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The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.

Individual differences in biological ageing (i.e., the rate of physiological response to the passage of time) may be due in part to genotype-specific variation in gene action. However, the sources of heritable variation in human age-related gene expression profiles are largely unknown. We have profiled genome-wide expression in peripheral blood mononuclear cells from 1240 individuals in large families and found 4472 human autosomal transcripts, representing ∼4349 genes, significantly correlated with age. We identified 623 transcripts that show genotype by age interaction in addition to a main effect of age, defining a large set of novel candidates for characterization of the mechanisms of differential biological ageing. We applied a novel SNP genotype × age interaction test to one of these candidates, the ubiquilin-like gene UBQLNL , and found evidence of joint cis -association and genotype by age interaction as well as trans -genotype by age interaction for UBQLNL expression. Both UBQLNL expression levels at recruitment and cis genotype are associated with longitudinal cancer risk in our study cohort.

Several measures of lipoprotein phenotype are significant predictors of cardiovascular risk. Although such lipoprotein phenotypes are under strong genetic control, it is not clear to what extent they are controlled by the same - and by different - genes and whether these relationships may be altered in different dietary environments. Therefore, we measured six lipoprotein traits (three LDL traits - LDLC and apoB concentrations and LDL size - and three HDL traits - HDLC and apoA1 concentrations and HDL size) on each of three diets differing in level of fat and cholesterol. In bivariate analyses, all but two metabolically related trait pairs were genetically correlated, though none were completely correlated, implying additive genetic effects by both pleiotropic and unique genes. In comparing genetic correlations for the same pair of traits across diet, we detected evidence of diet effects on genetic control of these metabolically related traits; specifically, increasing level of dietary cholesterol was associated with a significant decrease in the genetic correlation of apoA1 with HDL size, and a significant increase in the genetic correlations of LDL size with LDLC and apoB. The results suggest a complex network of genes affecting lipoprotein metabolism: the genes may exert both unique and pleiotropic effects; the genes may exert detectable effects in many or only in specific dietary environments.

The clinical spectrum of tooth-eruption disorders includes both syndromic and nonsyndromic problems ranging from delayed eruption to a complete failure of eruption. A defect in the differential apposition/resorption mechanism in alveolar bone can cause conditions, such as tooth ankylosis, primary failure of eruption (PFE), failure of eruption caused by inadequate arch length, and canine impaction. As our knowledge of the molecular events underlying normal tooth eruption has increased, so too has our understanding of clinical eruption disorders. The recent finding that one gene, parathyroid hormone receptor 1 ( PTH1R ), is causative for familial cases of PFE suggests that other disturbances in tooth eruption may have a genetic etiology. In this report, we evaluated the current terminology (ie, ankylosis, PFE, secondary retention) used to describe nonsyndromic eruption disorders, in light of this genetic discovery. We observed that some patients previously diagnosed with ankylosis were subsequently found to have alterations in the PTH1R gene, indicating the initial misdiagnosis of ankylosis and the necessary reclassification of PFE. We further investigated the relationship of the PTH1R gene, by using a network pathway analysis, to determine its connectivity to previously identified genes that are critical to normal tooth eruption. We found that PTH1R acts in a pathway with genes, such as parathyroid hormone related peptide ( PTHrP ), that have been shown to be important in bone remodeling, hence eruption, in a rat model. Thus, recent advances in our understanding of normal and abnormal tooth eruption should allow us in the future to develop a clinical nomenclature system that is determined more by the molecular genetic cause of the eruption failures versus the clinical appearance of the various eruption disorders.

A great deal of research into the determinants of bone strength has unequivocally demonstrated that variation in bone strength is highly subject to genetic factors. Increasing attention in skeletal genetic studies is being paid to indicators of bone quality that complement studies of BMD, including studies of the genetic control of bone geometry. The aim of this study is to investigate the degree to which normal population-level variation in femoral midshaft geometry in a population of pedigreed baboons (Papio hamadryas spp.) can be attributed to the additive effect of genes. Using 110 baboons (80 females, 30 males), we 1) characterize normal variation in midshaft geometry of the femur with regard to age and sex, and 2) determine the degree to which the residual variation is attributable to additive genetic effects. Cross-sectional area (CSA), minimum (I(MIN)) and maximum (I(MAX)) principal moments of inertia, and polar moment of inertia (J) were calculated from digitized images of transverse midshaft sections. Maximum likelihood-based variance decomposition methods were used to estimate the mean effects of age, sex, and genes. Together age and sex effects account for approximately 56% of the variance in each property. In each case the effect of female sex is negative and that of age is positive, although of a lower magnitude than the effect of female sex. Increased age is associated with decreased mean cross-sectional geometry measures in the oldest females. Residual h(2) values range from 0.36 to 0.50, reflecting genetic effects accounting for 15% to 23% of the total phenotypic variance in individual properties. This study establishes the potential of the baboon model for the identification of genes that regulate bone geometric properties in primates. This model is particularly valuable because it allows for experimental designs, environmental consistency, availability of tissues, and comprehensive assessments of multiple integrated bone phenotypes that are not possible in human populations. The baboon is of particular importance in genetic studies, because it provides results that are likely highly relevant to the human condition due to the phylogenetic proximity of baboons to humans.

Both lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity, a biomarker of inflammation, and concentration of its primary associated lipoprotein, LDL, are correlated with adverse coronary outcomes. We previously reported a quantitative trait locus (QTL) corresponding to HSA2p24.3-p23.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-cholesterol (LDL-C) concentration in baboons fed a basal diet. Here, our goal was to locate pleiotropic QTLs influencing both traits in the same baboons fed a high-cholesterol, high-fat (HCHF) diet, and to assess whether shared genetic effects on these traits differ between diets. We assayed Lp-PLA(2) activity and LDL-C concentration in 683 baboons fed the HCHF diet. We used a bivariate maximum likelihood-based variance components approach in whole-genome linkage screens to locate a QTL [logarithm of odds (LOD) = 3.13, genome-wide P = 0.019] corresponding to HSA19q12-q13.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-C levels in the HCHF diet. We additionally found significant evidence of genetic variance in response to diet for Lp-PLA(2) activity (P = 0.0017) and for LDL-C concentration (P = 0.00001), revealing a contribution of genotype-by-diet interaction to covariation in these two traits. We conclude that the pleiotropic QTLs detected at 2p24.3-p23.2 and 19q12-q13.2 on the basal and HCHF diets, respectively, exert diet-specific effects on covariation in Lp-PLA(2) activity and LDL-C concentration.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), the major portion of which is bound to low-density lipoprotein, is an independent biomarker of cardiovascular disease risk. To search for common genetic determinants of variation in both Lp-PLA(2) activity and LDL cholesterol (LDL-C) concentration, we assayed these substances in serum from 679 pedigreed baboons. Using a maximum likelihood-based variance components approach, we detected significant evidence for a QTL affecting Lp-PLA(2) activity (LOD=2.79, genome-wide P=0.039) and suggestive evidence for a QTL affecting LDL-C levels (LOD=2.16) at the same location on the baboon ortholog of human chromosome 2p. Because we also found a significant genetic correlation between the two traits (rho(G)=0.50, P0.00001), we conducted bivariate linkage analyses of Lp-PLA(2) activity and LDL-C concentration. These bivariate analyses improved the evidence (LOD=3.19, genome-wide P=0.015) for a QTL at the same location on 2p, corresponding to the human cytogenetic region 2p24.3-p23.2. The QTL-specific correlation between the traits (rho(Q)=0.62) was significantly different from both zero and 1 (P[rho(Q)=0]=0.047; P[rho(Q)=1]=0.022), rejecting the hypothesis of co-incident linkage and consistent with incomplete pleiotropy at this locus. We conclude that polymorphisms at the QTL described in this study exert some genetic effects that are shared between Lp-PLA(2) activity and LDL-C concentration.

Circulating soluble intercellular adhesion molecule-1 (sICAM-1) is a biochemical marker of inflammation. We performed variance-components-based quantitative genetic analyses in SOLAR of sICAM-1 in 1170 individuals from Mexican American families in the San Antonio Family Heart Study. The trait is heritable ( h 2 =0.50±0.06, P −6 ). Multipoint linkage analysis using a ∼10-cM microsatellite map revealed a region on Chromosome 19p near marker D19S586 showing strong evidence of linkage for sICAM-1 (empirically adjusted univariate-equivalent LOD=4.95), coincident with the structural gene ICAM1 . This region has been identified previously as a QTL for inflammatory, autoimmune, and metabolic syndrome traits. There is significant evidence ( P =0.0023) of locus heterogeneity for sICAM-1 in this sample: a subset of pedigrees contributes most of the linkage signal for sICAM-1 on Chromosome 19, suggesting a logical focus for future genetic dissection of the trait.

Because obesity leads to a state of chronic, low-grade inflammation and oxidative stress, we hypothesized that the contribution of genes to variation in a biomarker of these two processes may be influenced by the degree of adiposity. We tested this hypothesis using samples from the San Antonio Family Heart Study that were assayed for activity of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a marker of inflammation and oxidative stress. Using an approach to model discrete genotypexenvironment (GxE) interaction, we assigned individuals to one of two discrete diagnostic states (or "adiposity environments"): nonobese or obese, according to criteria suggested by the World Health Organization. We found a genomewide maximum LOD of 3.39 at 153 cM on chromosome 1 for Lp-PLA(2). Significant GxE interaction for Lp-PLA(2) at the genomewide maximum (P=1.16 x 10(-4)) was also found. Microarray gene-expression data were analyzed within the 1-LOD interval of the linkage signal on chromosome 1. We found two transcripts--namely, for Fc gamma receptor IIA and heat-shock protein (70 kDa)--that were significantly associated with Lp-PLA(2) (P

Construction of genetic linkage maps for nonhuman primate species provides information and tools that are useful for comparative analysis of chromosome structure and evolution and facilitates comparative analysis of meiotic recombination mechanisms. Most importantly, nonhuman primate genome linkage maps provide the means to conduct whole genome linkage screens for localization and identification of quantitative trait loci that influence phenotypic variation in primate models of common complex human diseases such as atherosclerosis, hypertension, and diabetes. In this study we improved a previously published baboon whole genome linkage map by adding more loci. New loci were added in chromosomal regions that did not have sufficient marker density in the initial map. Relatively low heterozygosity loci from the original map were replaced with higher heterozygosity loci. We report in detail on baboon chromosomes 5, 12, and 18 for which the linkage maps are now substantially improved due to addition of new informative markers.

Background Inflammation and oxidative stress are processes that mark early metabolic abnormalities in vascular diseases. Objectives We explored the effects of a high-fat, high-cholesterol (HFHC) diet on vascular responses in baboons and the potential response-attenuating effects of vitamin E and coenzyme Q(10) (CoQ(10)) supplementation. Design We used a longitudinal design by subjecting 21 baboons (Papio hamadryas) to sequential dietary challenges. Results After being maintained for 3 mo on a baseline diet (low in fat and cholesterol), 21 baboons were challenged with an HFHC diet for 7 wk. The serum C-reactive protein (CRP) concentrations did not change. Subsequent supplementation of the HFHC diet with the antioxidant vitamin E (250, 500, or 1000 IU/kg diet) for 2 wk reduced serum CRP concentrations from 0.91 +/- 0.02 to 0.43 +/- 0.06 mg/dL. Additional supplementation with CoQ(10) (2 g/kg diet) further reduced serum CRP to approximately 30% of baseline (0.28 +/- 0.03 mg/dL; P = 0.036 compared with the HFHC diet). Introduction of the HFHC diet itself significantly decreased serum P-selectin (from 48.8 +/- 7.2 to 32.9 +/- 3.7 ng/dL, P = 0.02) and von Willebrand factor (from 187.0 +/- 10.1 to 161.9 +/- 9.0%, P = 0.02) concentrations. However, neither vitamin E alone nor vitamin E plus CoQ(10) significantly altered the serum concentrations of P-selectin or von Willebrand factor. Conclusions Dietary supplementation with vitamin E alone reduces the baseline inflammatory status that is indicated by the CRP concentration in healthy adult baboons. Cosupplementation with CoQ(10), however, significantly enhances this antiinflammatory effect of vitamin E.

Primitive mammalian molar morphology is characterised in part by a ridge of enamel that encircles the entire base of the molar crown, the cingulum. Many higher primates have reduced the cingulum, but often retain remnant features on the lingual surface of maxillary molars and the labial surface of mandibular molars. Two of these remnants in cercopithecoid primates, the interconulus and interconulid, are morphologically similar though the interconulus is found on maxillary molars and the interconulid is located on mandibular molars. Here we present results from a quantitative genetic analysis of expression of these two traits in a sample of 479 modern savannah baboons from the Southwest Foundation for Biomedical Research (SFBR). We found that both traits are significantly heritable with little variance attributable to other factors, such as sex, age, and molar crown size. Bivariate analyses yielded point estimates for genetic correlations between left and right side expression that are either equal to or not significantly different from 1.0; meaning that 100% of their additive genetic variance is due to the effects of the same gene or suite of genes. By contrast, our estimates of the genetic correlations between maxillary and mandibular expression of this trait range from 0.52 to 0.72, suggesting that 28–52% of the additive genetic variance in the interconulus and interconulid is due to the effects of shared genes. These results demonstrate that intra-arch expression is characterised by complete pleiotropy whereas inter-arch expression is caused by incomplete pleiotropy. These results are relevant to dental developmental studies as well as paleontological analyses of the evolution of the primate dentition.

The effects of aging are evident in multiple organ systems, tissues, cell types, and molecules; all complex phenotypes affected by multiple shared and unique environmental factors and genes, which makes identifying the role of genetics in human aging difficult. Researchers have used yeast, nematodes, fruit flies, and mice to search for genes that influence the aging process. Given the phylogenetic distance and anatomic and physiologic dissimilarities of these organisms from humans, directly extrapolating these results to our species is problematic. However, nonhuman primates have a high degree of genetic, anatomic and physiologic similarity with humans and, thus, they may assist in the detection, characterization, and identification of genetic and environmental influences on human aging. Our goal is to demonstrate that effects of genes on variation in lifespan, a surrogate measure of aging, can be detected in a nonhuman primate species. Using variance component analysis, heritability of age at death was estimated to be 0.23±0.08 ( P =0.0003) in 674 baboons from the Southwest Foundation for Biomedical Research (SFBR). This research demonstrates that lifespan is under partial genetic control. Given these findings, we believe that the baboon has potential as a model of human aging.

We fed 634 baboons three diets to assess the separate effects of increasing dietary fat and cholesterol intakes on three independent measures of HDL phenotype: concentrations of HDL cholesterol and apoAI, and size distributions of HDL cholesterol. Increasing dietary fat significantly increased concentrations of HDL cholesterol and apoAI (both, P

Summary Common disorders with genetic susceptibilities involve the action of multiple genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An important route to the disentangling of this complex inheritance is through the study of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol (HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle–size classes and the concentrations and proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigrees implicated two loci, one on chromosome 8 and the other on chromosome 15, that influence a component of HDL-C—namely, unesterified HDL 2a -C. Multivariate analyses of multiple HDL phenotypes and simultaneous multilocus analysis of the quantitative-trait loci identified permit further characterization of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, whereas the chromosome 15 locus appears to influence both HDL-C concentration and distribution of cholesterol among HDL particle sizes.

Leptin is the peptide product of the OB gene, which is associated with obesity in some strains of mice. Because dyslipidemias are frequently associated with obesity, we have begun to characterize the pathways connecting these related traits. In this investigation we tested for correlation of HDL phenotype measures with leptin concentrations using data from 1159 participants in the San Antonio Family Heart Study, a study of risk factors for cardiovascular disease in Mexican Americans living in and around San Antonio, Texas. In a subset of 288 unrelated individuals, we tested for correlation of leptin with nine different measures of HDL phenotype and found that only three were significantly related. However, stepwise regression analysis suggested that only two measures, HDL triglyceride concentrations (HDL-TG) and the proportion of apo A-I on HDL particles larger than HDL3 (Large HDL-apo A-I), were independently correlated with leptin. Because obesity and HDL phenotypes are both under strong genetic control, we conducted a trivariate genetic analysis, using the entire data set, to test the hypothesis that the phenotypic correlations were due to the effects of shared genes (i.e., pleiotropy). Heritabilities for the three traits were estimated to be 0.47 for leptin, 0.46 for HDL-TG, and 0.46 for Large HDL-apo A-I. Results from the genetic analyses revealed that the phenotypic correlation of leptin with HDL-TG was nongenetic (i.e., shared environment), while the phenotypic correlation with Large HDL-apo A-I was due to pleiotropy (i.e., shared genes). These results confirmed the result derived from the subset of unrelated individuals that the two measures of HDL are independently correlated with leptin. To our knowledge, this is the first report of a relationship between leptin and any aspect of lipoprotein phenotype. A better understanding of the genes responsible for this relationship may provide a molecular explanation for the aggregation of atherogenic phenotypes, such as diabetes, obesity, and dyslipoproteinemia.

Previous studies have shown that the inverse relationship between HDL cholesterol (HDL-C) and triglyceride (TG) levels, risk factors for cardiovascular disease, is due largely to the effects of shared genes. HDL-C and TG are also known to be related to endogenous sex hormone levels, however the nature of the relationships is unclear. The objective of this study is to ascertain the extent to which these relationships are determined by shared genes. We conducted a multivariate quantitative genetic analysis of HDL-C, TG, dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) in 635 people from 27 pedigrees participating in the San Antonio Family Heart Study. Heritabilities (h2) and genetic and environmental correlations (rho G and rho E) were estimated simultaneously by maximum likelihood methods. All four traits showed significant (P0.05) heritabilities: h2HDL-C = 0.38, h2TG = 0.54, h2DHEAS = 0.43, h2SHBG = 0.26. Significant genetic correlations were detected between HDL and each of the other traits: rho G(HDL-TG) = -0.56, rho G(HDL-DHEAS) = 0.23 and rho G(HDL-SHBG) = -0.56. However, there were no significant genetic correlations between TG and either measure of sex hormones. Thus, at least three separate groups of genes influence HDL-C levels in Mexican Americans: one group that has pleiotropic effects on HDL and TG, one group influences both HDL-C and SHBG and a third influences both HDL-C and DHEAS.