Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels, but the specific genetic determinants of HDL cholesterol (HDL-C) levels have not been elucidated. In this study, the effects of variation in the genomic regions encoding hepatic lipase, apolipoprotein AI/CIII/AIV, and the cholesteryl ester transfer protein on plasma HDL-C levels were examined in 73 normotriglyceridemic, Caucasian nuclear families. Genetic factors accounted for 56.5 +/- 13% of the interindividual variation in plasma HDL-C levels. For each candidate gene, adjusted plasma HDL-C levels of sibling pairs who shared zero, one, or two parental alleles identical-by-descent were compared using sibling-pair linkage analysis. Allelic variation in the genes encoding hepatic lipase and apolipoprotein AI/CIII/AIV accounted for 25 and 22%, respectively, of the total interindividual variation in plasma HDL-C levels. In contrast, none of the variation in plasma HDL-C levels could be accounted for by allelic variation in the cholesteryl ester transfer protein. These findings indicate that a major fraction of the genetically determined variation in plasma HDL-C levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci.
The Genetic Analysis Workshop (GAW) 16 Problem 3 comprises simulated phenotypes emulating the lipid domain and its contribution to cardiovascular disease risk. For each replication there were 6,476 subjects in families from the Framingham Heart Study (FHS), with their actual genotypes for Affymetrix 550 k single-nucleotide polymorphisms (SNPs) and simulated phenotypes. Phenotypes are simulated at three visits, 10 years apart. There are up to 6 "major" genes influencing variation in high- and low-density lipoprotein cholesterol (HDL, LDL), and triglycerides (TG), and 1,000 "polygenes" simulated for each trait. Some polygenes have pleiotropic effects. The locus-specific heritabilities of the major genes range from 0.1 to 1.0%, under additive, dominant, or overdominant modes of inheritance. The locus-specific effects of the polygenes ranged from 0.002 to 0.15%, with effect sizes selected from negative exponential distributions. All polygenes act independently and have additive effects. Individuals in the LDL upper tail were designated medicated. Subjects medicated increased across visits at 2%, 5%, and 15%. Coronary artery calcification (CAC) was simulated using age, lipid levels, and CAC-specific polymorphisms. The risk of myocardial infarction before each visit was determined by CAC and its interactions with smoking and two genetic loci. Smoking was simulated to be commensurate with rates reported by the Centers for Disease Control. Two hundred replications were simulated.
To determine the mode of inheritance of hypertrophic cardiomyopathy 193 first degree relatives (parents, siblings, and offspring) of 50 patients with hypertrophic cardiomyopathy were assessed by clinical examination, electrocardiography, M mode and cross sectional echocardiography, and necropsy when available. Thirty nine (20%) first degree relatives had hypertrophic cardiomyopathy--37% of parents, 25% of siblings, and 8% of offspring. Eight (23%) of 35 affected relatives diagnosed by echocardiography had normal clinical and electrocardiographic findings. In the total study group 43% of the male population and 30% of the female population were affected. This difference is statistically significant. In 28/50 families there was familial occurrence of hypertrophic cardiomyopathy. Familial occurrence was demonstrated in 17 of 18 families in which five or more family members were assessed. In 15 families the pattern of inheritance was consistent with an autosomal dominant trait; in the other 13 the affected members were identified in a single generation and the pattern of inheritance could not be determined.
We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30–70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.
The correlations between systolic blood pressure (SBP) and total cholesterol levels (CHOL) might result from genetic or environmental factors that determine variation in the phenotypes and are shared by family members. Based on 330 nuclear families in the Framingham Heart Study, we used a multivariate normal model, implemented in the software FISHER, to estimate genetic and shared environmental components of variation and genetic and shared environmental correlation between the phenotypes. The natural logarithm of the phenotypes measured at the last visit in both Cohort 1 and 2 was used in the analyses. The antihypertensive treatment effect was corrected before adjustment of the systolic blood pressure for age, sex, and cohort.
The univariate correlation coefficient was statistically significant for sibling pairs and parent-offspring pairs, but not significant for spouse pairs. In the bivariate analysis, the cross-trait correlation coefficients were not statistically significant for all relative pairs. The shared environmental correlation was statistically significant, but the genetic correlation was not significant.
There is no significant evidence for a close genetic correlation between systolic blood pressure and total cholesterol levels. However, some shared environmental factors may determine the variation of both phenotypes.
To assess the association between breast feeding and blood lipid levels in adolescence.
Population based prospective birth cohort study.
City of Pelotas, Brazil.
All hospital births taking place in 1982; 79% of all males (n = 2250) were followed up for 18 years, and 2089 blood samples were available.
Main outcome measures
Total cholesterol and fractions (very low density lipoprotein cholesterol (VLDL), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL)), LDL/HDL ratio, serum triglycerides.
Three breast feeding variables were studied: total duration of breast feeding, duration of exclusive or predominant breast feeding, and ever compared with never breast fed. Adjusted analyses were controlled for family income, household assets index, maternal education, maternal pre‐pregnancy body mass index (BMI), skin colour, birth weight, gestational age, maternal smoking during pregnancy, and adolescent BMI, and behavioural variables (fat content of diet, physical activity, smoking, and alcohol drinking). Only one association reached borderline significance (p = 0.05): LDL cholesterol was slightly higher among never (mean 41.0 mg/dl; 95% CI 39.4 to 42.7) than among ever breast fed men (38.6 mg/dl; 95% CI 38.6 to 40.3), in the adjusted analyses. All other associations were not significant (p⩾0.09). There was no evidence of effect modification according to preterm status, intrauterine growth retardation, socioeconomic level, growth velocity in the first two years of life, or nutritional status at 2 years of age.
There was no clear association between breast feeding duration and serum lipid concentrations at the age of 18 years in this sample of Brazilian men.
breast feeding; cholesterol; triglycerides; cohort studies
The triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) has been advocated as a simple clinical indicator of insulin resistance. Thresholds of TG/HDL-C appeared to depend on ethnicity. However, no studies have specifically compared the accuracy of TG/HDL-C with and without other clinical and demographic factors in predicting insulin resistance in Taiwanese adults. The aim of the present investigation was to use TG/HDL-C and other clinical available factors to predict insulin resistance in Taiwanese adults.
A total of 812 subjects were recruited from at the time of their general health examination at the Buddhist Dalin Tzu Chi General Hospital, Taiwan. Demographic information and clinical characteristics were obtained. Insulin resistance was defined by the homeostasis model assessment for insulin resistance (HOMA-IR). Simple and multiple logistic regression analyses were used to obtain probabilities of insulin resistance (HOMA-IR > 2) using TG/HDL-C with (Model 2) and without (Model 1) other clinical variables. A receiver operating characteristic (ROC) analysis was conducted to evaluate the ability of the two models to correctly discriminate between subjects of low and elevated HOMA-IR.
Female sex, greater waist circumferences, and higher ALT levels were significantly associated with the risk of elevated HOMA-IR in addition to TG/HDL-C in the multiple logistic regression (Model 2). The area under the ROC curve (AUC) of Model 2 was 0.71 [95% CI = 0.67-0.75] and was significantly higher (P = 0.007) than the AUC 0.66 [95% CI = 0.62-0.71] of Model 1.
The diagnostic accuracy of insulin resistance, defined by HOMA-IR, using TG/HDL-C can be significantly enhanced by including three additional clinically available factors - sex, waist circumferences, and ALT levels.
prediction; insulin resistance; Chinese; ethnic groups
Familial nervous system cancers are rare and limited data on familial aspects are available particularly on site-specific tumours.
Data from five Nordic countries were used to analyse familial risks of nervous system tumours. Standardised incidence ratios (SIRs) were calculated for offspring of affected relatives compared with offspring of non-affected relatives.
The total number of patients with nervous system tumour was 63 307, of whom 32 347 belonged to the offspring generation. Of 851 familial patients (2.6%) in the offspring generation, 42 (4.7%) belonged to the families of a parent and at least two siblings affected. The SIR of brain tumours was 1.7 in offspring of affected parents; it was 2.0 in siblings and 9.4 in families with a parent and sibling affected. For spinal tumours, the SIRs were much higher for offspring of early onset tumours, 14.0 for offspring of affected parents and 22.7 for siblings. The SIRs for peripheral nerve tumours were 16.3 in offspring of affected parents, 27.7 in siblings and 943.9 in multiplex families.
The results of this population-based study on medically diagnosed tumours show site-, proband- and age-specific risks for familial tumours, with implications for clinical genetic counselling and identification of the underlying genes.
brain tumour; spinal tumour; peripheral nerve tumour; familial risk
This study examined prospectively the association of baseline plasma HDL-cholesterol levels with incidence of lung cancer in 14, 547 members of the Atherosclerosis Risk in Communities (ARIC) cohort. There were 259 cases of incident lung cancer identified during follow-up from 1987 through 2000. Results of this study indicated a relatively weak inverse association of HDL-cholesterol with lung cancer that was dependent on smoking status. The hazard ratio of lung cancer incidence in relation to low HDL-cholesterol, adjusted for race, gender, exercise, alcohol consumption, body mass index, triglycerides, age, and cigarette pack-years of smoking, was 1.45 (95% confidence interval 1.10, 1.92). This association was observed among former smokers (hazard ratio: 1.77, 95% confidence interval 1.05, 2.97), but not current smokers. The number of cases among never smokers in this study was too small (n=13) for meaningful interpretation of effect estimates. Excluding cases occurring within five years of baseline did not appreciably change the point estimates, suggesting lack of reverse causality. The modest association of low plasma HDL-cholesterol with greater incident lung cancer observed in this study is in agreement with existing case-control studies.
cohort studies; HDL cholesterol; lipoproteins; lung neoplasms
Offspring of at least 1 parent with type 2 diabetes are more resistant to the insulin action, exhibit higher incidence of dyslipidemia and are more prone to cardiovascular diseases. The association between Lp(α) and coronary heart disease is well established. An association between Lp(α) concentration and insulin sensitivity was examined in this study.
We investigated the serum LP(α) in 41 offspring of 41 families of type 2 diabetic subjects (group I) with normal glucose tolerance, compared to 49 offspring who their parents had no history of type 2 diabetes, matched for sex, age, BMI, WHR and blood pressure (group II). Serum Lp(α), triglycerides, insulin resistant index, HDL, LDL-cholesterol and insulin were measured.
The offspring of type 2 diabetic subjects had higher fasting serum triglycerides (mean ± SD 199.3 ± 184.2 vs. 147.1 ± 67.9 ng/dl, p < 0.05) lower HDL-cholesterol (37.3 ± 9.0 vs. 44.6 ± 7.8, p < 0.001) and particularly higher Insulin resistance Index (HOMA-IR) (2.84 ± 1.39 vs. 1.67 ± 0.77, p < 0.001).
They also had higher serum LP(α) concentration (15.4 ± 6.7 vs. 8.6 ± 6.0, p < 0.001). By simple linear analysis in the offspring of type 2 diabetic parents there was no correlation of Lp(α) concentration with insulin resistance index Homa-IR (r = 0,016 p = NS).
We conclude that serum LP(α) is significantly increased in offspring of type 2 diabetic subjects but was not related to insulin sensitivity.
In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults.
To estimate the heritability of ADHD in adults as assessed by the ADHD index scored from the CAARS (Conners' Adult ADHD Rating Scales).
Phenotype data from over 12,000 adults (twins, siblings and parents) registered with the Netherlands Twin Register were analyzed using genetic structural equation modeling.
Main outcome measures
Heritability estimates for ADHD from the twin-family study.
Heritability of ADHD in adults is estimated around 30% in men and women. There is some evidence for assortative mating. All familial transmission is explained by genetic inheritance, there is no support for the hypothesis that cultural transmission from parents to offspring is important.
Heritability for ADHD features in adults is present, but is substantially lower than it is in children.
The multiple metabolic syndrome is defined by a clustering of risk factors for cardiovascular disease. We sought to evaluate the familial correlations of the components of the syndrome using data from the Framingham Heart Study original and offspring cohorts as provided for the Genetic Analysis Workshop 13. Measures of plasma cholesterol (total and HDL), body mass index (BMI), and systolic blood pressure were used from selected calendar years of exams. Familial correlations were calculated using FCOR in S.A.G.E.
The sibling correlations were relatively high for all measures and exams, from 0.17 for systolic blood pressure to 0.27 for HDL cholesterol. The parent-child correlations were very similar, except for systolic blood pressure. The avuncular correlations were much smaller and the cousin correlations were even smaller. For HDL cholesterol the avuncular correlation was half the sibling correlation and the cousin correlation was half that again. Spousal correlations ranged from 0.07 for systolic blood pressure to 0.34 for BMI. Correlations were somewhat lower from 1984 to 1987 examinations than from 1971 to 1975 examinations, except for spousal correlations for systolic blood pressure and BMI.
The results of the family pair correlations are suggestive of genetic determinants of lipid levels and BMI. These components have been shown to be predictive of cardiovascular disease as well as diabetes. Genes in common with each of the components might also influence development of cardiovascular disease and diabetes, both complex diseases.
The aim of the present study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity and glucose metabolism in adult Alaskan Eskimos. The present family study included 1214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 ± 0.11 for LDL2 (intermediate) to 0.89 ± 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions and HDL size and measures of adiposity, LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity and glucose regulation.
Duplicate plasma specimens from 24 persons were sent to a community hospital, a commercial laboratory, and a university lipid research laboratory at two separate times to assess the intralaboratory and interlaboratory variations of total and high-density cholesterol measurements. For all three laboratories, the 95% confidence limits for the reproducibility of total cholesterol levels are about +/- 5.5%. For high-density lipoprotein (HDL) values, they are +/- 7%, +/- 14.45%, and +/- 9%. Interlaboratory differences for total cholesterol at the 95% confidence level are +/- 7.7% and for HDL +/- 18.4%. Construction of a "cardiac risk ratio" of total to HDL cholesterol levels is subject to confusion because small errors in HDL cholesterol levels produce large errors in the ratio.
Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence is not conclusive but it is consistent in pointing to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. Empirical familial risks should be used as guidance for the planning of SNP studies. We provide calculations for the assessment of familial risks for assumed allele frequencies and gene effects (odds ratios) for different modes of inheritance. Based on these data, we discuss the gene effects that could account for the unexplained proportion of familial breast and lung cancer. As a conclusion, we are concerned about the indiscriminate use of a genetic tool to cancers, which are mainly environmental in origin. We consider the likelihood of a successful application of SNPs in gene-environment studies small, unless established environmental risk factors are tested on proven candidate genes.
genotyping; interactions; genomics; multiple comparisons; molecular epidemiology.
Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.
In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).
Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.
Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
A long-standing puzzle in gerontology is the sex dependence of human longevity and its inheritance. We have analysed the sex-linked pattern of inheritance of longevity from 643 nuclear families on the historical population register of a French valley. We have focused on mean conditional life expectancy at a minimum age of 50 years, thus, in the present study, longevity refers to late or post-reproductive survival. A comparison of parents' and offspring's longevity has shown the existence of a heritable component of late survival in this population. We have found that the heritable component was substantially larger for daughters compared to sons. Moreover, this result appeared to be specific to late survival, that is, when only post-reproductive mortality for parental and offspring generations is taken into account. The stronger resemblance of parents to their daughters was no longer observed when considering younger ages at death for the offspring. This observation explains the hitherto unaccountable diversity of data in previous studies.
We examined associations of serum lipids and lipoproteins with benign prostatic hyperplasia (BPH) in a cohort of community dwelling men.
Subjects and Methods
This analysis was conducted in the Rancho Bernardo Study, a prospective, community-based cohort study. BPH was defined as a history of non-cancer prostate surgery or a medical diagnosis of BPH. Logistic regression modeling—with adjustments for age and stratification by diabetes diagnosis—was utilized to estimate the odds ratio (OR) of BPH associated with fasting serum concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and the triglyceride to HDL ratio.
Among 531 eligible participants, 259 (48%) reported BPH and 272 (52%) reported no BPH. Men with BPH (75.8 years, range 76.1 to 80.1 years) were older than men without BPH (72.7 years, range 72.4 to 74.0 years). There were no significant associations of total cholesterol (p-trend = 0.52), HDL cholesterol (p-trend = 0.56), triglycerides (p-trend = 0.30), or triglyceride to HDL ratio (p-trend = 0.13) with BPH risk. In a subset analysis in men with diabetes, those in the highest tertile (>133 mg/dL) of LDL cholesterol, compared with those in the lowest tertile (<110 mg/dL), were 4-times more likely to have BPH (OR 4.00, 95% CI 1.27–12.63, p-trend=0.02). These results were not explained by statin use.
In this cohort of community dwelling men, higher serum LDL was associated with increased risk of BPH among diabetics. These data suggest that diabetic men with increased LDL cholesterol are at increased risk for BPH. This observation is consistent with the concept that cardiac risk factors are involved with BPH pathogenesis.
benign prostatic hyperplasia; dyslipidemia; cholesterol; trigylceride; risk factor; lower urinary tract symptoms
Our aim was to characterize familial risks for type 2 diabetes by the type and number of affected family members, including half-siblings, adoptees, and spouses, to quantify risks and estimate the contribution of environmental effect.
RESEARCH DESIGN AND METHODS
Families were identified from the Multigeneration Register, and type 2 diabetic patients were obtained from the Hospital Discharge Register. Standardized incidence ratios were calculated for offspring with type 2 diabetes whose family members were hospitalized for type 2 diabetes at ages >39 years compared with those lacking affected family members.
The number of hospitalized type 2 diabetic patients was 157,549. Among 27,895 offspring, 27.9% had a parent or sibling also hospitalized for type 2 diabetes. The familial relative risk (RR) ranged from 2.0 to >30, depending on the number and type of probands. The highest RRs of type 2 diabetes were found in individuals who had at least two siblings affected by type 2 diabetes, irrespective of the parental disease. Adoptees showed no risk from adopted parents.
The study, the largest yet published, showed that familial RRs varied by the number and type of affected family member. However, much of the familial clustering remains yet to be genetically explained. The high risk should be recognized in clinical genetic counseling. The data from adoptees confirmed the genetic basis of the familial associations, but those from half siblings and spouses suggested that a smaller part of familial clustering may be accounted for by environmental factors.
Traditional lipid indices have been associated with type 2 diabetes, but it remains uncertain which lipid index is the best discriminator for diabetes. In this study, we aimed to assess lipoproteins, traditional lipid variables, and other variables to discover their association with diabetes in the Taiwanese population.
Data from a nationwide cross-sectional population-based survey of 3087 men and 3373 women in 2002 were analyzed in this study. All participants were assessed for anthropometry, glycosylated hemoglobin, fasting sugar and lipid profiles with triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoprotein A1 (ApoA1) and B (ApoB). The ratio of LDL-C/HDL-C, ApoB/ApoA1, ApoB/LDL-C and ApoA1/HDL-C and other variables were analyzed to determine their potential roles in type 2 diabetes in the Taiwanese population. The Odds ratios (ORs) of the risk variables for diabetes were estimated using logistic regression and were adjusted for confounding factors.
The increased ratio of ApoA1/HDL-C was significantly associated with diabetes in men (top tertile vs. lowest: OR 2.98; 95% CI: 1.12 - 7.92; P-trend = 0.030) and women (top tertile vs. lowest: OR 2.15; 95% CI: 1.00 - 4.59; P-trend = 0.047). A modest increased diabetic risk was evident with ApoB/LDL-C in women (top tertile vs. lowest: OR 2.03; 95% CI: 1.07- 3.85; P-trend = 0.028), but not in men (top tertile v. lowest: OR 1.69; 95% CI: 0.79- 3.62; P-trend = 0.198).
ApoA1/HDL-C had a significant linear association with diabetes in both sexes and was superior to other lipid and lipoprotein variables among the general Taiwanese population.
Apolipoprotein A1; Apolipoprotein B; High density lipoprotein-cholesterol; Low density lipoprotein-cholesterol; Diabetes
The clinical efficacy of the Chinese therapeutic food (specifically hawthorn fruit and Chinese kiwifruit-extract compound) on dyslipidemia was evaluated in this placebo-controlled, double blind, paired clinical trial conducted in Melbourne, Australia. Forty-three participants diagnosed with moderate dyslipidemia and met the study criteria were randomly assigned to Group A or B, with baseline characteristics matched. Twenty-seven participants completed all the tests, the blood lipid profile including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglycerides (TG) was analysed. The traditional Chinese medicine diagnosis was made based on participants' symptoms and signs. The results indicate that a four-week intake of the compound increased the serum HDL-c levels by 5% (P = 0.026) and decreased the ratios of TC/HDL-c and LDL-c/HDL-c (P = 0.012 and P = 0.044, resp.). The placebo intake did not significantly change the blood lipid profile. In the initial 43 participants with dyslipidemia, 76.7% of them were diagnosed with “Spleen deficiency” and 58.1% with “Liver qi stagnation.” The intake of hawthorn fruit and Chinese kiwifruit extract compound may increase the serum levels of HDL-c and decrease the ratios of TC/HDL-c and LDL-c/HDL-c, therefore, may reduce the risk of cardiovascular disease.
Copy Number Variation (CNV) is increasingly implicated in disease pathogenesis. CNVs are often identified by statistical models applied to data from single nucleotide polymorphism (SNP) panels. Family information for samples provides additional information for CNV inference. Two modes of PennCNV (the Joint-call and Posterior-call), which are some of the most well-developed family-based CNV calling methods, use a “Joint-model” as a main component. This models all family members’ CNV states together with Mendelian inheritance. Methods based on the Joint-model are used to infer CNV calls of cases and controls in a pedigree, which may be compared to each other to test an association. Although benefits from the Joint-model have been shown elsewhere, equality of call rates in parents and offspring has not been evaluated previously. This can affect downstream analyses in studies that compare CNV rates in cases versus controls in pedigrees. In this paper, we show that the Joint-model can introduce different CNV call rates among family members in the absence of a true difference. First, we show that the Joint-model may analytically introduce differential CNV calls because of asymmetry of the model. We demonstrate these differential call rates using single-marker simulations. We show that call rates using the two modes of PennCNV also differ between parents-offspring in one multi-marker simulated dataset and two real datasets. Our results advise need for caution in use of the Joint-model calls in CNV association studies with family-based datasets.
Schizophrenia; Calling Algorithm; Family-Based Study; CNV burden
The identification of genetic variants related to blood lipid levels within a large, population-based and nationally representative study might lead to a better understanding of the genetic contribution to serum lipid levels in the major race/ethnic groups in the U.S. population.
Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), we examined associations between 22 polymorphisms in 13 candidate genes and four serum lipids: high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG). Univariate and multivariable linear regression and within-gene haplotype trend regression were used to test for genetic associations assuming an additive mode of inheritance for each of the three major race/ethnic groups in the United States (non-Hispanic white, non-Hispanic black, and Mexican American).
Variants within APOE (rs7412, rs429358), PON1 (rs854560), ITGB3 (rs5918), and NOS3 (rs2070744) were found to be associated with one or more blood lipids in at least one race/ethnic group in crude and adjusted analyses. In non-Hispanic whites, no individual polymorphisms were associated with any lipid trait. However, the PON1 A-G haplotype was significantly associated with LDL-C and TC. In non-Hispanic blacks, APOE variant rs7412 and haplotype T-T were strongly associated with LDL-C and TC; whereas, rs5918 of ITGB3 was significantly associated with TG. Several variants and haplotypes of three genes were significantly related to lipids in Mexican Americans: PON1 in relation to HDL-C; APOE and NOS3 in relation to LDL-C; and APOE in relation to TC.
We report the significant associations of blood lipids with variants and haplotypes in APOE, ITGB3, NOS3, and PON1 in the three main race/ethnic groups in the U.S. population using a large, nationally representative and population-based sample survey. Results from our study contribute to a growing body of literature identifying key determinants of plasma lipoprotein concentrations and could provide insight into the biological mechanisms underlying serum lipid and cholesterol concentrations.
The measurements of serum high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) were repeated in 170 apparently healthy farming women once a year for three years (1980-2) to examine the variability of the results within the same individual. Although the mean HDL-C and TC values varied to some extent year by year, higher correlation coefficients between any pair and smaller coefficients of variation in the three annual measurements indicated that the within subject variability of HDL-C and TC is much smaller than that of TG. Variation of HDL-C appeared to be associated with lipidaemia. When the effects of age and menopause were eliminated, it was found that non-normolipidaemic people had wider individual variation both in HDL-C and TG. The importance of TG determination for HDL-C evaluation in health examination is emphasised.
Heritability estimates of general intelligence in adulthood generally range from 75 to 85%, with all heritability due to additive genetic influences, while genetic dominance and shared environmental factors are absent, or too small to be detected. These estimates are derived from studies based on the classical twin design and are based on the assumption of random mating. Yet, considerable positive assortative mating has been reported for general intelligence. Unmodeled assortative mating may lead to biased estimates of the relative magnitude of genetic and environmental factors. To investigate the effects of assortative mating on the estimates of the variance components of intelligence, we employed an extended twin-family design. Psychometric IQ data were available for adult monozygotic and dizygotic twins, their siblings, the partners of the twins and siblings, and either the parents or the adult offspring of the twins and siblings (N = 1314). Two underlying processes of assortment were considered: phenotypic assortment and social homogamy. The phenotypic assortment model was slightly preferred over the social homogamy model, suggesting that assortment for intelligence is mostly due to a selection of mates on similarity in intelligence. Under the preferred phenotypic assortment model, the variance of intelligence in adulthood was not only due to non-shared environmental (18%) and additive genetic factors (44%) but also to non-additive genetic factors (27%) and phenotypic assortment (11%).This non-additive nature of genetic influences on intelligence needs to be accommodated in future GWAS studies for intelligence.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-011-9507-9) contains supplementary material, which is available to authorized users.
Twin-study; Assortative mating; Intelligence; Cognitive ability; Genetic dominance