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Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper- and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG) patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and type III HLP. The frequency of the rare allele of APOC3 3238 G>C and APOA5 -1131 T>C (in linkage disequilibrium) was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs 5.8%, respectively, (P<0.05). Furthermore, the frequencies of the APOA5 c.56 G>C polymorphism and LPL c.27 G>A mutation were higher in type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 -1131 T>C, c.56 G>C and/or LPL c.27 G>A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7, 95% confidence interval=1.8-7.5, P<0.0001). The HTG patients showed similar allele frequencies of the APOA5, APOC3 and LPL polymorphisms, whereas the NDCP showed similar allele frequencies as the normolipidemic APOE2/2. Patients with the APOC3 3238 G>C/APOA5 -1131 T>C polymorphism showed a more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type III HLP in APOE2/2.

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., Study Design: A cross-sectional comparison and prospective follow-up was conducted in two unselected cohorts of 661 and 552 subjects. All subjects were aged 85 years and over. We determined the prevalence of C282Y homozygous and heterozygous subjects, and the association between the C282Y mutation and iron metabolism, all-cause and specific causes of death., Results: Prevalence of C282Y homozygosity in both cohorts was 0.2% (1/661 and 1/552, respectively) and of C282Y heterozygosity was 12.4% (82/661) and 11.4% (63/552), respectively. These estimates coincide exactly with reported estimates in younger age groups. Median ferritin level was 97 microg L-1 (IQR 39-162) for heterozygous carriers and 89 microg L-1 (IQR 41-157) for noncarriers (P = 0.66). The serum ferritin concentration for one C282Y homozygous subject, a woman aged 86 years at the time of enrollment in 1986, was 392 microg L-1. Cardiovascular morbidity was comparable between the C282Y heterozygous subjects and the noncarriers in both study cohorts. All-cause and cardiovascular mortality of carriers of the C282Y mutation was similar to that in noncarriers., Conclusions: We found two C282Y homozygous subjects, illustrating that homozygosity can be compatible with survival in very old ages. C282Y heterozygosity was not associated with history of cardiovascular disease morbidity, all cause mortality, cardiovascular mortality, or biochemical phenotype of haemochromatosis at old age.

Lack of expression of HLA class I antigens is frequently observed on primary uveal melanoma, and is correlated with improved patient survival. Several mechanisms may contribute to the observed loss of HLA class I expression, including changes at the DNA level. In this study, we used microsatellite analysis as a molecular genetic approach to examine loci on chromosome 6p for loss of heterozygosity (LOH). Three pairs of microsatellite markers were used to screen 20 formalin-fixed, paraffin-embedded uveal melanomas for LOH on the short arm of chromosome 6. In all cases, normal adjacent scleral tissue was used as a control. We identified LOH in eleven cases from microsatellite locus D6S105 to the telomere, in eight cases from microsatellite locus D6STNFa to the telomere (area includes D6S105), and in seven cases from microsatellite locus D6S291 to the end of chromosome 6p (includes D6STNFa and D6S105). In seven cases, retention of heterozygosity was found at all three loci using these primers. Our results suggest that loss of heterozygosity on chromosome 6p is a common feature in uveal melanoma. We did not find a correlation between the presence of LOH and locus-specific HLA-A and -B expression.

The use of unrelated donors for bone marrow transplantation is associated with an increased morbidity and mortality when compared with HLA identical siblings. We have demonstrated previously that matching of unrelated donors and recipients for TNFa microsatellites is correlated with lower CTLp frequencies. Matching of unrelated donors and recipients for other non-HLA sequences in the major histocompatibility complex has been reported to result in less graft-versus-host disease and improved survival. It has been argued that matching for non-HLA sequences in the MHC in addition to the HLA genes themselves results in matching for the entire MHC and is therefore the equivalent of providing an HLA identical sibling donor. In order to test this hypothesis we have examined TNFa microsatellites of unrelated donor recipient pairs in whom matching for HLA loci, non-HLA sequences near HLA B (beta-block markers) and non-HLA sequences near DRB1 (delta-block markers) had been determined. All 17 patients who were matched for HLA and non-HLA markers were also matched for TNF microsatellites. This data supports the idea that matching for HLA genes and non-HLA markers results in matching at all other loci in the MHC.

Polymorphism at the level of two microsatellite loci (D6S273 and TNFa) was studied in Croatian population. The most frequent alleles at D6S273 locus are D6S273 134 bp and 136 bp, while at TNFa locus two most frequent alleles are TNFa 117 bp and 99 bp. This study confirms the irregularity in distribution of microsatellite alleles in different populations with the predominance of two or three alleles on these two investigated microsatellite loci.

It has proved difficult to identify high-risk patients for atherosclerosis and to determine how they might respond to medication. Recently, a common promoter variant of the human stromelysin-1 gene has been reported, which has been shown to affect the transcription. We investigated whether this polymorphism had any impact on the risk of events, especially restenosis and progression of coronary artery disease and whether the effect was modulated by treatment with pravastatin. The stromelysin-1 genotype was determined for 496 men with coronary artery disease and cholesterol levels between 4.0 and 8.0 mmol/L, participating in the Regression Growth Evaluation Statin Study (REGRESS) study, a clinical trial assessing the effect of the lipid-lowering drug pravastatin on the progression of atherosclerosis. Patients in the placebo group with 5A6A or 6A6A genotypes had more clinical events than patients with the 5A5A genotype (26% and 12%, respectively, p = 0.03). In the pravastatin group, the risk of clinical events in patients with 5A6A or 6A6A genotypes was lower, compared with placebo, whereas it was unchanged in those with a 5A5A genotype (p value for interaction: 0.038). Also, the incidence of repeat angioplasty in the placebo group was greater in patients with the 6A6A or 5A6A genotypes, compared with 5A homozygotes (38% and 40%, respectively, vs 11%, p = 0.09). Again, treatment substantially reduced the incidence in heterozygotes and 6A homozygotes (0% and 15%, respectively), whereas it was unchanged in 5A homozygotes (28%, p for interaction: 0.002). These effects were independent of the effects of pravastatin on the lipid levels. Thus, this study suggests that the stomelysin-1 promoter polymorphism confers a genotype-specific response to medication in determining clinical event-free survival and the risk for symptom-driven repeat angioplasty. This variant may therefore act as a predictor, not only of disease progression, but also of response to therapy and risk of restenosis.

We analyzed the HLA-A, -B, -DR and -DQ phenotypes and 12 microsatellite locus genotypes within and close to the major histocompatibility complex in a panel of 98 randomly selected, healthy, unrelated Dutch Caucasoid individuals. Allele frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Also, the linkage disequilibrium patterns between HLA and microsatellite loci were studied. The HLA-A, -B, -DR, -DQ and six microsatellite loci centromeric of the HLA-A showed HWE. In contrast, all microsatellites telomeric of the HLA-A showed deviation from HWE due to excess of homozygosity. Linkage disequilibrium analyses provided strong evidence that among the tested microsatellite loci only the alleles of the D6STNFa locus are in linkage disequilibrium with both HLA-B and -DR. Our results suggest that selection acting on the HLA genes includes the D6STNFa locus and linked genes.