of the APOE*4 allele was 2.3 times higher among EOAD cases compared to controls. Among patients, the allele frequency was 1.6 times higher in those with a positive family history than in those without. A significant increase in risk of EOAD was found for subjects homozygous for APOE*4 regardless of family history of dementia, but an increase in EOAD risk for APOE*4 heterozygotes could only be shown in subjects with a positive family history. Our study demonstrates a significant association between APOE*4 and EOAD which is modified by family history of dementia.

A genome wide association analysis in the GENDER study.

Percutaneous coronary intervention (PCI) has become an effective therapy to treat coronary artery diseases. However, one of the major drawbacks of PCI is the occurrence of restenosis in 8 to 40% of all treated patients. The GENetic Determinants of Restenosis (GENDER) project was designed to study the association between genetic polymorphisims and clinical restenosis. The discovery of genetic variants associated to the occurrence of restenosis after PCI may provide a more tailored therapy and may serve as rationale for new antirestenotic therapies. So far, several candidate gene approaches had already been performed in the GENDER samples but a Genome Wide Association Scan (GWAS) was still lacking. Here, we present preliminary results from the GWAS we are currently carrying out in the GENDER population. (Neth Heart J 2009;17:262-4.).

Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree.

By the careful screening of familial dysbetalipoproteinemic (FD) patients, five probands showing heterozygosity for the APOE*3-Leiden allele were found. Genealogical studies revealed that these probands share common ancestry in the 17th century. In a group of 128 family members, spanning three generations, 37 additional heterozygous APOE*3-Leiden gene carriers were detected. Although with a variable degree of severity, all carriers exhibited characteristics of FD such as (a) elevated levels of cholesterol in the very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fractions, (b) elevated ratios of cholesterol levels in these density fractions over total plasma levels of triglycerides, and (c) strongly increased plasma levels of apolipoprotein E (apoE). Multiple linear regression analysis revealed that most of the variability in expression of FD in APOE*3-Leiden allele carriers can be explained by age. Body mass index showed a less significant influence on the expression of FD. Gender had no effect on the expression in E*3-Leiden allele carriers, nor did it influence the age of onset of FD. In the group of APOE*3-Leiden allele carriers, we found that the E*2 allele enhances the expression of FD, whereas the E*4 allele had the opposite effect. Isoelectric focusing of plasma and of isolated VLDL, IDL, and high density lipoprotein density fractions showed that in E*3-Leiden allele carriers the apoE3-Leiden variant largely predominates over its normal apoE counterpart, especially in the VLDL and IDL density fractions. We conclude that in APOE*3-Leiden allele carriers FD is dominantly inherited with a high rate of penetrance, i.e., the presence of normally functioning apoE molecules in the plasma does not prevent the age-related expression of this disease.

Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*2 (Lys146-->Gln) Allele carriers.

Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with familial dysbetalipoproteinemia (FD) carrying the APOE*2 (Lys146-->Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2 (Lys146-->Gln) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89 +/- 0.37 vs 0.30 +/- 0.27 and 1.86 +/- 0.37 vs 0.68 +/- 0.27 mmol/liter, respectively) and plasma apolipoprotein (apo) E levels (28.1 +/- 1.6 vs 4.6 +/- 1.1 mg/dl), which is characteristic for FD. By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2 (Lys146-->Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lys146-->Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects.

Male-specific risk of first and recurrent venous thrombosis: a phylogenetic analysis of the Y chromosome.

Essentials Men have an unexplained higher risk of a first and recurrent venous thrombosis (VT) than women. We studied the role of the major European Y chromosome haplogroups in first and recurrent VT. In contrast to a study on coronary artery disease, haplogroup I was not linked to VT risk. Haplogroup E-carriers may have an increased risk of recurrent VT, but a larger study is needed. SUMMARY: Background The risk of venous thrombosis (VT) recurrence is higher in men than in women. When reproductive risk factors are excluded, this sex difference is also apparent for a first VT. The current explanations for this difference are insufficient. Objectives To study the association between chromosome Y haplogroups and the risks of a first and recurrent VT. Methods Y chromosomes of 3742 men (1729 patients; 2013 controls) from the MEGA case-control study were tracked into haplogroups according to the phylogenetic tree. We calculated the risk of a first VT by comparing the major haplogroups with the most frequent haplogroup. For recurrence risk, 1645 patients were followed for a mean of 5 years, during which 350 developed a recurrence (21%; MEGA follow-up study). We calculated recurrence rates for the major haplogroups, and compared groups by calculating hazard ratios. Results We observed 13 haplogroups, of which R1b was the most frequent (59%). The major haplogroups were not associated with a first VT, with odds ratios ranging from 1.01 to 1.15. Haplogroup E carriers had the highest recurrence rate (53.5 per 1000 person-years, 95% confidence interval [CI] 33.3-86.1), whereas haplogroup R1a carriers had the lowest recurrence rate (24.3 per 1000 person-years, 95% CI 12.6-46.6). As compared with haplogroup R1b carriers, both haplogroups were not significantly associated with recurrence risk. Conclusions In contrast to a study on coronary artery disease, our results do not show a clear predisposing effect of Y haplogroups on first and recurrent VT risk in men. It is therefore unlikely that Y variation can explain the sex difference in VT risk.

Phylogeographic Patterns in Africa and High Resolution Delineation of Genetic Clades in the Lion (Panthera leo).

Comparative phylogeography of African savannah mammals shows a congruent pattern in which populations in West/Central Africa are distinct from populations in East/Southern Africa. However, for the lion, all African populations are currently classified as a single subspecies (Panthera leo leo), while the only remaining population in Asia is considered to be distinct (Panthera leo persica). This distinction is disputed both by morphological and genetic data. In this study we introduce the lion as a model for African phylogeography. Analyses of mtDNA sequences reveal six supported clades and a strongly supported ancestral dichotomy with northern populations (West Africa, Central Africa, North Africa/Asia) on one branch, and southern populations (North East Africa, East/Southern Africa and South West Africa) on the other. We review taxonomies and phylogenies of other large savannah mammals, illustrating that similar clades are found in other species. The described phylogeographic pattern is considered in relation to large scale environmental changes in Africa over the past 300,000 years, attributable to climate. Refugial areas, predicted by climate envelope models, further confirm the observed pattern. We support the revision of current lion taxonomy, as recognition of a northern and a southern subspecies is more parsimonious with the evolutionary history of the lion.

Polymorphism at the tetranucleotide repeat locus DYS389 in 10 populations reveals strong geographic clustering.

Several short tandem repeat polymorphism loci at the non-recombining part of the Y chromosome have been described recently and are now widely used for the investigation of the history and the diversity of man. The tetranucleotide repeat polymorphism at the DYS389 locus consists of two repetitive stretches with different numbers of (TCTG)n (TCTA)m repeat units. To study the overall variability of this locus, 768 alleles from males from 10 human populations (two sub-Saharan African, four Caucasoid and four Asian/Amerind populations) were investigated. The alleles found in the populations of different geographic origin exhibited remarkable differences in the number and arrangement of repeats in the two repetitive stretches and up to nine different sequence variants for a single fragment length have been detected. So far 53 different alleles, i.e. haplotypes, have been observed. Analysis of molecular variance (AMOVA) indicates that at least 24.5% of the total genetic variance was found between the populations and that these differences were significant in most pairwise comparisons. We propose a model, in which both founder effects and genetic drift together with single step replication slippage mutations explain the picture of haplotype diversity observed with this single locus.

Y chromosomal polymorphisms reveal founding lineages in the Finns and the Saami.

Y chromosomal polymorphisms were studied in 502 males from 16 Eurasian ethnic groups including the Finns, Saami (Inari Lake area and Skolt Saami), Karelians, Mari, Mokshas, Erzas, Hungarians (Budapest area and Csángós), Khanty, Mansi, Yakuts, Koryaks, Nivkhs, Mongolians, and Latvians. The samples were analysed for polymorphisms in the Y chromosome specific Alu insertion (YAP) and six microsatellites (DYS19, DYS389-I and II, DYS390, DYS392, DYS393). The populations were also screened for the recently described Tat polymorphism. The incidence of YAP+ type was highest in the Csángós and in other Hungarians (37.5% and 17.5%, respectively). In the Karelians and the Latvians it was present at approximately the same level as commonly found in other European populations, whilst absent in our further samples of Eurasian populations, including the Finns and the Saami. Aside from the Hungarians, the C allele of the Tat polymorphism was common in all the Finno-Ugric speaking populations (from 8.2% to 63.2%), with highest incidence in the Ob-Ugrian Khanty. The C allele was also found in the Latvians (29.4%). The haplotypes found associated with the Tat C allele showed consistently lower density than those associated with the T allele, indicating that the T allele is the original form. The computation of the age of the Tat C suggested that the mutation might be a relatively recent event giving a maximum likelihood estimate of 4440 years (95% confidence interval about 3140-6200 years). The distribution patterns of the 222 haplotypes found varied considerably among the populations. In the Finns a majority of the haplotypes could be assigned to two distinct groups, one of which harboured the C allele of the Tat polymorphism, indicating dichotomous primary source of genetic variation among Finnish males. The presence of a bottleneck or founding effect in the male lineages of some of the populations, namely in the Finns and the Saami, would appear to be one likely interpretation for these findings.

Patterns of inter- and intra-group genetic diversity in the Vlax Roma as revealed by Y chromosome and mitochondrial DNA lineages.

Previous genetic studies, supported by linguistic and historical data, suggest that the European Roma, comprising a large number of socially divergent endogamous groups, may be a complex conglomerate of founder populations. The boundaries and characteristics of such founder populations and their relationship to the currently existing social stratification of the Roma have not been investigated. This study is an attempt to address the issues of common vs independent origins and the history of population fissioning in three Romani groups that are well defined and strictly endogamous relative to each other. According to linguistic classifications, these groups belong to the Vlax Roma, who account for a large proportion of the European Romani population. The analysis of mtDNA sequence variation has shown that a large proportion of maternal lineages are common to the three groups. The study of a set of Y chromosome markers of different mutability has revealed that over 70% of males belong to a single lineage that appears unique to the Roma and presents with closely related microsatellite haplotypes and MSY1 codes. The study unambiguously points to the common origins of the three Vlax groups and the recent nature of the population fissions, and provides preliminary evidence of limited genetic diversity in this young founder population.

Apolipoprotein E gene and sporadic frontal lobe dementia.

The apolipoprotein E gene has been associated with various types of dementia. We studied the connection between the APOE gene and the risk and onset of disease in 34 patients with clinically diagnosed frontal lobe dementia (FLD) derived from a population-based study in the Netherlands. A significant increased risk of FLD (odds ratio, 4.9; 95% CI, 1.1-20.1) was found for the apoE4E4 genotype when adjusting for age, sex, and family history of dementia other than FLD. The age at onset of the disease decreased as the number of APOE*4 alleles increased. Our population-based study suggests that persons who are homozygous for the APOE*4 allele are at increased risk for developing FLD.

Familial aggregation in frontotemporal dementia.

OBJECTIVE AND BACKGROUND: Frontotemporal dementia (FTD) is a common, non-Alzheimer's dementia. Its familial occurrence has been reported, but the frequency of positive family history is unknown. METHODS: We carried out a nationwide genetic-epidemiologic study of FTD in the Dutch population of 15 million people. The family history of dementia was analyzed in 74 FTD patients and 561 age- and gender-matched control subjects. RESULTS: We found one or more first-degree relatives with dementia before age 80 in 38% (28 of 74) of FTD patients, but only in 15% (84 of 561) of control subjects. Ten percent of FTD patients had two or more first-degree relatives with dementia compared with 0.9% of the control subjects. Seven percent of FTD patients showed the ApoE4E4 genotype versus 2.3% of the control subjects. The first-degree relatives of FTD had a risk of 22% for dementia before age 80 compared with 11% in relatives of control subjects. The age of onset of dementia in affected first-degree relatives of FTD patients (60.9+/-10.6 years) was significantly lower than among affected relatives of control subjects (72.3+/-8.5 years). The first-degree relatives of FTD patients were 3.5 times (95% CI, 2.4 to 5.2) more at risk for developing dementia before age 80 than relatives of control subjects. The hazard ratio in the subgroup with unknown linkage to chromosome 17 was 2.4 (95% CI, 1.5 to 3.7). CONCLUSION: This study documents the importance of genetic factors in a proportion of FTD patients with the age at onset of dementia in first-degree relatives being 11 years earlier than in the general population.

Apolipoprotein E polymorphism affects plasma levels of lipoprotein(a).

In a group of 303 healthy Caucasian adults of both sexes we studied the influence of the apolipoprotein E (apo E) polymorphism on plasma levels of Lipoprotein(a) (Lp(a). The APOE*2 allele was found to decrease the mean plasma Lp(a) level by 24.8%, whereas the APOE*4 allele increased the mean Lp(a) level by 25.7%. These effects were parallel to the effect of apo E polymorphism on plasma cholesterol and low density lipoprotein (LDL)-cholesterol. For the Lp(a) levels, the genetic variance associated with the APOE locus contributed about 4% to the total phenotypic variance. For plasma cholesterol and LDL-cholesterol this contribution was 4.5 and 6.3%, respectively. We also found a significant positive correlation between LDL-cholesterol and Lp(a) levels. Since the apo E polymorphism effects LDL-receptor activity, we conclude that, at least in healthy normolipidemic individuals, plasma levels of Lp(a) are modulated by the LDL-receptor activity.

Genetic polymorphism of apolipoprotein A-IV in five different regions of Europe. Relations to plasma lipoproteins and to history of myocardial infarction: the EARS study. European Atherosclerosis Research Study.

As a part of the EARS study we assessed the role of the common apo A-IV polymorphism in determining the hereditary predisposition to cardiovascular disease. The study population consisted of 1261 controls and 629 cases (students whose father had MI before 55 years) from five different European regions. The apo A-IV 1-1 phenotype accounted for 85% of the individuals. One per cent of subjects were homozygous for the apo A-IV2 allele. There was significant regional variation in the apo A-IV allele frequencies from North to South in Europe, with the lowest A-IV2 frequency in Finland. The distribution of the apo A-IV phenotypes was similar in cases and controls, as was the regional variation. The apo A-IV polymorphism did not affect HDL cholesterol. There was no correlation between apo A-IV alleles and the plasma concentration of apo A-IV. The plasma concentration of apo A-IV was lower in females than in males; furthermore, there was a significant difference in apo A-IV concentrations between oral contraceptive users and nonusers: users had the lowest values. As no strongly significant genetic difference could be demonstrated between plasma lipid concentration in cases and controls, and as the apo A-IV polymorphism did not significantly influence plasma lipid concentration, we conclude that the apo A-IV gene is not a major determinant of the risk for MI and/or CHD.

Relationship between apolipoprotein E and low density lipoprotein particle size.

The relationships between the particle size of low density lipoproteins (LDL) and various lipid parameters, including apolipoprotein (apo) E concentration and apo E phenotype, were analyzed in plasma samples obtained from 196 apparently healthy 35-year-old males. The LDL particle size was determined by gradient gel electrophoresis. Using stepwise multiple regression analysis it was found that LDL particle size correlated negatively to the plasma concentrations of triglyceride (r = -0.497, P < 0.001), apo E (r = -0.415, P < 0.001), apo B (r = 0.395, P < 0.001) and cholesterol (r = -0.235, P < 0.001) and correlated positively to the plasma concentrations of apo A-I (r = 0.297, P < 0.001) and apo A-II (r = 0.145, P < 0.05). However, the LDL particle size did not differ significantly among the different apo E phenotypes. Indeed, when entered as a variable in the multiple regression analysis, the apo E phenotype was not correlated to the LDL particle size. It is concluded that the LDL particle size is related to the plasma concentrations of triglyceride, apo E, apo B, apo A-I, apo A-II and cholesterol and is not affected by the apo E phenotype in healthy 35-year-old males.

Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146-->Gln) are inefficiently converted to cholesterol-rich lipoproteins.

The APOE*2(Lys146-->Gln) allele behaves like a dominant trait in the expression of familial dysbetalipoproteinemia (FD) (Smit et al., J. Lipid Res. 1990; 31: 45-53). FD patients carrying the APOE*2(Lys146-->Gln) allele exhibit less elevated cholesterol to triglyceride ratios in the d < 1.019 g/ml lipoprotein density fraction as compared to classical FD patients displaying homozygosity for the APOE*2(Arg158-->Cys) allele (0.8 vs. 1.4). Upon treatment of complete serum with lipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ratio of the d < 1.019 g/ml lipoprotein fraction in these FD patients increased only marginally (from 0.8 to 1.1), as compared with that of classical FD subjects (from 1.4 to 2.6) and non-FD control subjects (from 0.7 to 1.5). In order to obtain further evidence for an inefficient lipolysis of the d < 1.019 g/ml lipoprotein fraction in APOE*2(Lys146-->Gln) carriers, possibly in combination with a less efficient cholesteryl ester transfer protein (CETP) activity, blood samples of APOE*2(Lys146-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys149-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys146-->Gln) FD patients, the increase in plasma cholesterol was mainly confined to the very low density lipoprotein (VLDL) fraction, whereas in classical FD patients, the levels of cholesterol in the intermediate density lipoprotein (IDL) fraction was also dramatically increased (ratios of VLDL to IDL cholesterol are 4.7 and 2.6, respectively). Family analyses of the APOE*2(Lys146-->Gln) FD subjects showed that the apo E to apo B ratio in the d < 1.019 g/ml lipoprotein fraction of allele carriers is 3.5 times as high as that found in non-carriers (2.8 vs. 0.8, by wt.). Also, in the APOE*2(Lys146-->Gln) allele carrying family members, the ratio of cholesterol to triglyceride of the d < 1.019 g/ml lipoprotein fraction is less markedly elevated upon addition of LPL when compared to that in non-carrying controls (from 1.1 to 1.8 vs 0.7 to 1.6). The efficiency of the d < 1.019 g/ml lipoprotein fraction of APOE*2(Lys146-->Gln) FD patients to compete with low density lipoprotein (LDL) for binding to the LDL receptor is intermediate to that of controls and classical APOE*2(Arg158-->Cys) homozygous FD patients. These findings suggest that in APOE*2(Lys146-->Gln) allele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia.

In a group of 120 patients with heterozygous familial hypercholesterolemia (FH) the influence of the apolipoprotein E (apoE) polymorphism on pre-treatment plasma lipid levels and on the response to treatment with simvastatin was studied. The apoE phenotype distribution did not differ significantly between the FH group and a sample group of the Dutch population. Differences in pre-treatment lipid levels were not related to the apoE polymorphism in this FH population. After 12 weeks use of a daily dose of 40 mg simvastatin, the plasma total cholesterol, low density lipoprotein (LDL)-cholesterol and plasma triglyceride levels were reduced on average by 33%, 38% and 19%, respectively. At the same time high density lipoprotein (HDL)-cholesterol concentration increased on average by 7%. In the combined FH patient group (males and females) a considerable interindividual variation in response to simvastatin was observed, but was not related to the apoE polymorphism. However, considering males and females separately, we found that female FH patients with the apoE3E3 phenotype responded better on simvastatin treatment with respect to LDL-cholesterol than male FH patients with the apoE3E3 phenotype.

The lipoprotein lipase (Asn291-->Ser) mutation is associated with elevated lipid levels in families with familial combined hyperlipidaemia.

Familial combined hyperlipidaemia (FCHL) is one of the major genetic causes of coronary heart disease (CHD) and is characterised by elevated levels of plasma cholesterol and/or triglycerides in individuals within a single family. Decreased lipoprotein lipase (LPL) activity has been found in some cases of FCHL. A recent study revealed a common mutation in the LPL gene, LPL(Asn291-->Ser), with a frequency of 9.3% in Dutch FCHL patients (Reymer et al,. Circulation, 90 (1994) I-998). This mutation was found in 3 out of 17 FCHL families. Extensive family studies were subsequently performed to determine the effect of this mutation on the phenotypic expression of FCHL. Using a pedigree-based maximum likelihood estimate, we demonstrated that the LPL(Asn291-->Ser) mutation significantly affects the levels of plasma and very low density lipoprotein (VLDL) triglycerides (2.03 +/- 0.21 vs. 1.14 +/- 0.13 and 1.21 +/- 0.16 vs. 0.62 +/- 0.09 mmol/l, carriers and non-carriers, respectively) and VLDL- and high density lipoprotein (HDL) cholesterol (0.83 +/- 0.10 vs. 0.38 +/- 0.06 and 1.02 +/- 0.08 vs. 1.29 +/- 0.05 mmol l, carriers and non-carriers, respectively), but not those of plasma and low density lipoprotein (LDL) cholesterol. These findings indicate that the LPL(Asn291-->Ser) mutation is associated with elevated lipid levels, indicating it may be one of the genetic factors predisposing to FCHL in the families studied.

DNA-polymorphisms and plasma levels of vascular disease risk factors in Greenland Inuit--is there a relation with the low risk of cardiovascular disease in the Inuit?

Greenland Inuit are a population with a low risk of cardiovascular disease. Recently, we stated that frequencies of potentially high risk alleles of the apolipoproteins, fibrinogen, factor V, glycoprotein IIIa and factor VII (FVII) genes have different allele frequencies in the Inuit when compared with Caucasian populations. We have extended this study and evaluated whether or not this was also true for the genetic polymorphisms of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin-converting enzyme (ACE) and angiotensinogen in a group of 133 Greenland Inuit, aged 30-34 gamma. In addition, we compared the plasma levels of these factors and those of C-reactive protein (CRP) and D-Dimer in Inuit and in Danes, comparable for age and gender. Frequencies (f) were assessed of the alleles that are known as the potential high risk alleles in Caucasians. In the Inuit, the f(insertion allele) of the t-PA intron8ins311 polymorphism was 0.37 (CI 0.32-0.43), the f(4G allele) of the PAI-1 promoter polymorphism was 0.88 (CI 0.83-0.91), the f(deletion allele) of the ACE intron16ins287 polymorphism was 0.40 (CI 0.33-0.47) and the f(M-allele) of the angiotensinogen M/T353 polymorphism was 0.30(CI 0.25-0.38). As for fibrinogen and FVII polymorphisms, these frequencies are all significantly different from what is reported for Caucasian populations. In the Inuit, plasma levels of fibrinogen and D-Dimer were higher than in the Danes, the PAI-1 levels were lower and FVII, t-PA and CRP levels were comparable. The observed allele frequencies of the polymorphisms of t-PA, fibrinogen, FVII, ACE, angiotensinogen and the plasma levels of PAI-1 and D-Dimer were in accordance with the low CVD risk in the Inuit, considering the observed associations between these measures and CVD risk in Caucasian populations, but for other measures this was not the case (allele frequencies of the PAI-1 polymorphism, and plasma levels of fibrinogen, FVII and t-PA). In conclusion there are clear differences in genetic background and plasma levels of risk factors in Greenland Inuit compared with Caucasian populations, and these differences were sometimes, but not always, in accordance with the observed low cardiovascular disease risk of the Inuit population.

Using a roster and haplotyping is useful in risk assessment for persons with intermediate and reduced penetrance alleles in Huntington disease.

The risk of a person having a child with an inherited disorder, caused by an unstable triplet repeat, such as Huntington disease (HD), depends on the expansion of the mutation in that person, which is connected both to the biological nature of the mutation and to the person's relation to the carrier of the full mutation. Once the mutation causing HD was identified, we were able to diagnose sporadic patients. A sporadic patient can sometimes be connected to a known HD pedigree by using a roster. By haplotyping and calculating the posterior identity-by-descent probability, we could establish whether a connection was coincidental or not. Furthermore, we describe the frequency of intermediate and reduced penetrance alleles detected. Using the family history and the roster to search for a connection, we examined whether these alleles were on the HD haplotype of a family. It is important to know the origin of an intermediate or reduced penetrance allele because if it comes from an HD branch of the family or from the non-HD affected side of the pedigree, different risks for relatives and penetrance ensue. In our study, most intermediate alleles came from the non-HD-affected side of the pedigree and had a repeat size in the lower range with a negligible risk for expansion. Intermediate alleles on the HD haplotypes were larger and found in predictive test applicants from known families or relatives from new mutations with a higher risk for expansion. Reduced penetrance alleles in the higher range were mainly found in symptomatic and predictive test applicants from known families, with a considerable risk for penetrance, although at older age. We conclude that a roster, a thorough family history, and haplotyping in persons with intermediate and reduced penetrance alleles are essential in considering the risk of a person having (a child with) HD.

Lathosterol level in plasma is elevated in type III hyperlipoproteinemia, but not in non-type III subjects with apolipoprotein E2/2 phenotype, nor in type IIa or IIb hyperlipoproteinemia.

We measured the serum lathosterol level, a reflection of the rate of whole body cholesterol synthesis, in 15 patients with manifest type III hyperlipoproteinemia (HLP), in 20 subjects with apolipoprotein (apo) E2/2 phenotype, but without type III HLP, in 21 patients with type IIA and 10 patients with type IIB HLP. A group of 100 subjects with apo E3/3 phenotype served as reference. Using ANCOVA, lathosterol was adjusted for serum cholesterol and triglyceride concentrations, since these parameters were found to independently correlate with lathosterol. The adjusted means (+/- SEM), in mumol/L, in these groups were 12.9 +/- 1.1, 8.2 +/- 1.1, 4.8 +/- 0.9, 9.8 +/- 1.4, and 7.8 +/- 0.4, respectively. Type III HLP patients had significantly higher lathosterol levels than all other groups except type IIB HLP. In addition, lathosterol was significantly lower in type IIA patients than in all other groups. The serum levels of plant sterols, used as a reflection of cholesterol absorption, did not differ among the various groups after adjustment for serum cholesterol. These findings suggest that an overproduction of cholesterol is one factor discriminating E2/2 homozygotes with type III HLP from those without the disease.