Apolipoprotein A4-1/2 polymorphism and response of serum lipids to dietary cholesterol in humans

The response of serum lipids to dietary changes is to some extent an innate characteristic. One candidate genetic factor that may affect the response of serum lipids to a change in cholesterol intake is variation in the apolipoprotein A4 gene, known as the APOA4-1/2 or apoA-IVGln360His polymorphism. However, previous studies showed inconsistent results. We therefore fed 10 men and 23 women with the APOA4-1/1 genotype and 4 men and 13 women with the APOA4-1/2 or -2/2 genotype (carriers of the APOA4-2 allele) two diets high in saturated fat, one containing cholesterol at 12.4 mg/MJ, 136.4 mg/day, and one containing cholesterol at 86.2 mg/MJ, 948.2 mg/day. Each diet was supplied for 29 days in crossover design. The mean response of serum low density lipoprotein cholesterol was 0.44 mmol/l (17 mg/dl) in both subjects with the APOA4-1/1 genotype and in subjects with the APOA4-2 allele [95% confidence interval of difference in response, -0.20 to 0.19 mmol/l (-8 to 7 mg/dl)]. The mean response of high density lipoprotein cholesterol was also similar, 0.10 mmol/l (4 mg/dl), in the two APOA-4 genotype groups [95% confidence interval of difference in response, -0.07 to 0.08 mmol/l (-3 to 3 mg/dl)]. Thus, the APOA4-1/2 polymorphism did not affect the response of serum lipids to a change in the intake of cholesterol in this group of healthy Dutch subjects who consumed a background diet high in saturated fat. Knowledge of the APOA4-1/2 polymorphism is probably not a generally applicable tool for the identification of subjects who respond to a change in cholesterol intake.     

Linkage heterogeneity between the C3 and LDLR and the APOA4 and APOA1 loci in baboons.

We detected linkage in baboons between loci for the third component of complement (C3) and the low-density lipoprotein receptor (LDLR), lod score = 5.53, and loci for apolipoprotein A1 (APOA1) and apolipoprotein AIV (APOA4), lod score = 14.59. We also found evidence for linkage heterogeneity among the baboon pedigrees between LDLR and C3 (P = 0.04) and between APOA1 and APOA4 (P = 0.01).     

Genetic variation of apolipoproteins in North Indians

Genetic variation at three apolipoprotein loci (APOA4, APOH, and APOE) has been examined in nine endogamous populations of Punjab, North India. The overall pattern of allele frequency variation at different loci is compatible with that of European populations, but observed microvariation differentiates the populations according to their position in the Indian caste structure. The most common allele at the APOA4 locus was APOA4*1 with a narrow frequency range (89%-92%). APOH*2 allele frequency was highest in these populations (0.852-0.914). APOE*E4 allele frequency was relatively low (6%-10%) in the North Indian populations compared to its frequency in many European populations. The anthropological usage of these polymorphisms was evaluated using multivariate analyses. Genetic distance analysis and principal correspondence analysis showed that the North Indian populations are closest to Europeans, followed by Chinese and African populations. Overall, this study highlights the usefulness of apolipoproteins as genetic markers for clinical, population, and anthropological studies.     

Genetic relationship between equine apolipoproteins A4 and A1

Genetic polymorphism of equine apolipoprotein (APO) A4 was investigated using two-dimensional electrophoresis in four horse breeds, including Japanese native horses. A linkage relationship between the equine APOA4 and APOA1 structural loci was assumed from the segregation data of these loci in one family line of the Japanese Hokkaido native breed.     

Gene markers for alcohol-metabolizing enzymes among recombinant inbred strains of mice with differential behavioural responses towards alcohol

The genetic variability of alcohol dehydrogenase (C2 isozyme), aldehyde dehydrogenase (A2 isozyme) and aldehyde oxidase (A2 isozyme) has been examined among recombinant inbred strains of mice which have been previously studied concerning their differential behavioural responses towards alcohol. The results showed no correlation between biochemical phenotype for these loci and behavioural response.     

Gene markers for alcohol-metabolizing enzymes among recombinant inbred strains of mice with differential behavioural responses towards alcohol

The genetic variability of alcohol dehydrogenase (C₂ isozyme), aldehyde dehydrogenase (A₂ isozyme) and aldehyde oxidase (A₂ isozyme) has been examined among recombinant inbred strains of mice which have been previously studied concerning their differential behavioural responses towards alcohol. The results showed no correlation between biochemical phenotype for these loci and behavioural response.     

Clinical significance of apolipoprotein A5

PURPOSE OF REVIEW: We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease risk. Special emphasis was placed on the evidence emerging from the association between genetic variability at the apolipoprotein A5 locus, lipid phenotypes and disease outcomes. Moreover, we address recent reports evaluating apolipoprotein A5 gene-environment interactions in relation to cardiovascular disease and its common risk factors. RECENT FINDINGS: Several genetic association studies have continued to strengthen the position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors and pharmacological therapies. Moreover, genetic variants at this locus have been significantly associated with both coronary disease and stroke risks. SUMMARY: Apolipoprotein A-V has an important role in lipid metabolism, specifically for triglyceride-rich lipoproteins. However, its mechanism of action is still poorly understood. Clinical significance at present comes largely from genetic studies showing a consistent association with plasma triglyceride concentrations. Moreover, the effects of common genetic variants on triglyceride concentrations and disease risk are further modulated by other factors such as diet, pharmacological interventions and BMI. Therefore, these genetic variants could be potentially used to predict cardiovascular disease risk and individualize therapeutic options to decrease cardiovascular disease risk.     

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student''s t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins     

Evidence for genetic hitchhiking effect associated with insecticide resistance in Aedes aegypti.

Information on genetic variation within and between populations is critical for understanding the evolutionary history of mosquito populations and disease epidemiology. Previous studies with Drosophila suggest that genetic variation of selectively neutral loci in a large fraction of genome may be constrained by fixation of advantageous mutations associated with hitchhiking effect. This study examined restriction fragment length polymorphisms of four natural Aedes aegypti mosquito populations from Trinidad and Tobago, at 16 loci. These populations have been subjected to organophosphate (OP) insecticide treatments for more than two decades, while dichlor-diphenyltrichlor (DDT) was the insecticide of choice prior to this period. We predicted that genes closely linked to the OP target loci would exhibit reduced genetic variation as a result of the hitchhiking effect associated with intensive OP insecticide selection. We also predicted that genetic variability of the genes conferring resistance to DDT and loci near the target site would be similar to other unlinked loci. As predicted, reduced genetic variation was found for loci in the general chromosomal region of a putative OP target site, and these loci generally exhibited larger F(ST) values than other random loci. In contrast, the gene conferring resistance to DDT and its linked loci show polymorphisms and genetic differentiation similar to other random loci. The reduced genetic variability and apparent gene deletion in some regions of chromosome 1 likely reflect the hitchhiking effect associated with OP insecticide selection.     

Biology and applications of human minisatellite loci.

Highly repetitive minisatellites' include the most variable human loci described to date. They have proved invaluable in a wide variety of genetic analyses, and despite some controversies surrounding their practical implementation, have been extensively adopted in civil and forensic casework. Molecular analysis of internal allelic structure has provided detailed insights into the repeat-unit turnover mechanisms operating in germline mutations, which are ultimately responsible for the extreme variability seen at these loci.     

Genetic differentiation of the Tuva population with respect to the Alu insertions]

Polymorphism of three rural populations of the Tuva Republic was examined using a set of five autosomal Alu insertions at the ACE, PLAT, PV92, APOA1, and F13B loci. The allele frequency distribution patterns revealed in Tuvinians were typical to Mongoloid populations of Asia and were characterized by relatively high frequency of the Alu-repeat insertion at the PV92 and F13B loci along with relatively low insertion frequency at the APOA1 locus. With respect to the test systems used, Tuvinian populations examined displayed high levels of genetic diversity. The mean expected heterozygosity values in the populations of Kugurtug, Toora-Khem, and Teeli were 0.433, 0.407, and 0.437, respectively. The level of genetic diversity in the pooled Tuvinian sample was 0.432. The coefficient of genetic differentiation in the three populations studied was 1.45 pointing to relatively low level of genetic subdivision of the indigenous Tuvinian populations. However, estimates of genetic differentiation of the Tuvinian gene pool made by use of the Alu-repeat system were higher compared to those performed using classical protein systems, mtDNA, or Y-chromosomal haplotypes. Even though Tuvinian populations were characterized by common gene pool, some features specific to Western Tuvinian population could be distinguished. These features could be associated with higher contribution of the Caucasian component to the gene pool of this population. Phylogenetic analysis demonstrated close genetic relationships between the Tuvinian and Altaic ethnic populations.     

Conformational flexibility of apolipoprotein A-I amino- and carboxy-termini is necessary for lipid binding but not cholesterol efflux

Because of its critical role in HDL formation, significant efforts have been devoted to studying apolipoprotein A-I (APOA1) structural transitions in response to lipid binding. To assess the requirements for the conformational freedom of its termini during HDL particle formation, we generated three dimeric APOA1 molecules with their termini covalently joined in different combinations. The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1 molecules, respectively, using introduced cysteine residues to form disulfide linkages. We then tested the ability of these constructs to generate reconstituted HDL by detergent-assisted and spontaneous phospholipid microsolubilization methods. Using cholate dialysis, we demonstrate WT and all APOA1 mutants generated reconstituted HDL particles of similar sizes, morphologies, compositions, and abilities to activate lecithin:cholesterol acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously solubilizing short chain phospholipids into discoidal particles. We found lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1’s ability to promote cholesterol efflux via the ATP binding cassette transporter A1, whereas d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute other postulated arrangements like the “double super helix.” Furthermore, we conclude the conformational freedom of both the N- and C-termini of APOA1 is important in spontaneous microsolubilization of bulk phospholipid but is not critical for ABCA1-mediated cholesterol efflux.     

A sustained dietary change increases epigenetic variation in isogenic mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection.     

Electrophoretic variability of blood proteins among populations of two genera of african rodents: Arvicanthis and Mastomys from Senegal. Genetic polymorphism and geographic differences

Electrophoretic patterns of blood proteins and enzymes have been analysed among 152 Arvicanthis, 75 Mastomys huberti and 13 Mastomys erytholeucus captured in 19 localities in Senegal. Individual variability (genetic polymorphism) was observed at four loci, while other loci appeared monomorphic. Differences in electrophoretic migration of some proteins were observed among populations originating from distant geographic areas. The overall trait in Arvicanthis is that individual variability is rather poorly developed while populations diverge first by the extent of polymorphism and the loci concerned and also by different electrophoretic behaviour of some proteins.     

Sex-Linked Auxotrophic and Putative Auxotrophic Mutants of DROSOPHILA MELANOGASTER

Thirty-two mutants with improved growth response on a yeast-sucrose compared with a defined medium have been characterized with respect to ribonucleoside supplementability. Twenty mutants respond to either pyrimidine ribonucleoside. Four mutants respond to one or both purine ribonucleosides. Eight mutants ("putative" auxotrophs) do not respond to dietary RNA supplementation. Mapping and complementation studies suggest that eleven loci are represented: one, rudimentary, probably accounts for all pyrimidine requirers; there are three purine loci and seven at which the putative auxotrophs are found.     

Study of allelic polymorphism of (GATA)n-containing loci in parthenogenetic lizards Darevskia unisexualis (Lacertidae)

The genesis of mini- and microsatellite loci, which is under extensive study in humans and some other bisexual species, have been virtually overlooked in species with clonal mode of reproduction. Earlier, using multilocus DNA fingerprinting, we have examined variability of some mini- and microsatellite DNA markers in parthenogenetic lizards from the genus Darevskia. In particular, mutant (GATA)n-restrictive DNA fragments were found in Darevskia unisexualis. In the present study, we examined intraspecific polymorphism of three cloned loci of D. unisexualis--Du323, Du215, and Du281--containing (GATA)7GAT(GATA)2, GAT(GATA)9, and (GATA)10TA(GATA) microsatellite clusters, respectively. Different levels of intrapopulation and interpopulation variability of these loci were found. Locus Du281 showed the highest polymorphism--six allelic variants (in the sample of 68 DNA specimens). Three alleles were found for locus Du215. The Du325 locus was electrophoretically invariant. The primers chosen for loci Du323, Du215, and Du281 were also used for PCR analysis of homologous loci in two presumptive parental bisexual species, D. valentini and D. nairensis. The PCR products of the corresponding loci of the parental species had approximately the same size (approximately 200 bp) as their counterparts in D. unisexualis, but the polymorphism levels of the paternal, maternal, and hybrid species were shown to be somewhat different. These data on the structure of the D. unisexualis loci provide a possibility to study genetic diversity in the parthenogenetic species D. unisexualis and other related unisexual and bisexual species of this genus, which can provide new information on the origin of parthenogenetic species and on the phylogenetic relationships in the genus Darevskia. These data can also be used for resolving problems of marking the lizard genome, which is still poorly studied.     

Ontogeny of gene expression in Pomoxis (pisces: Centrarchidae)

The regulation of gene expression during embryogenesis was investigated in white and black crappie (Pomoxis spp.) and their reciprocal interspecific F₁ hybrids. The schedule of morphological development and the timing of isozyme expression were compared among the two species and both reciprocal maternal half-sibling F₁ hybrids. Although absolute rates of morphological development differed in response to incubation temperature, relative rates of morphological development (normalized to the onset of retinal pigment deposition) were similar among all crosses. Furthermore, these relative rates were similar to those previously documented for other centrarchid species. To assess differences in ontogenetic patterns of gene expression among the crosses, we examined expression for 39 enzymeencoding loci. Expression was not detected in the embryos for 16 loci due to low or nonexistent activity. Enzymatic activity from eight other loci were continuously detected throughout embryogenesis as a result of maternal enzyme in the egg. However, 15 loci initiated expression during the early development period investigated (fertilization through yolk sac absorption). We observed temporal variability in expression of these 15 loci among the crosses, either in the form of differential expression between parental species or as disturbances in the ontogeny of expression in interspecific hybrids. Such variability in expression suggests that some of the gene regulating mechanisms have diverged since Pomoxis species shared a common ancestral genome. © 1994 Wiley-Liss, Inc.     

APOA2 ?256T>C polymorphism interacts with saturated fatty acids intake to affect anthropometric and hormonal variables in type 2 diabetic patients

Recent studies have established the interaction between APOA2 −256T>C polymorphism and dietary saturated fatty acids intake in relation to obesity on healthy individuals. In the current study, we investigate the effects of this interaction on anthropometric variables and serum levels of leptin and ghrelin in patients with type 2 diabetes. In this cross-sectional study, 737 patients with type 2 diabetes mellitus (290 males and 447 females) were recruited from diabetes clinics in Tehran. The usual dietary intake of all participants during the last year was obtained by validated semiquantitative food frequency questionnaire. APOA2 genotyping was performed by real-time PCR on genomic DNA. No significant relation was obtained by univariate analysis between anthropometric variables and APOA2 genotypes. However, after adjusting for age, gender, physical activity and total energy intake, we identified a significant interaction between APOA2-saturated fatty acids intake and body mass index (BMI). After adjusting for potential confounders, serum levels of ghrelin in CC genotype patients were significantly higher than T allele carriers (p = 0.03), whereas the case with leptin did not reveal a significant difference. The result of this study confirmed the interaction between APOA2 −256T>C polymorphism and SFAs intake with BMI in type 2 diabetic patients. In fact, homozygous patients for the C allele with high saturated fatty acids intake had higher BMI. The APOA2 −256T>C polymorphism was associated with elevated levels of serum ghrelin.