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PubMed2004

Expression of fatty-acid-handling proteins in human adipose tissue in relation to obesity and insulin resistance.

AIMS/HYPOTHESIS: Protein-mediated trans-membrane and intracellular fatty acid trafficking are becoming increasingly recognised as biochemically and physiologically important concepts. Obesity and insulin resistance are polygenic disorders, heavily influenced by environmental and life-style factors, and are virtually always associated with disturbed fatty acid metabolism in adipose and other tissues. The aim of this study was to investigate mRNA expression levels of fatty-acid-handling proteins in adipose tissue in relation to markers of genetic and acquired obesity and insulin resistance. METHODS: We quantified mRNA expression of subcutaneous adipose tissue fatty-acid-handling proteins (ALBP, KLBP, FATP1, FATP4, CD36, ACS1) in 17 monozygotic twin-pairs with a range of intra-pair differences (Delta) in BMI and detailed measures of obesity and insulin resistance, allowing influences of genetic and non-genetic factors to be distinguished. RESULTS: In acquired obesity FATP4 expression was up-regulated independently of genetic background (DeltaFATP4 versus DeltaBMI; r=0.50, p=0.04; DeltaFATP4 versus Deltabody fat; r=0.59, p=0.01). Similarly, CD36 and FATP1 expression correlated with acquired differences in HDL cholesterol and non-esterified fatty acid concentrations respectively. Moreover, FATP4 and CD36 expression levels correlated with measures of obesity and insulin resistance that are influenced by both genetic and non-genetic factors (FATP4 versus BMI: r=0.53, p=0.0001; FATP4 versus body fat: r=0.51, p=0.002; FATP4 versus homeostasis model assessment [HOMA]: r=0.49, p=0.001; CD36 versus BMI: r=0.50, p=0.02; CD36 versus body fat: r=0.63, p=0.001; CD36 versus HOMA: r=0.34, p=0.06). CONCLUSIONS/INTERPRETATION: These findings indicate that expression of specific adipose tissue fatty-acid-handling proteins is related to obesity and insulin resistance, and that, in particular, FATP4 plays a role in acquired obesity. Our results suggest that facilitated fatty acid trafficking is a physiologically and pathologically relevant phenomenon in man.

Adipose Tissue↗
PubMed2005

Sex-specific effect of insulin-dependent diabetes 4 on regulation of diabetes pathogenesis in the nonobese diabetic mouse.

Many human autoimmune diseases are more frequent in females than males, and their clinical severity is affected by sex hormone levels. A strong female bias is also observed in the NOD mouse model of type I diabetes (T1D). In both NOD mice and humans, T1D displays complex polygenic inheritance and T cell-mediated autoimmune pathogenesis. The identities of many of the insulin-dependent diabetes (Idd) loci, their influence on specific stages of autoimmune pathogenesis, and sex-specific effects of Idd loci in the NOD model are not well understood. To address these questions, we analyzed cyclophosphamide-accelerated T1D (CY-T1D) that causes disease with high and similar frequencies in male and female NOD mice, but not in diabetes-resistant animals, including the nonobese diabetes-resistant (NOR) strain. In this study we show by genetic linkage analysis of (NOD x NOR) x NOD backcross mice that progression to severe islet inflammation after CY treatment was controlled by the Idd4 and Idd9 loci. Congenic strains on both the NOD and NOR backgrounds confirmed the roles of Idd4 and Idd9 in CY-T1D susceptibility and revealed the contribution of a third locus, Idd5. Importantly, we show that the three loci acted at distinct stages of islet inflammation and disease progression. Among these three loci, Idd4 alleles alone displayed striking sex-specific behavior in CY-accelerated disease. Additional studies will be required to address the question of whether a sex-specific effect of Idd4, observed in this study, is also present in the spontaneous model of the disease with striking female bias.

Alleles↗
PubMedDate not supplied

Bigenic connexin mutations in a patient with hidrotic ectodermal dysplasia.

Gap junctions are formed by a polygenic family of more than 20 different connexin proteins. They mediate intercellular communication via the direct exchange of ions, metabolites and secondary messengers, thus controlling and coordinating cellular activities. Mutations in five gap junction genes, including GJB2 (Cx26), GJB3 (Cx31), GJB4 (Cx30.3), GJB6 (Cx30) and GJA1 (Cx43) are known to cause inherited hearing loss and/or disorders of the skin and its appendages, often giving rise to overlapping phenotypes. In this study we present a patient with hidrotic ectodermal dysplasia, who had abortive features of oculo-dento-digital dysplasia, extensive hyperkeratosis of the skin. The patient harbored a novel sporadic mutation (V41L) in GJA1 (Cx43) as well as a heterozygous coding variant (R127H) of GJB2 (Cx26). Our findings suggest that GJA1 mutations can produce variable clinical phenotypes on the background of sequence variants in other connexins.

Child↗
PubMed2001

Apolipoprotein B Arg3500Gln mutation prevalence in children with hypercholesterolemia: a French multicenter study.

BACKGROUND: Familial defective apolipoprotein B-100, a dominantly inherited form of hypercholesterolemia caused by a single Arg3500Gln mutation, is silent in childhood but may confer a high risk of cardiovascular disease in adulthood. The objective was to determine the prevalence of familial defective apolipoprotein B-100 in hypercholesterolemic French children and to provide a basis for targeting screening efforts in this population. METHODS: One hundred ninety children attending 13 pediatric clinics distributed throughout France were included based on the presence of type IIa hypercholesterolemia with a plasma low-density lipoprotein-cholesterol level of more than 130 mg/dL. The Arg3500Gln mutation was detected in dried blood spots using a polymerase chain reaction assay combined with enzymatic restriction. RESULTS: Three hyperlipidemia phenotypes were found: monogenic dominant pure hypercholesterolemia (n = 117), polygenic hypercholesterolemia (n = 43), and combined hyperlipidemia (n = 11). Three unrelated children were heterozygous for the Arg3500Gln mutation; all three had monogenic dominant pure hypercholesterolemia (3/94 families; 3.2%), yielding a prevalence of 1.83% (3/164) in hypercholesterolemic children, which is similar to prevalences reported in European adults. CONCLUSIONS: The familial defective apolipoprotein B-100 mutation was common (1/31) in children with a phenotype of familial hypercholesterolemia, supporting screening in this population with the goal of preventing premature cardiovascular events.

Adolescent↗
PubMed2026

Impacts of host genetics on gut microbiome composition in Alzheimer's disease.

BACKGROUND: Host-microbiome interactions play essential roles in the development of Alzheimer's disease (AD), yet the host genetic impacts on gut microbial alterations in AD remain poorly understood. RESULTS: Here, we simultaneously profiled host genotype and gut microbiome in 252 Chinese individuals with varying degrees of cognitive disability. Using the latent Dirichlet allocation topic model, we identified the Anaerostipes-enriched enterosignature (ES-Ana) at the microbial subgroup level as significantly negatively associated with cognitive disability, which could be recapitulated in external cohorts. With the whole-genome sequencing data, we performed microbiome genome-wide association studies for the ES-Ana relative abundance. We prioritized 41 lead genetic variants and confirmed that the high ES-Ana relative abundance showed a negative correlation with the polygenic risk score of AD, indicating its protective effect against AD. Furthermore, we identified 174 ES-Ana-associated genes, which are enriched in AD-related biological functions and phenotypes, and exhibite pervasive underexpression in glial cells during brain aging. CONCLUSIONS: In summary, our study reveals the complex genetic effects on the gut microbiota in AD, and provides novel evidence for the roles of the gut-brain axis in AD. Video Abstract.

Alzheimer Disease↗
PubMed2026

Perceived partner substance use, genetic predispositions, and their associations with problematic alcohol use, emotional well-being, and relationship quality.

BACKGROUND: Romantic relationships are important contexts for substance use and emotional well-being. We tested the hypotheses that (i) genetic predispositions for alcohol consumption would be positively associated with partner substance use, (ii) partner substance use would moderate genetic influences on one's own alcohol outcomes, and (iii) partner discordance in substance use would be associated with lower emotional well-being and relationship quality. METHODS: Analyses included 2,357 participants (Mage = 51.4, 58.2% female) from the Collaborative Studies on the Genetics of Alcoholism. Focal measures included participants' reports of their own and their current partner's past-year substance use (frequencies of alcohol use, heavy drinking, drunkenness, cannabis use, and nicotine use), emotional well-being, and relationship quality. Participants' genetic predispositions were indexed with genome-wide polygenic scores for alcohol consumption (PGSAlc). Participant-partner substance use discordance was calculated as the difference between the participant's and their partner's use for each substance use measure, separately. RESULTS: Participant PGSAlc was not significantly associated with partners' perceived substance use. Frequent perceived partner alcohol use and heavy drinking significantly amplified the association between PGSAlc and alcohol use or drunkenness. Frequent perceived partner drunkenness and cannabis use significantly attenuated the association between PGSAlc and heavy drinking or frequency of alcohol use. Participant-partner discordance for several substance use measures was significantly associated with lower emotional well-being and relationship quality, controlling for participant and partner substance use main effects. CONCLUSIONS: The results highlight the importance of partner substance use in etiological models of alcohol use, emotional health outcomes, and relationship quality.

Humans↗
PubMed2001

Polymorphisms at the DRD2 locus in early-onset alcohol dependence in the Indian population.

The susceptibility to alcohol dependence is probably of polygenic origin. Association studies have attempted to identify possible candidate genes that may contribute to the risk to developing dependence. Severe forms of the alcoholism phenotype have been associated with an increased frequency of the Taq A1 allele at the DRD2 locus. Ethnic stratification and non-comparable phenotype may have contributed to the contradictory results in previous studies. We identified probands, using the Schedules of Assessment of Neuropsychiatry (SCAN) schedule, who had onset of alcohol dependence (ICD-10) before 25 years of age. Family members were interviewed using the Family Interview for Genetic Studies (FIGS) schedule to identify patients who had two first-degree relatives with alcohol dependence. Fifty subjects who fulfilled the criteria were selected for the study. These were compared to a normal population from a similar background. The allele frequencies did not differ between the two groups. The Taq1a polymorphism does not seem to be associated with alcoholism in this group of severely affected, young age of onset probands in the southern Indian population.

Journal Article↗
PubMed2005

Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo.

To circumvent the early lethality of manganese superoxide dismutase (SOD2)-deficient mice, we have used a skin-specific strategy with introduction of loxP sites flanking exon 3 of the SOD2 gene. To our surprise, when breeding a female keratin 14 Cre transgenic mouse to a SOD2 "floxed" male mouse, due to keratin 14 promoter-driven Cre expression in the oocytes, all offspring were heterozygous for SOD2. In sharp contrast to initial publications on SOD2(+/-) mice, the herein reported mice on a mixed genetic background (C57BL/6 x 129/Ola) in their heterozygous state (SOD(+/-)) revealed distinct ultrastructural damage of the myocard, with swelling and disruption of mitochondria and accumulation of lipid droplets, increased nitrotyrosine formation, and lipid peroxidation as well as activation of apoptosis signaling pathways in the heart in vivo. Strikingly, and so far unreported, we found a substantial decrease in the activity of the cytosolic copper, zinc superoxide dismutase (SOD1) in the heart tissue of SOD2(+/-) mice, suggesting that the breakdown of mitochondrial membranes in the heart of SOD2(+/-) mice results in the enhanced release of superoxide anion radicals or derivatives thereof with subsequent inactivation of cytosolic SOD1. This model may be particularly suited to long-term studies on age-related heart failure as well as other age-related diseases and the polygenic base of tissue-specific responses to oxidative injury.

Animals↗
PubMed2026

Genomic background of gestation length and calving-related traits in Holstein cattle.

The reproductive success of cows directly influences the profitability of dairy farms. Reproductive traits, particularly calving-related traits, generally have low heritability but sufficient additive genetic variance to enable genetic progress through genomic selection. Thus, the primary objectives of this study were to estimate genetic parameters and perform single-step genome-wide association studies (ssGWAS) for calf size, calving ease, gestation length, and stillbirth in Holstein cattle. Variance components were estimated based on animal models and Bayesian inference using a data set containing 226,717 animals with phenotypic records, 15,761 animals genotyped with 45,101 SNP markers, and 461,819 animals in the pedigree. SNP effects were estimated using the single-step GBLUP method. For direct and maternal genetic effects, heritability estimates (posterior standard deviation) ranged from 0.001 (0.002) for gestation length in heifers to 0.16 (0.001) for gestation length in cows. Genetic correlations ranged from -0.57 (0.01) between calving ease and stillbirth in heifers to 0.74 (0.01) between gestation length evaluated in heifers and cows. The ssGWAS results supported a highly polygenic architecture for calving-related traits, with most genomic signals not reaching genome-wide significance. A genome-wide significant association was detected for calving ease in cows on BTA23, highlighting FARS2 as a positional candidate gene. The strongest GWAS signals for each trait harbored additional biologically important candidate genes, including NPPA, NPPB, BCHE, EPHA4, DLD, and GTF2I. Given the generally low heritability estimates and the predominantly polygenic architecture observed for these traits, genomic selection may contribute to the genetic improvement of calving-related traits in Holstein cattle, with potential benefits for cow welfare, calf survival, and overall dairy production efficiency.

dairy cattle↗
PubMed1999

Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice.

An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren's syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/lpr, C3H/lpr, (MRL/lpr x C3H/lpr) F1 intercross, and MRL/lpr x (MRL/lpr x C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.

Animals↗
PubMed2003

Quantitative and molecular genetic determination of protein and fat deposition.

After 30 years of selection, breeding of the pig breed sus scrofa Piétrain has resulted in reduced backfat thickness (from 3.2 to 1.9 mm) and increased loin muscle area (40 to 60 cm2) which indicates high genetic determination of these body composition traits. The use of sophisticated quantitative genetic methods that include all genetic relationships of large populations has led to a high response to selection of these traits. Selection on feed intake, lean and fat tissue growth using nonlinear functions to optimise these traits during the entire growth period in a biological model offers the opportunity to further improve total genetic potential. Protein and lipid deposition rates during the entire growth period have to be known for this biological model to be applied; thus knowledge of the genetic background of these traits is of high economic value. With the use of molecular genetic methods, such as candidate gene and genome scan approaches, the identification of genes for obesity and growth can be obtained. In sus scrofa, candidate genes associated with obesity and growth include Leptin Receptor, Melanocortin-4 Receptor, Agouti related protein, Heart fatty acid binding protein 3, and Insulin-like growth factor 2. Some of these candidate genes also explain variation in obesity levels in humans. Initial genome-wide scans have identified quantitative trait loci (QTL) on chromosomes 1, 4, 5, 7 and X for obesity and on chromosomes 1, 4, 7, 8, 13 and 18 for growth. Physiological candidate genes and predispositional QTL for obesity are not always located on the same chromosome; this is known the "polygenic paradox". Use of a nonlinear growth function is recommended in order to give more insight into the physiological regulation of obesity traits. Sus scrofa is an excellent model organism to examine the genetic regulation of obesity. The conservation of DNA sequence and chromosomal segments between sus scrofa and homo sapiens will permit easy transfer of results to human studies.

Animal Husbandry↗
PubMed2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans↗
PubMed1986

Deployment of short-term assays for the detection of carcinogens; genetic and molecular considerations.

The deployment of short-term assays for the detection of carcinogens inevitably has to be based on the genetic alterations actually involved in carcinogenesis. This paper gives an overview of oncogene activation and other mutagenic events connected with cancer induction. It is emphasized that there are indications of DNA alterations in carcinogenicity, which are not in accordance with "conventional" mutations and mutation frequencies, as measured by short-term assays of point mutations, chromosome aberrations and numerical chromosome changes. This discrepancy between DNA alterations in carcinogenicity and the endpoints of short-term assays in current use include transpositions, insertion mutations, polygene mutations, gene amplifications and DNA methylations. Furthermore, tumourigenicity may imply an induction of a genetic instability, followed by a cascade of genetic alterations. The evaluation of short-term assays for carcinogenesis mostly involves two correlations that is, between mutation and animal cancer data on the one hand and between animal cancer data and human carcinogenicity on the other. It should be stressed that animal bioassays for cancer in general imply tests specifically for the property of chemicals to function as complete carcinogens, which may be a rather poor reflection of the actual situation in human populations. The primary aim of short-term mutagenicity assays is to provide evidence as to whether a compound can be expected to cause mutations in humans, and such evidence has to be considered seriously even against a background of negative cancer data. For the evaluation of data from short-term assays the massive amount of empirical data from different assays should be used and new computer systems in that direction can be expected to provide improved predictions of carcinogenicity.

Carcinogens↗
PubMed2025

Genomewide association study of a homogeneous multiple sclerosis cohort: Tumefactive demyelination.

BACKGROUND: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. OBJECTIVE: A GWAS was performed to identify variants associated with TD. METHODS: The case-control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p-value threshold of 5 × 10-8 was GWAS significant and 5 × 10-6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. RESULTS: Variants on chromosome 14 (rs117797734, p = 2.06 × 10-11, odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10-7, OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. CONCLUSION: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.

Humans↗
PubMed2006

Heritability and major gene effects on left ventricular mass in the Chinese population: a family study.

BACKGROUND: Genetic components controlling for echocardiographically determined left ventricular (LV) mass are still unclear in the Chinese population. METHODS: We conducted a family study from the Chin-San community, Taiwan, and a total of 368 families, 1145 subjects, were recruited to undergo echocardiography to measure LV mass. Commingling analysis, familial correlation, and complex segregation analysis were applied to detect component distributions and the mode of inheritance. RESULTS: The two-component distribution model was the best-fitting model to describe the distribution of LV mass. The highest familial correlation coefficients were mother-son (0.379, P < .0001) and father-son (0.356, P < .0001). Genetic heritability (h2) of LV mass was estimated as 0.268 +/- 0.061 (P < .0001); it decreased to 0.153 +/- 0.052 (P = .0009) after systolic blood pressure adjustment. Major gene effects with polygenic components were the best-fitting model to explain the inheritance mode of LV mass. The estimated allele frequency of the gene was 0.089. CONCLUSION: There were significant familial correlations, heritability and a major gene effect on LV mass in the population-based families.

Adolescent↗
PubMed2025

Prematurity and Genetic Liability for Autism Spectrum Disorder.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions. METHODS: We analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8,104 individuals with exome sequencing data. Statistical significance of differences in clinical measures was evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth. RESULTS: Individuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notably, preterm ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model, p=0.005) in comparison to the non-ASD preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD, reaching a probability close to 90% in SPARK. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65). CONCLUSIONS: Preterm birth may exacerbate the multimorbidity present in ASD, which was not due to the ASD genetic factors. However, increased genetic factors may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. We propose that incorporating genetic assessment into neonatal care could benefit early ASD identification and intervention for preterm infants.

Autism Spectrum Disorder↗
PubMed1999

[Frequency of occurrence of apolipoprotein E isoforms in patients with various types of hyperlipoproteinemias].

BACKGROUND: Apolipoprotein E is a polymorphic protein playing a crucial role in the metabolism of plasma lipoproteins. Three alleles referred to as epsilon 2, epsilon 3 and epsilon 4 code for three common isoforms of apoE. The most frequent allele in the population at large is epsilon 3 allele. epsilon 2 and epsilon 4 alleles are connected with lipoprotein disorders as well as with other diseases. The aim of our study was to establish frequencies of apoE coding alleles in patients with different types of hyperlipidaemia (HLP) and to reveal differences in their distribution in comparison with the general population. METHODS AND RESULTS: Therefore apoE genotype was assayed in 752 patients with primary HLP and 291 subjects randomly selected from the general Czech population. Allele frequencies were determined separately in a group of patients with familial hypercholesterolaemia (FH), polygenic hypercholesterolaemia (PHC), familial combined hyperlipidaemia (FCH) and in patients with type III. hyperlipidaemia (III). In patients with HLP a significantly higher frequency of epsilon 4 allele than in control subjects was found. In the group of FH patients frequency of the epsilon 2 allele was higher than in control subjects. In patients with PHC a significantly higher frequency of the epsilon 4 allele and lower frequency of the epsilon 2 allele were observed. In the group of FCH patients distribution of epsilon alleles did not differ from the control group. Frequency of the epsilon 2 allele in patients with type III. hyperlipidaemia was significantly higher than in controls. CONCLUSIONS: We conclude that there exist significant differences in frequencies of apoE coding alleles between patients with primary hyperlipidaemia and a randomly selected population sample. The revealed differences in allelic distribution suggest that the impact of apoE polymorphism is not uniform in all types of hyperlipidaemia.

Alleles↗
PubMed2026

Appreciating diversity: a review of the Iranian genomic landscape.

Understanding population structure is crucial for designing and interpreting human genetic studies. This is of particular importance for Iran as a large, ethnically diverse country whose population has often been treated as a genetically homogenous entity. Here, we synthesize published literature on the genetic structure of the Iranian population. We further complement this by recapitulating the geographic, historic, and ethnic background, by comparisons with neighboring countries, and by reviewing autozygosity in Iran. This synthesis confirms large genetic diversity, likely building upon an autochthonous component that was reshaped by multiple migrations. The substantial autosomal substructure falls apart into groups of largely shared genetic ancestry (Central Iranian Cluster) and those with substantial admixture in the past. Structure with respect to uniparental markers is less pronounced. We also find consistency for generally high but varying levels of autozygosity, influenced by ethnicity, residence, and socioeconomic factors. Finally, we recapitulate some examples for geographical differences in disease prevalence and (founder) mutation carrier frequency. Our synthesis emphasizes the need to account for this diversity in human genetic studies in the Iranian population. We provide conclusions for the design of such studies and state expectations on the transferability of genetic findings and genomic predictions, such as polygenic scores, within Iran as well as to neighboring countries. Iran's diversity and geographic location provide renewed motivation for conducting population genetic and ancient DNA studies as well as providing genomic reference resources in this part of the world.

Journal Article↗