Similar Value Demonstrated in the Short-Term Outcomes of Superior Capsular Reconstruction and Reverse Shoulder Arthroplasty for Massive Rotator Cuff Tears.

Purpose: The purposes of this study were to investigate the difference in value (benefit to cost ratio) of dermal allograft superior capsular reconstruction (SCR) versus reverse total shoulder arthroplasty (rTSA) for the treatment of massive rotator cuff tears (MRCTs) without arthritis; to compare the patient populations selected for the operations and report pre- and postoperative functional data; and to understand other characteristics of the 2 operations, including operating time, use of institutional resources, and complications. Methods: A retrospective, single-institution analysis during the study period 2014-2019 with MRCT treated with SCR or rTSA by 2 surgeons with complete institutional cost data and minimum 1-year clinical follow-up with American Shoulder and Elbow Surgeons (ASES) score. Value was defined as ΔASES/(total direct costs/$10,000). Results: Thirty patients underwent rTSA and 126 patients SCR during the study period with significant differences noted in patient demographics and tear characteristics between the groups (patients who underwent rTSA were older, less male, had more pseudoparalysis, had greater Hamada and Goutallier scores, and had more proximal humeral migration). Value was 25 and 29 (ΔASES/$10,000) for rTSA and SCR, respectively (P = .7). The total costs of rTSA and SCR were $16,337 and $12,763, respectively (P = .7). Both groups experienced substantial improvements in ASES scores: 42 for rTSA vs 37 for SCR (P = .6). The operative time for SCR was much longer (204 vs 108 minutes, P < .001) but complication rate lower (3% vs 13%, P = .02) versus rTSA. Conclusions: In a single institutional analysis of the treatment of MRCT without arthritis, rTSA and SCR demonstrated similar value; however, the value calculation is highly dependent on institution specific variables and duration of follow-up. The operating surgeons demonstrated different indications in selecting patients for each operation. rTSA had an advantage over SCR in shorter operative time, whereas SCR demonstrated a lower complication rate. Both SCR and rTSA are demonstrated to be effective treatments for MRCT at short-term follow-up. Level of Evidence: III, retrospective comparative study.

Distal biceps tendon repair: cost analysis of single- versus double-incision techniques in an ambulatory surgery center.

Background: The purpose of this study was to compare the cost differences for single- versus double-incision distal biceps repair at an ambulatory surgery center (ASC) given that similar clinical outcomes have been reported between these methods. Methods: A retrospective review of financial and medical records was completed for patients who underwent distal biceps tendon repair over a three-year period at a single private orthopedic practice. Variables analyzed include the cost to the ASC of operative time and the cost of differential surgical supplies, specifically implants and disposable supplies. Results: A total of 10 surgeons performed 104 repairs. Nine surgeons performed repairs through a single incision with use of cortical button or suture anchor fixation, and one surgeon performed transosseous suture fixation through a double-incision approach. The median tourniquet time and procedure length were 31 (interquartile range [IQR] 27-40) and 44 (IQR 39-54) minutes for single-incision repairs and 68 minutes (IQR 61-75) and 110 minutes (IQR 103-113) for double-incision repairs which were significantly different across groups (P < .001, P < .001). The total surgical cost (operative time, implants, and disposables) for single-incision repairs was a median of $758 (IQR 732-803) compared with $606 (IQR 567-629) for double-incision repairs (P < .001). However, the procedure cost with implants (not including disposables) was not significantly different for single- (median [Mdn] = $500 [IQR 475-552]) and double-incision repairs (Mdn $552 [IQR 514-564]) (P = .14) although the procedure cost with disposables (not including implant costs) favored single-incision repairs (Mdn = $478 [IQR 452-523]) over double-incision repairs (Mdn = $606 [IQR 567-629]) (P < .001). Conclusion: In a single surgery center, single-incision distal biceps repairs utilizing an implant were performed more expeditiously than double-incision repairs with a transosseous technique but incurred greater surgical costs. Differences in surgical time cost between the two approaches could be consequential for ASCs and other stakeholders.

Proteomics in non-human primates: utilizing RNA-Seq data to improve protein identification by mass spectrometry in vervet monkeys.

BACKGROUND: Shotgun proteomics utilizes a database search strategy to compare detected mass spectra to a library of theoretical spectra derived from reference genome information. As such, the robustness of proteomics results is contingent upon the completeness and accuracy of the gene annotation in the reference genome. For animal models of disease where genomic annotation is incomplete, such as non-human primates, proteogenomic methods can improve the detection of proteins by incorporating transcriptional data from RNA-Seq to improve proteomics search databases used for peptide spectral matching. Customized search databases derived from RNA-Seq data are capable of identifying unannotated genetic and splice variants while simultaneously reducing the number of comparisons to only those transcripts actively expressed in the tissue. RESULTS: We collected RNA-Seq and proteomic data from 10 vervet monkey liver samples and used the RNA-Seq data to curate sample-specific search databases which were analyzed in the program Morpheus. We compared these results against those from a search database generated from the reference vervet genome. A total of 284 previously unannotated splice junctions were predicted by the RNA-Seq data, 92 of which were confirmed by peptide spectral matches. More than half (53/92) of these unannotated splice variants had orthologs in other non-human primates, suggesting that failure to match these peptides in the reference analyses likely arose from incomplete gene model information. The sample-specific databases also identified 101 unique peptides containing single amino acid substitutions which were missed by the reference database. Because the sample-specific searches were restricted to actively expressed transcripts, the search databases were smaller, more computationally efficient, and identified more peptides at the empirically derived 1 % false discovery rate. CONCLUSION: Proteogenomic approaches are ideally suited to facilitate the discovery and annotation of proteins in less widely studies animal models such as non-human primates. We expect that these approaches will help to improve existing genome annotations of non-human primate species such as vervet.

Novel insights into early neuroanatomical evolution in penguins from the oldest described penguin brain endocast.

Digital methodologies for rendering the gross morphology of the brain from X-ray computed tomography data have expanded our current understanding of the origin and evolution of avian neuroanatomy and provided new perspectives on the cognition and behavior of birds in deep time. However, fossil skulls germane to extracting digital endocasts from early stem members of extant avian lineages remain exceptionally rare. Data from early-diverging species of major avian subclades provide key information on ancestral morphologies in Aves and shifts in gross neuroanatomical structure that have occurred within those groups. Here we describe data on the gross morphology of the brain from a mid-to-late Paleocene penguin fossil from New Zealand. This most basal and geochronologically earliest-described endocast from the penguin clade indicates that described neuroanatomical features of early stem penguins, such as lower telencephalic lateral expansion, a relatively wider cerebellum, and lack of cerebellar folding, were present far earlier in penguin history than previously inferred. Limited dorsal expansion of the wulst in the new fossil is a feature seen in outgroup waterbird taxa such as Gaviidae (Loons) and diving Procellariiformes (Shearwaters, Diving Petrels, and allies), indicating that loss of flight may not drastically affect neuroanatomy in diving taxa. Wulst enlargement in the penguin lineage is first seen in the late Eocene, at least 25 million years after loss of flight and cooption of the flight stroke for aquatic diving. Similar to the origin of avian flight, major shifts in gross brain morphology follow, but do not appear to evolve quickly after, acquisition of a novel locomotor mode. Enlargement of the wulst shows a complex pattern across waterbirds, and may be linked to sensory modifications related to prey choice and foraging strategy.

A large area, silicon photomultiplier-based PET detector module.

The introduction of silicon photomultipliers (SiPM) has facilitated construction of compact, efficient and magnetic field-hardened positron emission tomography (PET) scanners. To take full advantage of these devices, methods for using them to produce large field-of-view PET scanners are needed. In this investigation, we explored techniques to combine two SiPM arrays to form the building block for a small animal PET scanner. The module consists of a 26 × 58 array of 1.5 × 1.5mm2 LYSO elements (spanning 41 × 91mm2) coupled to two SensL SiPM arrays. The SiPMs were read out with new multiplexing electronics developed for this project. To facilitate calculation of event position with multiple SiPM arrays it was necessary to spread scintillation light amongst a number of elements with a small light guide. This method was successful in permitting identification of all detector elements, even at the seam between two SiPM arrays. Since the performance of SiPMs is enhanced by cooling, the detector module was fitted with a cooling jacket, which allowed the temperature of the device and electronics to be controlled. Testing demonstrated that the peak-to-valley contrast ratio of the light detected from the scintillation array was increased by ∼45% when the temperature was reduced from 28 °C to 16 °C. Energy resolution for 511 keV photons improved slightly from 18.8% at 28 °C to 17.8% at 16 °C. Finally, the coincidence timing resolution of the module was found to be insufficient for time-of-flight applications (∼2100 ps at 14 °C). The first use of these new modules will be in the construction of a small animal PET scanner to be integrated with a 3T clinical magnetic resonance imaging scanner.

Molecular prioritization strategies to identify functional genetic variants in the cardiovascular disease-associated expression QTL Vanin-1.

There is now good evidence that non-coding sequence variants are involved in the heritability of many common complex traits. The current 'gold standard' approach for assessing functionality is the in vitro reporter gene assay to assess allelic differences in transcriptional activity, usually followed by electrophoretic mobility shift assays to assess allelic differences in transcription factor binding. Although widely used, these assays have inherent limitations, including the lack of endogenous chromatin context. Here we present a more contemporary approach to assessing functionality of non-coding sequence variation within the Vanin-1 (VNN1) promoter. By combining 'gold standard' assays with in vivo assessments of chromatin accessibility, we greatly increase our confidence in the statistically assigned functional relevance. The standard assays revealed the -137 single nucleotide variant to be functional but the -587 variant to have no functional relevance. However, our in vivo tests show an allelic difference in chromatin accessibility surrounding the -587 variant supporting strong functional potential at both sites. Our approach advances the identification of functional variants by providing strong in vivo biological evidence for function.

Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease.

Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics, SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P = 0.0027), a synonymous LRP1B SNP (rs35821928, P = 0.0001), an UTR-3 RND3 SNP (rs115015150, P = 0.0024) and a missense GCA SNP (rs17783344, P = 0.0020). We replicated the LCT SNP association (P = 0.02) and observed a borderline association for the GCA SNP (P = 0.07) in an independent Australian case-control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover, these four SNP associations could not be replicated in two additional case-control populations from Norway and Finland. These four SNPs, however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of pre-eclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVD-related risk factors.

OS077. The chromosome 2q22 preeclampsia susceptibility locus reveals shared novel risk factors for CVD.

INTRODUCTION: We have previously localized a preeclampsia susceptibility locus on chromosome 2q22 in 34 Australian and New Zealand (AUS/NZL) families. Using an extended number of AUS/NZL families (n=74) we have now performed a comprehensive molecular genetics dissection of this locus. OBJECTIVES: Identify causal genetic risk factors for preeclampsia at the 2q22 risk locus. METHODS: To prioritize positional candidate genes for analysis we used a combination of bioinformatics, SNPing, whole-genome transcriptional profiling and proximity to the peak linkage signal. Prioritized genes were earmarked for exon-centric re-sequencing in 48 founder individuals from the 74 AUS/NZL families. All identified sequence variants were genotyped back in this extended familial cohort. Variants showing the strongest genetic association were genotyped in independent case-control cohorts from Australia (n=1095), Norway (n=3397) and Finland (n=1519), and in a large cohort of Mexican American families rich in quantitative cardiovascular disease (CVD) risk traits. RESULTS: We interrogated 1598 variants from 52 genes and identified four independent SNPs to be significantly associated with preeclampsia susceptibility in the 74 AUS/NZL families. These four SNPs reside in four novel preeclampsia candidate genes: LCT (rs2322659, p=0.002), LRP1B (rs35821928, p=0.0001), RND3 (rs115015150, p=0.002) and GCA (rs17783344, p=0.002). We could only replicate the LCT SNP association in the Australian case-control population (p=0.04, combined p=0.001). These four SNPs are however, significantly associated with several quantitative CVD risk traits such as oxidative stress indicators, inflammatory biomarkers and obesity risk factors. CONCLUSION: Previous independent studies have reported significant genetic associations with total cholesterol levels and obesity risk factors for variants within LCT and LRP1B, respectively. RND3 inhibits the biological activity of a downstream effector protein, ROCK, which is known to affect endothelial dysfunction, inflammation, oxidative stress and vascular re-modeling. Grancalcin (GCA) is known to impact the adhesive properties of fibronectin, a marker for endothelial vascular injury. To our knowledge, data from the current study present for the first time empirical evidence of possible shared genetic risk factors underlying both preeclampsia and other CVD-related traits.

Diverse biological activities of the vascular non-inflammatory molecules - the Vanin pantetheinases.

The Vanin genes are a family that encode pantetheinases involved in recycling Coenzyme A, catalysing the breakdown of intermediate pantetheine to vitamin B5 for reuse in CoA biosynthesis. The role of pantetheinase in this most fundamental of cellular processes, was substantially characterised by the 1970s. The next 20 years saw little further interest in pantetheinase until various genetic studies implicated the Vanin locus in a range of normal and disease phenotypes, and a consequent interest in the other product of pantetheinase activity, cysteamine. This report seeks to bring together the early biochemical studies with recent biological data implicating cysteamine as a regulator of the oxidative state of a cell. Numerous studies now report a role for Vanin in inflammation, oxidative stress, cell migration and numerous diseases including cardiovascular disease.

Eight week exposure to a high sugar high fat diet results in adiposity gain and alterations in metabolic biomarkers in baboons (Papio hamadryas sp.).

BACKGROUND: Baboons (Papio hamadryas Sp.) develop features of the cardiometabolic syndrome and represent a clinically-relevant animal model in which to study the aetiology of the disorder. To further evaluate the baboon as a model for the study of the cardiometabolic syndrome, we developed a high sugar high fat diet and hypothesized that it could be used to induce adiposity gain and affect associated circulating biomarkers. METHODS: We developed a diet enriched with monosaccharides and saturated fatty acids that was composed of solid and liquid energy sources. We provided a group of baboons (n = 9) ad libitum access to this diet for 8 weeks. Concurrently, a control group (n = 6) was maintained with ad libitum access to a low sugar low fat baseline diet and normal water for 8 weeks. Body composition was determined by dual-energy X-ray absorptiometry and circulating metabolic biomarkers were measured using standard methodology before and after the 8 week study period. RESULTS: Neither body composition nor circulating biomarkers changed in the control group. Following the 8 weeks, the intervention group had a significant increase in fat mass (1.71 ± 0.98 vs. 3.23 ± 1.70 kg, p = 0.004), triglyceride (55 ± 13 vs. 109 ± 67 mg/dL, p = 0.006,), and leptin (1.19 ± 1.40 vs. 3.29 ± 2.32 ng/mL, p = 0.001) and a decline in adiponectin concentrations (33530 ± 9744 vs. 23330 ± 7863 ng/mL, p = 0.002). Percentage haemoglobin A1C (4.0 ± 0.3 vs. 6.0 ± 1.4, p = 0.002) also increased in the intervention group. CONCLUSIONS: Our findings indicate that when exposed to a high sugar high fat diet, young adult male baboons develop increased body fat and triglyceride concentrations, altered adipokine concentrations, and evidence of altered glucose metabolism. Our findings are in keeping with observations in humans and further demonstrate the potential utility of this highly clinically-relevant animal model for studying diet-induced metabolic dysregulation.

Quantitative loci regulating plasma levels of gamma glutamyl transferase and albumin and their genetic correlations with cardiovascular risk factors.

gamma Glutamyl transferase (GGT) and albumin (ALB) are two markers of liver function. These two proteins have been associated with non-alcoholic fatty liver disease and cardiovascular disease. The objectives of this study were to explore the genetic factors that influence variation in the plasma levels of GGT and ALB and to evaluate their genetic correlations with cardiovascular risk factors. Baboons from the Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, TX, were used as an animal model. The baboons were fed a standard monkey chow diet ad libitum. Fasting plasma concentrations of GGT, ALB, triglycerides, total cholesterol and LDL cholesterol were measured in 350 pedigreed adult baboons by standard assay procedures. A maximum likelihood-based variance decomposition approach implemented in the computer program SOLAR was used to conduct genetic analyses. The heritabilities of GGT (h(2) = 0.55; P < 0.0001) and ALB (h(2) = 0.42; P < 0.01) were significant. No statistically significant associations were found between GGT and the cardiovascular-related phenotypes. Genetic correlations between ALB and total cholesterol, LDL cholesterol and triglycerides were significant. A QTL (LOD = 2.8) for GGT plasma levels was identified on the baboon homologue of human chromosome 22 between markers D22S304 and D22S280. A QTL (LOD = 2.3) near marker D10S1432 was detected on the baboon homologue of human chromosome 10 for ALB. These results imply that variations in the plasma levels of GGT and ALB are under significant genetic regulation and that a common genetic component influences ALB and cardiovascular risk factor phenotypes.

Association of monocyte chemoattractant protein-1 with adipocyte number, insulin resistance and liver function markers.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is an inflammatory chemokine known to induce adipocyte dedifferentiation and insulin resistance. Inflammation, insulin resistance, and obesity have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). METHODS: Fasting plasma from 43 baboons were assayed for MCP-1, insulin, glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Adipocyte number and volume were measured via biopsies of omental adipose tissue. The homeostatic model assessment method (HOMA) was used to estimate systemic insulin resistance. RESULTS: Sex and age adjusted correlations were significant for MCP-1 with adipocyte number (r = -0.42; P = 0.01), adipocyte volume (r = 0.38; P = 0.02), HOMA (r = 0.45; P = 0.004), ALT (r = 0.46; P = 0.03) and AST (r = 0.45; P = 0.03). CONCLUSIONS: These results suggest that MCP-1 is related with adipocyte dedifferentiation and systemic insulin resistance, thereby potentially contributing to the development of NAFLD.

A nutrition and physical activity intervention promotes weight loss and enhances diet attitudes in low-income mothers of young children.

The purpose of this study was to evaluate a nutrition and physical activity program for reducing body weight and improving nutrition attitudes in mothers of young children. A convenience sample of 114 intervention mothers and 33 comparison mothers was recruited from public health clinics and community centers. Eligibility criteria included Hispanic, African American, or white ethnicity; body mass index of at least 25 kg/m(2); low income (< 200% of the federal poverty index); and youngest child aged 1 to 4 years. For intervention participants, height, weight, percentage of body fat, waist circumference, demographics, nutrition attitudes, and dietary intake were measured at weeks 0 and 8; height, weight, percentage of body fat, and waist circumference were reassessed at 6 months. Overweight mothers in the comparison group provided anthropometric and demographic data at weeks 0 and 8. Changes in anthropometrics, attitudes, and dietary intake were evaluated in intervention mothers. Anthropometric data of intervention vs comparison group mothers were examined. Differences in anthropometrics and attitude scores between weight loss responders (> or = 2.27 kg) and nonresponders (< 2.27 kg) were assessed at week 8. Intervention participants lost weight (x = -2.7 kg; P < .001), whereas comparison mothers gained a slight amount of weight (x = 0.1 kg) by week 8. Weight loss responders had healthier eating attitudes (5.6 vs 5.2; P < .01) and fewer perceived barriers (2.4 vs 2.9; P < .05) than nonresponders postintervention. In conclusion, this dietary and physical activity curriculum is a valuable resource for weight management programs serving low-income women.

A genetic contribution to circulating cytokines and obesity in children.

Cytokines are considered to be involved in obesity-related metabolic diseases. Study objectives are to determine the heritability of circulating cytokine levels, to investigate pleiotropy between cytokines and obesity traits, and to present genome scan results for cytokines in 1030 Hispanic children enrolled in VIVA LA FAMILIA Study. Cytokine phenotypes included monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), leptin, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), transforming growth factor beta 1 (TGF-beta1), C-reactive protein (CRP), regulated upon activation, normal T-cell expressed and secreted (RANTES) and eotaxin. Obesity-related phenotypes included body mass index (BMI), fat mass (FM), truncal FM and fasting serum insulin. Heritabilities ranged from 0.33 to 0.97. Pleiotropy was observed between cytokines and obesity traits. Positive genetic correlations were seen between CRP, leptin, MCP-1 and obesity traits, and negative genetic correlations with adiponectin, ICAM-1 and TGF-beta1. Genome-wide scan of sICAM-1 mapped to chromosome 3 (LOD=3.74) between markers D3S1580 and D3S1601, which flanks the adiponectin gene (ADIPOQ). Suggestive linkage signals were found in other chromosomal regions for other cytokines. In summary, significant heritabilities for circulating cytokines, pleiotropy between cytokines and obesity traits, and linkage for sICAM-1 on chromosome 3q substantiate a genetic contribution to circulating cytokine levels in Hispanic children.

Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon.

Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte samples from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues.

Characterization of ghrelin in pedigreed baboons: evidence for heritability and pleiotropy.

BACKGROUND: Ghrelin is an orexigenic hormone that is produced primarily in the stomach, and stimulates food intake via its receptors situated in the hypothalamus. OBJECTIVE: The purpose of this study was to characterize baboon ghrelin cDNA and investigate the genetic influence on the variation in plasma ghrelin levels in baboons. METHODS AND PROCEDURES: The sample consisted of 376 baboons (263 females, 113 males) from a pedigreed colony at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Ghrelin cDNA was cloned by reverse-transcription polymerase chain reaction (RT-PCR) and sequenced. Real-time RT-PCR was performed to quantify mRNA from the collected tissues. Genetic contribution to plasma ghrelin was estimated using a variance components method implemented in SOLAR. RESULTS: The baboon coding region and predicted amino acid sequence for ghrelin showed 97 and 96% sequence identity with humans, respectively. Maximum expression of ghrelin mRNA was detected in hypothalamus and stomach. Mean +/- s.e. plasma levels of ghrelin were 3,406 +/- 99 pg/ml. A significant heritability was observed for plasma ghrelin (h(2)= 0.25, P < 0.001). A genome-wide scan revealed the evidence of suggestive linkage for a locus affecting plasma ghrelin on chromosome 9q22 (between markers D9S910 and D9S261, logarithm of the odds (LOD) score = 2.3). Significant genetic correlations (P < 0.001) among ghrelin, body weight, and leptin were observed. DISCUSSION: These results indicate a significant genetic component in the variation of plasma ghrelin in baboons and reveal a high degree of similarity between baboon and human ghrelin with respect to its cDNA and its correlation with other obesity traits.

Genetics of variation in adiponectin in pedigreed baboons: evidence for pleiotropic effects on adipocyte volume and serum adiponectin.

To detect and localize the effects of genes influencing variation in adiponectin mRNA and protein levels, we conducted statistical genetic analyses of circulating concentrations of adiponectin and adiponectin (ADIPOQ) mRNA expression in omental adipose tissue in adult, pedigreed baboons (Papio anubis). An omental adipose tissue biopsy and blood sample were collected from 427 baboons from the colony at the Southwest Foundation for Biomedical Research, San Antonio, TX. Total RNA was isolated from adipose tissue and adiponectin mRNA levels were assayed by real-time, quantitative reverse transcriptase-PCR. Adiponectin, insulin, glucose, cholesterol, high-density lipoproteins and triglycerides were measured in fasting serum. Quantitative genetic analyses were conducted for adiponectin mRNA and serum protein using a maximum likelihood-based variance decomposition approach. A genome-wide linkage analysis was conducted using adiponectin mRNA and protein levels as phenotypes. Significant heritability was estimated for ADIPOQ mRNA levels (h2=0.19+/-0.07, P=0.01) and protein levels (h2=0.28+/-0.14, P=0.003). Genetic correlations were found between adiponectin protein and body weight (rho(G)=-0.51, P=0.03), cell volume (rho(G)=-0.73, P=0.04), serum triglycerides (rho(G)=-0.67, P=0.03), and between adiponectin mRNA and glucose (rho(G)=0.93, P<0.01). A logarithm of odds score of 2.9 was found for ADIPOQ mRNA levels on baboon chromosome 4p, which is orthologous to human 6p21. There is a significant genetic component affecting variation in the analyzed traits, and common genes may be influencing adiponectin expression, adipocyte volume, body weight and circulating triglycerides. The region on 6p21 has been linked to diabetes-related phenotypes in human studies.

Adipokine expression is associated with adipocyte volume in baboons.

Baboons show significant variation in body weight and composition, coupled with insulin resistance and phenotypes associated with the metabolic syndrome. An omental adipose tissue biopsy and a fasting blood sample were collected from 40 unrelated adult baboons from the colony at Southwest Foundation for Biomedical Research in San Antonio, TX. Serum was separated for analyses of circulating levels of glucose, insulin, adiponectin, resistin, interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1 or CCL-2). Adipose tissue biopsies were analyzed for cell volume and number. Total RNA was isolated from adipose tissue and adiponectin, resistin, delta-resistin, MCP-1 and IL-6 mRNA abundance were measured using real time, quantitative RT-PCR. Partial correlation coefficients were calculated among adipokine expression, fat tissue cell volume, and circulating levels of proteins. Cell volume was significantly correlated with expression of MCP-1 (r=0.44, p<0.05) and IL-6 mRNA (r=0.47, p<0.01). A step wise regression analysis was conducted with adipose tissue cell volume as dependent variable. The model identified IL-6 mRNA levels in adipose tissue as the only predictor. These observations support the role of IL-6 as a possible paracrine regulator in adipose tissue.

A chromosome 11q quantitative-trait locus influences change of blood-pressure measurements over time in Mexican Americans of the San Antonio Family Heart Study.

Although previous genome scans have searched for quantitative-trait loci (QTLs) influencing variation in blood pressure (BP), few have investigated the rate of change in BP over time as a phenotype. Here, we compare results from genomewide scans to localize QTLs for systolic, diastolic, and mean arterial BPs (SBP, DBP, and MBP, respectively) and for rates of change in systolic, diastolic, and mean arterial BPs (rSBP, rDBP, and rMBP, respectively), with use of the longitudinal data collected about Mexican Americans of the San Antonio Family Heart Study (SAFHS). Significant evidence of linkage was found for rSBP (LOD 4.15) and for rMBP (LOD 3.94) near marker D11S4464 located on chromosome 11q24.1. This same chromosome 11q region also shows suggestive linkage to SBP (LOD 2.23) and MBP (LOD 2.37) measurements collected during the second clinic visit. Suggestive evidence of linkage to chromosome 5 was also found for rMBP, to chromosome 16 for rSBP, and to chromosomes 1, 5, 6, 7, and 21 for the single-time-point BP traits collected at the first two SAFHS clinic visits. We also present results from fine mapping the chromosome 11 QTL with use of SNP-association analysis within candidate genes identified from a bioinformatic search of the region and from whole-genome transcriptional expression data collected from 1,240 SAFHS participants. Our results show that the use of longitudinal BP data to calculate the rate of change in BP over time provides more information than do the single-time measurements, since they reveal physiological trends in the subjects that a single-time measurement could never capture. Further investigation of this region is necessary for the identification of the genetic variation responsible for QTLs influencing the rate of change in BP.

Genome-wide scan of plasma cholecystokinin in baboons shows linkage to human chromosome 17.

OBJECTIVE: Cholecystokinin (CCK) is known to inhibit food intake and is an important signal for controlling meal volume, indicating a possible role in weight regulation. Our objective was to investigate genetic influences on plasma CCK in baboons. RESEARCH METHODS AND PROCEDURES: Subjects were 376 baboons (males = 113, females = 263) from the Southwest National Primate Research Center, housed at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Anthropometric and biochemical parameters were analyzed. Genetic effects on plasma CCK were estimated by the maximum likelihood-based variance components method implemented in the software program SOLAR (Sequential Oligogenic Linkage Analysis Routines). RESULTS: Male baboons (32.7 +/- 6 kg) were much heavier than females (20.2 +/- 4 kg). Similarly, mean (+/- standard deviation) plasma CCK values were also higher in male baboons (13.8 +/- 6 pM) than female baboons (12.5 +/- 4 pM). Significant heritabilities were observed for plasma CCK (0.14 +/- 0.1, p < 0.05), body weight (h2 = 0.62 +/- 0.15, p < 10(-8)), and glucose (h2 = 0.68 +/- 0.17, p < 10(-7)). A genome-wide scan of plasma CCK detected a strong signal for a quantitative trait locus (QTL) on chromosome 17p12-13 [logarithm of the odds (LOD) = 3.1] near marker D17S804. Suggestive evidence of a second QTL was observed on chromosome 4q34-35 (LOD = 2.3) near marker D4S2374. DISCUSSION: A substantial contribution of additive genetic effects to the variation in plasma levels of CCK was demonstrated in baboons. The identification of a QTL for plasma CCK on chromosome 17p is significant, as several obesity-related traits such as BMI, leptin, adiponectin, and acylation stimulating protein have already been mapped to this region.