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Results for “polygenic background”

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PubMed1988

Inheritance of human platelet thermolabile phenol sulfotransferase (TL PST) activity.

Sulfate conjugation is an important pathway in the biotransformation of drugs and neurotransmitters. The thermolabile (TL) form of the enzyme phenol sulfotransferase (PST) catalyzes the sulfation of catecholamine neurotransmitters and drugs such as methyldopa and acetaminophen. Platelet TL PST activity was measured in blood samples from 232 individuals in 49 nuclear families. Correlations ranged from 0.43 to 0.45 for parent-offspring pairs and from 0.44 to 0.47 for siblings. Mother-father correlations were not significantly different from zero. Although evidence was not unequivocal, both segregation and commingling analyses provided some support for a major gene influence on TL PST activity, with other variation due to polygenic background. In both sets of analyses, however, support for a major gene hypothesis depended upon skewness in the TL PST activity distribution. A polygenic model with high heritability (0.77) was most strongly supported with the log transformed data. These results confirm and extend a previous report of high heritability of TL PST based on a study of twins. In addition, our results raise the possibility of a major gene effect on this important catecholamine- and drug-metabolizing enzyme--a possibility that can now be evaluated using biochemical techniques.

Adolescent↗

PubMed1987

Etiologic heterogeneity in alcoholism.

Etiologic heterogeneity in alcohol abuse was evaluated in 195 extended pedigrees, comprising 288 nuclear families of 140 male and 55 female Caucasian American hospitalized alcoholics. Previous adoption studies in Sweden demonstrated differential heritability of two patterns of alcohol abuse in men: type-2 alcoholism exhibited early onset of abuse associated with criminal behavior, while type-1 abuse began at a later age, uncomplicated by antisocial traits. Alcohol abuse in female Swedish adoptees was relatively homogeneous and similar to the late-onset, type-1 abuse. The notion of etiologic heterogeneity, as suggested by the Stockholm Adoption Studies, was examined in the American pedigrees by contrasting the models of familial transmission of susceptibility to alcoholism obtained via segregation analyses of families of male versus female probands. Families of male probands demonstrated significant familial resemblance, accounted for by a multifactorial-polygenic background in addition to a major (gene) effect. In contrast, familial resemblance in the pedigrees of female probands was attributed solely to a multifactorial-polygenic effect. We considered whether some families of male alcoholics were similar to families of female probands, who expressed type-1 abuse predominantly. Pedigrees of male probands were separated in two groups: (1) "female-like" families had a better likelihood for the model obtained for families of female probands than the one for families of all male probands, (2) "male-like" families had a better likelihood for the model of familial transmission describing families of all male probands. A statistically significant difference in the pattern of familial transmission was observed between the "male-like" and "female-like" groups. Discriminant function analysis of alcohol-related symptoms showed that the familial subtypes differed in clinical features as well. Alcohol abuse by male relatives in "male-like" families was characterized by the early onset of inability to abstain entirely from alcohol or lack of desire to stop drinking; in contrast, abuse in "female-like" families was characterized by late onset of guilt feelings and loss of control over binge drinking.

Adolescent↗

PubMed2005

Genomic approaches to schizophrenia.

BACKGROUND: Genetic epidemiologic studies suggest that individual variation in susceptibility to schizophrenia is substantially genetic. However, like other common disorders, the mode of transmission is complex and probably reflects oligogenic inheritance against a polygenic background. OBJECTIVE: The goal of this article was to introduce genomics as an approach to understanding the causes of schizophrenia. CONCLUSIONS: Genomic approaches to schizophrenia are becoming increasingly feasible as data from the Human Genome Project accumulate and technology improves. Attempts to identify genes for schizophrenia have been based on 4 main approaches: genetic linkage studies, studies of chromosomal abnormalities associated with the disorder, association studies, and convergent genomics. Several strong linkages have been found, and there is emerging consensus regarding at least some of the chromosomal regions likely to contain schizophrenia genes. However, moving from linked region to susceptibility gene is still difficult, given our poor understanding of the pathophysiology and population genetics, and the complexity of the phenotype. Despite this difficulty, positional candidate genes have been identified, and in 2 instances-neuregulin 1 and dysbindin-1-support has come from several studies. The rates of schizophrenia seen in individuals with deletions of chromosome 22q11, as well as linkage data,suggest that this chromosomal region might contain a susceptibility locus.

Chromosome Aberrations↗

PubMed2026

Associations of red blood cell fatty acids with personality traits: 10-year follow-up in the Kibbutzim Family Study (KFS).

BACKGROUND: The ability of hostility and type-A personality to predict cardiovascular outcomes makes understanding antecedents of these personality traits an important public health objective. OBJECTIVES: This study aimed to examine whether blood-measured fatty acids (the exposure) are associated with hostility and type-A personality (the outcome), while accounting for lifestyle, sociodemographic factors, and polygenic background. METHODS: Personality traits, sociodemographic, and lifestyle data were obtained in 1992-1993 from 452 family members living in kibbutz settlements in Israel (visit 1) and remeasured 8 to 10 y later in 379 individuals (visit 2). Red blood cell (RBC) fatty acid concentrations were determined in visit 1 by gas chromatography. Longitudinal associations of visit 1 fatty acids with visit 2 personality traits were examined using linear models, before and after controlling for baseline personality scores. The contribution of environmental factors to personality scores beyond heritability was estimated by variance decomposition. RESULTS: In longitudinal analysis, 1% increase in visit 1 total n-6 (ω-6) fatty acid was associated with a 0.328-unit decrease in visit 2 type-A score [95% confidence interval (CI): -0.571, -0.085]. After adjustment for baseline personality levels, the association was slightly attenuated (β= -0.204; CI: -0.399, -0.009). One percent higher total n-6 was also associated with 1.119 units lower visit 2 hostility score (CI: -2.777, 0.038; P = 0.055). Finally, independent of the genetic contribution (32%-38% of adjusted variability in hostility and type-A personality), 1% increase in total n-3 and total n-6 was associated with 2.539 (CI: -3.907, -1.171) and 0.201 (CI: -0.365, -0.037) units lower hostility and type-A scores, respectively. CONCLUSIONS: Higher RBC total n-6 fatty acid concentrations are associated with lower type-A personality scores. After adjustment for baseline personality levels, the associations between total n-6 and hostility and between total n-3 and hostility are attenuated. These findings support further investigation of the relationship between fatty acid biology and personality traits using study designs better suited to causal inference.

Humans↗

PubMed1996

Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.

We used segregation analysis to investigate the genetic basis of variation in dystopia canthorum, one of the key diagnostic features of Waardenburg syndrome type 1 (WS1). We sought to determine whether the W-index, a quantitative measure of this craniofacial feature, is influenced primarily either by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. We studied both WS1-affected individuals and their WS1-unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations are consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggest that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influence variation in dystopia canthorum. Our approach should be applicable for assessing the genetic architecture of variation associated with other genetic diseases.

Alleles↗

PubMed2026

Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.

Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.

common variants↗

PubMed2001

Mapping loci causing susceptibility to anal atresia in pigs, using a resource pedigree.

BACKGROUND/PURPOSE: Very little information on the genetic background for anal atresia (anorectal malformations; AA) in humans has been described. A strikingly similar natural anomaly occurs in piglets. The authors have used this as an animal model for various research purposes. The affected piglets were treated surgically soon after birth, raised, and used for breeding. The authors have generated a resource pedigree segregating for this naturally occurring nonsyndromal AA and describe here the first attempt to map susceptibility loci by marker analysis. METHODS: A pig pedigree with a high incidence of AA has been established by selective breeding using 3 probands from the Landrace and Large White breeds. It has been maintained by intrafamilial crossing for more than 15 years. A backcross pedigree has now been generated by mating 4 AA females to an unaffected male from the Chinese Meishan breed. F(1) animals were both intercrossed and backcrossed to affected AA animals. A genome scan was carried out using the F(0), F(1), and affected backcross progeny. Ninety-two microsatellite loci were analyzed using fluorescently labelled primers and an ABI377 sequencer. Linkage analysis was done with the CRI-MAP 2.4 software. RESULTS: Crossing affected parents increased the incidence of abnormalities from 30% to 61.9%. All 39 F(1) pigs were unaffected. In the F(1) intercross, only 3 of 205 (1.5%) were affected, whereas 42 of 523 (8.0%) backcross progeny were affected. The marked difference in the incidence of affected progeny in the F(1) intercross and in the backcross indicates the presence of multiple genes causing AA. The genome scan showed suggestive evidence for the presence of a susceptibility locus on pig chromosome 15 (lod score 2.7 for a pig microsatellite marker SW2072). CONCLUSIONS: The results clearly show that AA has a oligogenic or polygenic background. The genome scan showed one suggestive locus causing AA on pig chromosome 15. The long-term goal is to identify causative genes for this malformation by comparative positional candidate cloning. This study provides, for the first time, linkage mapping of nonsyndromal anorectal malformations with a polygenic inheritance.

Animals↗

PubMed2006

Use of routinely collected amniotic fluid for whole-genome expression analysis of polygenic disorders.

BACKGROUND: Neural tube defects related to polygenic disorders are the second most common birth defects in the world, but no molecular biologic tests are available to analyze the genes involved in the pathomechanism of these disorders. We explored the use of routinely collected amniotic fluid to characterize the differential gene expression profiles of polygenic disorders. METHODS: We used oligonucleotide microarrays to analyze amniotic fluid samples obtained from pregnant women carrying fetuses with neural tube defects diagnosed during ultrasound examination. The control samples were obtained from pregnant women who underwent routine genetic amniocentesis because of advanced maternal age (>35 years). We also investigated specific folate-related genes because maternal periconceptional folic acid supplementation has been found to have a protective effect with respect to neural tube defects. RESULTS: Fetal mRNA from amniocytes was successfully isolated, amplified, labeled, and hybridized to whole-genome transcript arrays. We detected differential gene expression profiles between cases and controls. Highlighted genes such as SLA, LST1, and BENE might be important in the development of neural tube defects. None of the specific folate-related genes were in the top 100 associated transcripts. CONCLUSIONS: This pilot study demonstrated that a routinely collected amount of amniotic fluid (as small as 6 mL) can provide sufficient RNA to successfully hybridize to expression arrays. Analysis of the differences in fetal gene expressions might help us decipher the complex genetic background of polygenic disorders.

Amniotic Fluid↗

PubMed1987

Hypertension and the genetics of red cell membrane abnormalities.

Hypertension represents the upper 15-25% of the blood pressure distribution in industrialized countries. The trait is practically absent in primitive societies and is made manifest by diet and lifestyles in industrialized countries. High blood pressure is an important risk factor for strokes, heart disease and renal disease. The frequency of hypertension is higher among blacks than among whites in the USA. Various twin, family and adoption studies indicate a strong genetic effect on blood pressure. The genetic mechanisms are unknown. Membrane transport variability has been studied in red cells as a surrogate for analogous alterations in smooth muscle or renal cells. Among the various transport systems, erythrocyte sodium-lithium countertransport (CT) has been consistently elevated in variable proportions of Caucasian hypertensives. Genetic studies of countertransport levels have shown familial aggregation and higher concordance for monozygotic than dizygotic twins. Complex segregation analysis suggests the action of a major gene superimposed on a polygenic background. The postulated gene (B) raises CT activity and has a population frequency of 0.25. CT levels of the common AA homozygotes and AB heterozygotes cannot be distinguished from each other, whereas CT activity of BB homozygotes (6% of the population) is significantly elevated. Although the CT gene contributes only 2.7% to 3.5% of the variability of blood pressure over its entire range, 14% to 20% of persons with systolic hypertension (greater than 140 mmHg) are BB homozygotes rather than the expected 6% to 7%. A much lower frequency of elevated countertransport activity among black hypertensives suggests genetic heterogeneity in the pathogenesis of high blood pressure. Further investigations on the mechanism and genetic linkage relationships of the putative CT gene may aid in elucidating an important mechanism of blood pressure elevation and will allow molecular approaches in the future.

Antiporters↗

PubMed1993

Complex segregation analysis of antibodies to thyroid peroxidase in Old Order Amish families.

Autoimmune thyroid disease (AITD) may be characterized by the measurement in serum of antibodies to thyroid peroxidase. A population of Old Order Amish individuals and families was investigated to determine the prevalence of these antibodies and to examine hypotheses about the mode of transmission of thyroid antibodies. Complex segregation analyses were performed on 4 large multigenerational Old Order Amish families composed of 26 nuclear families containing 199 first degree relatives. Several alternative hypotheses of genetic transmission were examined. Hypotheses of no transmission, polygenic inheritance, single locus transmission, and mixed inheritance were compared. The analyses incorporated population prevalences obtained from a random sample of individuals. Results suggest that the pattern of transmission of thyroid antibodies in these families is consistent with a mixed model in which the major gene is transmitted in an autosomal dominant pattern. The mixed model postulates that there is a single gene of major effect as well as a polygenic component that can act separately and/or together to confer susceptibility for this phenotype. The parameter estimates for the major locus are: gene frequency (q), 0.16 +/- 0.01; maximum male penetrance, 0.35; and maximum female penetrance, 0.70. The heritability of the polygenic background is estimated at 0.41.

Adolescent↗

PubMed1998

Familial clustering of rheumatoid arthritis with other autoimmune diseases.

Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

Adult↗

PubMed2006

A wider perspective on puberty.

The mechanisms that control the onset of puberty remain within the purview of the neurobiologists who first recognised the concept of removal of a restraint factor to permit reawakening of puberty. The discovery of a ligand-activated G protein receptor-signalling pathway upstream of the GnRH pulse generator adds further weight to the role of the hypothalamus in the central regulation of puberty. The physical pointers to puberty are the mainstay of assessing timing and tempo in a clinical setting but non-invasive and indirect methods of assessment only are appropriate for population studies in normal children. That puberty can be regarded as a sensor recognises the observation of secular changes in pubertal timing and perhaps qualitative aspects of tempo. The influences on the sensor include marked changes in nutrition and an environmental exposure to low-dose chemical mixtures interacting with a polygenic background.

Breast↗

PubMed2005

IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes.

Maturity-onset diabetes of the young (MODY) is a monogenic autosomal-dominant form of diabetes mellitus with onset before 25 years of age. Genetic variation in insulin promoter factor-1 (IPF1) (MODY4) is uncommon but may contribute to early- or late-onset diabetes as part of a polygenic background. IPF1 is a homeodomain transcription factor required for pancreas development. Our aim was to identify whether IPF1 gene mutations play a role in Italian early-onset type 2 diabetic (T2D) patients and what functional impact mutations may have in the beta cell. We screened 40 Italian early-onset type 2 diabetic probands for IPF1 mutations, performed oral glucose tolerance tests in the unaffected family members, and performed in vitro functional studies of the mutant variant. In an extended family (Italy-6) of 46 members with clinical phenotypes of gestational diabetes, MODY, and T2D, a single nucleotide change of CCT to ACT was identified at codon 33 resulting in a Pro to Thr substitution (P33T) in the IPF1 transactivation domain that also contributes to an altered metabolic status in the unaffected NM subjects. Of the 22 genotyped Italy-6 members, 9 carried the P33T allele (NM), of whom 5 have either T2D or elevated fasting glucose levels. Oral glucose tolerance tests showed higher glucose levels at 90 minutes in unaffected NM compared with unaffected NN subjects. Of the 5 female pregnant carriers of the IPF1 mutation, 4 had pregnancies complicated by reduced birth weights, miscarriages, or early postnatal deaths. In studies in vitro, the IPF1 mutant protein (P33T) showed a reduction in DNA-binding and transcriptional activation functions as compared to the wild-type IPF1 protein. Our findings suggest that the P33T IPF1 mutation may provide an increased susceptibility to the development of gestational diabetes and MODY4 in the Italy-6 pedigree.

Abortion, Spontaneous↗

PubMed1999

Loss of heterozygosity in human skin.

Loss of heterozygosity (LOH) is a genetic mechanism by which a heterozygous somatic cell becomes either homozygous or hemizygous because the corresponding wild-type allele is lost. LOH has today been recognized as a major cause of malignant growth. This article gives a comprehensive review of skin disorders in which an origin from LOH has been either documented at the molecular level or postulated on the basis of clinical evidence. LOH has been shown to cause basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, but this mechanism can likewise be taken as an important model to explain the origin of many other skin diseases such as benign hamartomas; type 2 segmental manifestation of autosomal dominant skin disorders; a pronounced segmental manifestation of acquired skin disorders with a polygenic background, superimposed on symmetric lesions of the usual type; paired mutant patches in the form of either allelic or nonallelic twin spotting; and the exceptional familial occurrence of some nevi, reflecting paradominant transmission. completion of this learning activity, readers should be familiar with the mechanism of LOH and its general significance for the biology of plants, animals, and humans. Participants should understand that this mechanism plays a crucial role not only in cutaneous malignant growth but also in the development of benign skin disorders, and they should be able to examine such diseases with a prepared mind to gain a better understanding of their origin.

Animals↗

PubMed2000

Estimation of additive, dominance and epistatic variance components using finite locus models implemented with a single-site Gibbs and a descent graph sampler.

In a previous contribution, we implemented a finite locus model (FLM) for estimating additive and dominance genetic variances via a Bayesian method and a single-site Gibbs sampler. We observed a dependency of dominance variance estimates on locus number in the analysis FLM. Here, we extended the FLM to include two-locus epistasis, and implemented the analysis with two genotype samplers (Gibbs and descent graph) and three different priors for genetic effects (uniform and variable across loci, uniform and constant across loci, and normal). Phenotypic data were simulated for two pedigrees with 6300 and 12,300 individuals in closed populations, using several different, non-additive genetic models. Replications of these data were analysed with FLMs differing in the number of loci. Simulation results indicate that the dependency of non-additive genetic variance estimates on locus number persisted in all implementation strategies we investigated. However, this dependency was considerably diminished with normal priors for genetic effects as compared with uniform priors (constant or variable across loci). Descent graph sampling of genotypes modestly improved variance components estimation compared with Gibbs sampling. Moreover, a larger pedigree produced considerably better variance components estimation, suggesting this dependency might originate from data insufficiency. As the FLM represents an appealing alternative to the infinitesimal model for genetic parameter estimation and for inclusion of polygenic background variation in QTL mapping analyses, further improvements are warranted and might be achieved via improvement of the sampler or treatment of the number of loci as an unknown.

Epistasis, Genetic↗

PubMed2004

Genotype-assisted optimum contribution selection to maximize selection response over a specified time period.

Genotype-assisted selection (GAS), i.e. selection for an identified quantitative trait locus (QTL) and polygenic background genes, has been shown to increase short-term genetic gain but may reduce long-term genetic gains. In order to avoid this reduction of long-term gain, multi-generation optimization of truncation selection schemes is needed. This paper presents a multi-generation optimization of optimum contribution (OC) selection with selection on an identified QTL. This genotype-assisted optimum contribution (GAOC) selection method assumes that the optimum selection differential at the QTL is constant over the time horizon, and achieves this by controlling the increase of the frequency of the positive QTL allele. Implementation was straightforward by an additional linear restriction in the OC algorithm. GAOC achieved 35.2%, 2.3% and 1.1%, respectively, more cumulative genetic gain than OC selection (ignoring the QTL) using time horizons of 5, 10 and 15 generations. When one-generation optimization of GAS was used instead of multi-generation optimization, these figures were 2.8%, 3.1% and 3.2%, respectively. Simulated annealing was used to optimize the increases of the frequency of the positive QTL allele in order to test the optimality of GAOC. This latter resulted in genetic gains that were always within 0.4% of those of GAOC. In practice, short-term genetic gains are also important, which makes one-generation optimization of genetic gain closer to optimal.

Data Interpretation, Statistical↗

PubMed1999

Genetic and environmental sources of QT interval variability in Israeli families: the kibbutz settlements family study.

QT interval prolongation not attributed to long QT syndromes is reported to be associated with increased risk of sudden and nonsudden cardiac death. Genetic and environmental determinants of QTc interval were investigated in an unselected free living population sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 214 males and 227 females aged 15-97 years. There was a significant familial aggregation of adjusted QT interval levels, as indicated by inter- and intraclass correlation coefficients significantly different from zero. Complex segregation analysis applied to the sex- and age-adjusted data was not conclusive and heterogeneous etiologies for individual differences were suggested. There was evidence for a single recessive locus (q = 0.173) with a major effect in addition to polygenic effects (h2 = 0.41) that explained the mixture of distributions. In parallel, a nontransmitted environmental major factor in addition to polygenic effects that explained the adjusted variation in QTc could not be rejected. Similar results were obtained upon the adjustment for sex, age, and environmental covariables. The major factor, either genetic or environmental, and polygenic-loci accounted for about 20 and 33% of the adjusted QTc variation, respectively. Furthermore, sex, age, measured environmental covariables, the unmeasured major factor, and the unmeasured polygenes could account for 63% of the variation of QTc in these families. Our data provide evidence for a major factor, either genetic or environmental, in addition to a polygenic background, influencing QT interval levels in a population-based sample of pedigrees.

Adolescent↗

PubMed2002

Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia.

The nature of the genetic and environmental factors influencing low density lipoprotein (LDL) particle size in patients with familial combined hyperlipidaemia (FCHL) is under debate. We measured LDL peak particle size in 553 subjects belonging to 48 Finnish FCHL families. Individuals with high triglyceride (TG) concentrations (phenotype IV) or combined hyperlipidaemia (phenotype IIB) had significantly smaller LDL particles than those with hypercholesterolaemia (phenotype IIA) or unaffected subjects (P<0.001). In stepwise regression analyses, serum TGs (r(2)=43%, P<0.001) and high density lipoprotein cholesterol (HDL-C) (r(2)=4.5%, P<0.001) were the only significant predictors of LDL peak particle size. Familial correlations support the conclusion that LDL peak particle size is familial, and most probably influenced by genes in these families. Segregation analysis of LDL peak particle size, a quantitative trait, was performed to model this genetic influence. Our results suggest a polygenic background for LDL size with a recessive major gene that may contribute to large LDL peak particle size in women. Serum TG and HDL-C concentrations predict the majority of variations in LDL particle size.

Adult↗