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Obesity is associated with a chronic low inflammatory state characterized by elevated levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the cysteine-cysteine (CC) chemokine family and is increased in obesity. The purpose of this study was to identify loci regulating serum MCP-1 in obese Hispanic children from the Viva La Familia Study. A genome-wide association (GWA) analysis was performed in 815 children, ages 4-19 years, using genotypes assayed with the Illumina HumanOmni1-Quad v1.0 BeadChips. All analyses were performed in SOLAR using a linear regression-based test under an additive model of allelic effect, while accounting for the relatedness of family members via a kinship variance component. The strongest association for MCP-1 levels was found with a non-synonymous single nucleotide polymorphism (SNP), rs12075, resulting in an amino acid substitution (Asp42Gly) in the Duffy antigen receptor for chemokines (DARC) gene product (minor allele frequency=43.6%, p=1.3 × 10(-21)) on chromosome 1. Four other DARC SNPs were also significantly associated with MCP-1 levels (p<10(-16)-10(-6)). The Asp42Gly variant was associated with higher levels of MCP-1 and accounted for approximately 10% of its variability. In addition, MCP-1 levels were significantly associated with SNPs in chemokine receptor 3 (CCR3) and caspase recruitment domain family, member 9 (CARD9). In summary, the association of the DARC Asp42Gly variant with MCP-1 levels replicates previous GWA results substantiating a potential role for DARC in the regulation of pro-inflammatory cytokines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10(-5)), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥1.2) with MS. Furthermore, we examined 29 single-nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, α transducing 3 (GNAT3, 11 SNPs) gene, located within the 1-LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk (RR) = 1.6 and P = 0.004, RR = 1.7, respectively) and several other related traits. These two variants explained ~18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately threefold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans.

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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Cigarette smoking is a risk factor for type 2 diabetes. Genetic variants in the nicotinic acetylcholine receptor (nAChR) genes have been associated with smoking phenotypes and are likely to influence diabetes. Although each single variant may have only a minor effect, the joint contribution of multiple single nucleotide polymorphisms (SNPs) to the occurrence of disease may be larger. In this study, we conducted a gene-family analysis to investigate the joint impact of 61 tag SNPs in 7 nAChRs genes on insulin resistance and type 2 diabetes in 3,665 American Indians recruited by the Strong Heart Family Study. Results show that although multiple SNPs showed marginal individual association with insulin resistance and type 2 diabetes, only a few can pass adjustment for multiple testing. However, a gene-family analysis considering the joint impact of all 61 SNPs reveals significant association of the nAChR gene family with both insulin resistance and type 2 diabetes (both P < 0.0001), suggesting that genetic variants in the nAChR genes jointly contribute to insulin resistance and type 2 diabetes among American Indians. The effects of these genetic variants on insulin resistance and diabetes are independent of cigarette smoking per se.

Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations.

Background: In 2002 Takamatsu and co-workers described the human DSCR9 gene and observed that it was transcriptionally active in human testicular tissue, but no protein was identified as a product of this transcript. Similar results were obtained in chimpanzee tissue. This gene has not been detected in species other than primates, suggesting that DSCR9 is exclusively found in these mammals., Results: We report evidence of DSCR9 expression in placenta, testis and kidney of baboon (Papio hamadryas). We used primers specific for DSCR9 to amplify transcripts through reverse transcription (RT) coupled to polymerase chain reaction (PCR). Furthermore, PCR was used to amplify the complete DSCR9 gene from genomic DNA from three baboons. We amplified and sequenced five overlapping segments that were assembled into the 3284 bp baboon DSCR9 gene, including the putative promoter and the entire transcriptional unit (5'-UTR, CDS and 3'-UTR)., Conclusions: The baboon DSCR9 gene is highly similar to the human counterpart. The isolated transcripts from baboon tissues (placenta, testis and kidney) of three different baboons correspond to the human orthologous gene.

The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of ω-3 and ω-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10(-28) and 10(-5)). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10(-75) and 10(-7)) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity.

Background and Purpose: We hypothesized that the P-selectin (SELP) gene, localized to a region on chromosome 1q24, pleiotropically contributes to increased blood pressure and cerebral atrophy. We tested this hypothesis by performing genetic correlation analyses for 13 mRNA gene expression measures from P-selectin and 11 other genes located in 1q24 region and three magnetic resonance imaging derived indices of cerebral integrity., Methods: The subject pool consisted of 369 (219F; aged 28-85, average = 47.1 ± 12.7 years) normally aging, community-dwelling members of large extended Mexican-American families. Genetic correlation analysis decomposed phenotypic correlation coefficients into genetic and environmental components among 13 leukocyte-based mRNA gene expressions and three whole-brain and regional measurements of cerebral integrity: cortical gray matter thickness, fractional anisotropy of cerebral white matter, and the volume of hyperintensive WM lesions., Results: From the 13 gene expressions, significant phenotypic correlations were only found for the P- and L-selectin expression levels. Increases in P-selectin expression levels tracked with decline in cerebral integrity while the opposite trend was observed for L-selectin expression. The correlations for the P-selectin expression were driven by shared genetic factors, while the correlations with L-selectin expression were due to shared environmental effects., Conclusion: This study demonstrated that P-selectin expression shared a significant variance with measurements of cerebral integrity and posits elevated P-selectin expression levels as a potential risk factor of hypertension-related cerebral atrophy.

Serum sodium concentration is the clinical index of systemic water balance. Although disordered water balance is common and morbid, little is known about genetic effects on serum sodium concentration at the population level. Prior studies addressed only participants of European descent and either failed to demonstrate significant heritability or showed only modest effect. We investigated heritability of serum sodium concentration in large cohorts reflecting a range of races/ethnicities, including the Framingham Heart Study (FHS, non-Hispanic Caucasian), the Heredity and Phenotype Intervention Heart Study (HAPI, Amish Caucasian), the Jackson Heart Study (JHS, African American), the Strong Heart Family Study (SHFS, American Indian), and the Genetics of Kidney Disease in Zuni Indians Study (GKDZI, American Indian). Serum sodium was transformed for the osmotic effect of glucose, and participants with markedly elevated glucose or reduced estimated glomerular filtration rate (eGFR) were excluded. Using a standard variance components method, incorporating covariates of age, glucose, and eGFR, we found heritability to be high in African American and American Indian populations and much more modest in non-Hispanic Caucasian populations. Estimates among females increased after stratification on sex and were suggestive among female participants in FHS (0.18 ± 0.12, P = 0.057) and male participants in JHS (0.24 ± 0.16, P = 0.067) and statistically significant among female participants in JHS (0.44 ± 0.09, P = 1 × 10 ⁻⁷), SHFS (0.59 ± 0.05, P = 9.4 × 10⁻⁴⁶), and GKDZI (0.46 ± 0.15, P = 1.7 × 10⁻⁴), and male participants in HAPI (0.18 ± 0.12, P = 0.03) and SHFS (0.67 ± 0.07, P = 5.4 × 10⁻²⁶). Exclusion of diuretic users increased heritability among females and was significant in all cohorts where data were available. In aggregate, these data strongly support the heritability of systemic water balance and underscore sex and ethnicity-specific effects.

Background: Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance., Methods: We searched PubMed to identify genome linkage analyses of renal function traits in humans, such as estimated glomerular filtration rate (GFR), albuminuria, serum creatinine concentration and creatinine clearance. We contacted authors for numerical data and extracted information from individual studies. We applied the GSMA nonparametric approach to combine results across 14 linkage studies for GFR, 11 linkage studies for albumin creatinine ratio, 11 linkage studies for serum creatinine and 4 linkage studies for creatinine clearance., Results: No chromosomal region reached genome-wide statistical significance in the main analysis which included all scans under each phenotype; however, regions on Chromosomes 7, 10 and 16 reached suggestive significance for linkage to two or more phenotypes. Subgroup analyses by disease status or ethnicity did not yield additional information., Conclusions: While heterogeneity across populations, methodologies and study designs likely explain this lack of agreement, it is possible that linkage scan methodologies lack the resolution for investigating complex traits. Combining family-based linkage studies with genome-wide association studies may be a powerful approach to detect private mutations contributing to complex renal phenotypes.

Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.

A theory of aging holds that senescence is caused by a dysregulated nuclear factor kappa B (NF-κB) signal transduction network (STN). We adopted a systems genetics approach in our study of the NF-κB STN. Ingenuity Pathways Analysis (IPA) was used to identify gene/gene product interactions between NF-κB and the genes in our transcriptional profiling array. Principal components factor analysis (PCFA) was performed on a sub-network of 19 genes, including two initiators of the toll-like receptor (TLR) pathway, myeloid differentiation primary response gene (88) (MyD88) and TIR (Toll/interleukin-1 receptor)-domain-containing adapter-inducing interferon-β (TRIF). TLR pathways are either MyD88-dependent or TRIF-dependent. Therefore, we also performed PCFA on a subset excluding the MyD88 transcript, and on another subset excluding two TRIF transcripts. Using linkage analysis we found that each set gave rise to at least one factor with a logarithm of the odds (LOD) score greater than 3, two on chromosome 15 at 15q12 and 15q22.2, and another two on chromosome 17 at 17p13.3 and 17q25.3. We also found several suggestive signals (2

The current genetic and recombination maps of the cat have fewer than 3,000 markers and a resolution limit greater than 1 Mb. To complement the first-generation domestic cat maps, support higher resolution mapping studies, and aid genome assembly in specific areas as well as in the whole genome, a 15,000(Rad) radiation hybrid (RH) panel for the domestic cat was generated. Fibroblasts from the female Abyssinian cat that was used to generate the cat genomic sequence were fused to a Chinese hamster cell line (A23), producing 150 hybrid lines. The clones were initially characterized using 39 short tandem repeats (STRs) and 1,536 SNP markers. The utility of whole-genome amplification in preserving and extending RH panel DNA was also tested using 10 STR markers; no significant difference in retention was observed. The resolution of the 15,000(Rad) RH panel was established by constructing framework maps across 10 different 1-Mb regions on different feline chromosomes. In these regions, 2-point analysis was used to estimate RH distances, which compared favorably with the estimation of physical distances. The study demonstrates that the 15,000(Rad) RH panel constitutes a powerful tool for constructing high-resolution maps, having an average resolution of 40.1 kb per marker across the ten 1-Mb regions. In addition, the RH panel will complement existing genomic resources for the domestic cat, aid in the accurate re-assemblies of the forthcoming cat genomic sequence, and support cross-species genomic comparisons., (Copyright © 2012 S. Karger AG, Basel.)

The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates-organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin-in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.

Background: Despite overwhelming evidence that major depression is highly heritable, recent studies have localized only a single depression-related locus reaching genome-wide significance and have yet to identify a causal gene. Focusing on family-based studies of quantitative intermediate phenotypes or endophenotypes, in tandem with studies of unrelated individuals using categorical diagnoses, should improve the likelihood of identifying major depression genes. However, there is currently no empirically derived statistically rigorous method for selecting optimal endophentypes for mental illnesses. Here, we describe the endophenotype ranking value, a new objective index of the genetic utility of endophenotypes for any heritable illness., Methods: Applying endophenotype ranking value analysis to a high-dimensional set of over 11,000 traits drawn from behavioral/neurocognitive, neuroanatomic, and transcriptomic phenotypic domains, we identified a set of objective endophenotypes for recurrent major depression in a sample of Mexican American individuals (n = 1122) from large randomly selected extended pedigrees., Results: Top-ranked endophenotypes included the Beck Depression Inventory, bilateral ventral diencephalon volume, and expression levels of the RNF123 transcript. To illustrate the utility of endophentypes in this context, each of these traits were utlized along with disease status in bivariate linkage analysis. A genome-wide significant quantitative trait locus was localized on chromsome 4p15 (logarithm of odds = 3.5) exhibiting pleiotropic effects on both the endophenotype (lymphocyte-derived expression levels of the RNF123 gene) and disease risk., Conclusions: The wider use of quantitative endophenotypes, combined with unbiased methods for selecting among these measures, should spur new insights into the biological mechanisms that influence mental illnesses like major depression., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cell-mediated transgenesis, based on somatic cell nuclear transfer (SCNT), provides the opportunity to shape the genetic make-up of cattle. Bovine primary fetal fibroblasts, commonly used cells for SCNT, have a limited lifespan, and complex genetic modifications that require sequential transfections can be challenging time and cost-wise. To overcome these limitations, SCNT is frequently used to rejuvenate the cell lines and restore exhausted growth potential. We have designed a construct to be used in a 2-step cassette exchange experiment. Our transgene contains a puromycin resistance marker gene and an enhanced green fluorescence protein (EGFP) expression cassette, both driven by a strong mammalian promoter, and flanked by loxP sites and sequences from the bovine β-casein locus. Several transgenic cell lines were generated by random insertion into primary bovine cell lines. Two of these original cell lines were rederived by SCNT and new primary cells, with the same genetic makeup as the original donors, were established. While the original cell lines were puromycin-resistant and had a characteristic EGFP expression profile, all rejuvenated cell lines were sensitive to puromycin, and displayed varied EGFP expression, indicative of various degrees of silencing. When the methylation states of individual CpG sites within the transgene were analyzed, a striking increase in transgene-specific methylation was observed in all rederived cell lines. The results indicate that original transgenic donor cells and their rejuvenated derivatives may not be equivalent and differ in the functionality of their transgene sequences.

Quantitative ultrasound (QUS) traits are correlated with bone mineral density (BMD), but predict risk for future fracture independent of BMD. Only a few studies, however, have sought to identify specific genes influencing calcaneal QUS measures. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing normal variation in QUS traits. QUS measures were collected from a total of 719 individuals (336 males and 383 females) from the Fels Longitudinal Study who have been genotyped and have at least one set of QUS measurements. Participants ranged in age from 18.0 to 96.6 years and were distributed across 110 nuclear and extended families. Using the Sahara ® bone sonometer, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI) were collected from the right heel. Variance components based linkage analysis was performed on the three traits using 400 polymorphic short tandem repeat (STR) markers spaced approximately 10 cM apart across the autosomes to identify QTL influencing the QUS traits. Age, sex, and other significant covariates were simultaneously adjusted. Heritability estimates (h²) for the QUS traits ranged from 0.42 to 0.57. Significant evidence for a QTL influencing BUA was found on chromosome 11p15 near marker D11S902 (LOD = 3.11). Our results provide additional evidence for a QTL on chromosome 11p that harbors a potential candidate gene(s) related to BUA and bone metabolism.

Genes play an important role in lifelong skeletal health. Genes that influence bone building during childhood have the potential to affect bone health not only throughout childhood but also into adulthood. Given that peak bone mass is a significant predictor of adult fracture risk, it is imperative that the genetic underpinnings of the normal pediatric skeleton are uncovered. In a sample of 600 10-year-old children from 144 families in the Fels Longitudinal Study, we examined radiographic cortical bone measures of the second metacarpal. Morphometic measurements included bone width, medial and lateral cortical thicknesses, and the calculated cortical index representing the amount of cortex relative to bone width. We then conducted genome-wide linkage analysis on these traits in 440 genotyped individuals using the SOLAR analytic platform. Significant quantitative trait loci (QTL) were identified for bone traits on three separate chromosomes. A QTL for medial cortical thickness was localized to chromosome 2p25.2. A QTL for lateral cortical thickness was localized to chromosomal region 3p26.1-3p25.3. Finally, a QTL detected for cortical index was localized to the 17q21.2 chromosomal region. Each region contains plausible candidate genes for pediatric skeletal health, some of which confirm findings from studies of adulthood bone, and for others represent novel candidate genes for skeletal health., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts., Methods and Results: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities., Conclusions: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

Objectives: The thickness of the brain's cortical gray matter (GM) and the fractional anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory with age. The two measures are positively correlated and may be modulated by common biological mechanisms. We employed four types of genetic analyses to localize individual genes acting pleiotropically upon these phenotypes., Methods: Whole-brain and regional GM thickness and FA values were measured from high-resolution anatomical and diffusion tensor MR images collected from 712, Mexican American participants (438 females, age = 47.9 ± 13.2 years) recruited from 73 (9.7 ± 9.3 individuals/family) large families. The significance of the correlation between two traits was estimated using a bivariate genetic correlation analysis. Localization of chromosomal regions that jointly influenced both traits was performed using whole-genome quantitative trait loci (QTL) analysis. Gene localization was performed using SNP genotyping on Illumina 1M chip and correlation with leukocyte-based gene-expression analyses. The gene-expressions were measured using the Illumina BeadChip. These data were available for 371 subjects., Results: Significant genetic correlation was observed among GM thickness and FA values. Significant logarithm of odds (LOD ≥ 3.0) QTLs were localized within chromosome 15q22-23. More detailed localization reported no significant association (p < 5·10(-5)) for 1565 SNPs located within the QTLs. Post hoc analysis indicated that 40% of the potentially significant (p ≤ 10(-3)) SNPs were localized to the related orphan receptor alpha (RORA) and NARG2 genes. A potentially significant association was observed for the rs2456930 polymorphism reported as a significant GWAS finding in Alzheimer's disease neuroimaging initiative subjects. The expression levels for RORA and ADAM10 genes were significantly (p < 0.05) correlated with both FA and GM thickness. NARG2 expressions were significantly correlated with GM thickness (p < 0.05) but failed to show a significant correlation (p = 0.09) with FA., Discussion: This study identified a novel, significant QTL at 15q22-23. SNP correlation with gene-expression analyses indicated that RORA, NARG2, and ADAM10 jointly influence GM thickness and WM-FA values.

Genetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.

Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 (∼14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452&#95;139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452&#95;139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children.

Variation in anthropometric measurements due to sexual dimorphism can be the result of genotype by sex interactions (G×S). The purpose of this study was to examine the sex-specific genetic architecture in anthropometric measurements in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Maximum likelihood-based variance components decomposition methods, implemented in SOLAR, were used for G×S analyses. Anthropometric measurements included BMI, waist circumference (WC), waist/height ratio, percent body fat (%BF), and subscapular and triceps skinfolds. Except for WC, mean values of all phenotypes were significantly different in men and women (P < 0.05). All anthropometric measures were significantly heritable (P < 0.001). In a preliminary analysis not allowing for G×S interaction, evidence of linkage was detected between markers D19S414 and D19S220 on chromosome 19 for WC (logarithm of odds (lod) = 3.5), %BF (lod = 1.7), BMI (lod = 2.4), waist/height ratio (lod = 2.5), subscapular (lod = 2.1), and triceps skinfolds (lod = 1.9). In subsequent analyses which allowed for G×S interaction, linkage was again found between these traits and the same two markers on chromosome 19 with significantly improved lod scores for: WC (lod = 4.5), %BF (lod = 3.8), BMI (lod = 3.5), waist/height ratio (lod = 3.2), subscapular (lod = 3.0), and triceps skinfolds (lod = 2.9). These results support the evidence of a G×S interaction in the expression of genetic effects resulting in sexual dimorphism in anthropometric phenotypes and identify the chromosome 19q12-13 region as important for adiposity-related traits in Alaskan Eskimos.

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits., Competing Interests: The authors have declared that no competing interests exist.

The genetic architecture of the craniofacial complex has been the subject of intense scrutiny because of the high frequency of congenital malformations. Numerous animal models have been used to document the early development of the craniofacial complex, but few studies have focused directly on the genetic underpinnings of normal variation in the human craniofacial complex. This study examines 80 quantitative traits derived from lateral cephalographs of 981 participants in the Fels Longitudinal Study, Wright State University, Dayton, Ohio. Quantitative genetic analyses were conducted using the Sequential Oligogenic Linkage Analysis Routines analytic platform, a maximum-likelihood variance components method that incorporates all familial information for parameter estimation. Heritability estimates were significant and of moderate to high magnitude for all craniofacial traits. Additionally, significant quantitative trait loci (QTL) were identified for 10 traits from the three developmental components (basicranium, splanchnocranium, and neurocranium) of the craniofacial complex. These QTL were found on chromosomes 3, 6, 11, 12, and 14. This study of the genetic architecture of the craniofacial complex elucidates fundamental information of the genetic architecture of the craniofacial complex in humans., (Copyright © 2011 Wiley-Liss, Inc.)

Objective: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians., Methods: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota., Results: Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10⁻⁶) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10⁻⁵). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21., Conclusions: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10., (© 2010 Wiley-Liss, Inc.)

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.

Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P= 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.

Background: The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes., Study Design: A community-based participatory research approach was used to recruit family members of individuals with kidney disease., Setting & Participants: The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs. PREDICTOR OUTCOMES & MEASUREMENTS: Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was >or=0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria., Results: Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes., Limitations: Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions., Conclusions: Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and cardiovascular disease. The study design serves as a paradigm for the conduct of research in relatively isolated, endogamous, underserved populations., (Copyright (c) 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The aim of this 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 1,214 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 the 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 LDL(2) (intermediate) and 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, HDL size and measures of adiposity, and 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.

Plasma levels of aspartate aminotransferase (AST), a liver enzyme, are elevated in patients with visceral obesity. This study examined whether adipocyte volume is under the influence of genetic factors and evaluated its genetic correlations with AST. Fasting plasma levels of 344 pedigreed baboons from the Southwest National Primate Research Center in San Antonio, TX, USA, were assayed for AST. Adipocyte volume was measured using biopsies of omental adipose tissue. Adipocyte volume, body weight, and plasma AST were heritable. Genetic correlations between the measured adiposity-related phenotypes and AST were significant. A quantitative trait locus (LOD score 3.2) for adipocyte volume was identified on the baboon homolog of human chromosome 6 near marker D6S1028. These results suggest that omental adipocyte volume is under genetic regulation and that shared genetic factors influence adiposity-associated traits and AST.

Context: Chemerin is a new adipokine associated with obesity and the metabolic syndrome. Gene expression levels of chemerin were elevated in the adipose depots of obese compared with lean animals and was markedly elevated during differentiation of fibroblasts into mature adipocytes., Objective: The objective of the study was to identify factors that affect the regulation and potential function of chemerin using a genetics approach., Design, Setting, Patients, and Intervention: Plasma chemerin levels were measured in subjects from the San Antonio Family Heart Study, a large family-based genetic epidemiological study including 1354 Mexican-American individuals. Individuals were randomly sampled without regard to phenotype or disease status., Main Outcome Measures: A genome-wide association analysis using 542,944 single-nucleotide polymorphisms in a subset of 523 of the same subjects was undertaken. The effect of chemerin on angiogenesis was measured using human endothelial cells and interstitial cells in coculture in a specially formulated medium., Results: Serum chemerin levels were found to be highly heritable (h(2) = 0.25; P = 1.4 x 10(-9)). The single-nucleotide polymorphism showing strongest evidence of association (rs347344; P = 1.4 x 10(-6)) was located within the gene encoding epithelial growth factor-like repeats and discoidin I-like domains 3, which has a known role in angiogenesis. Functional angiogenesis assays in human endothelial cells confirmed that chemerin significantly mediated the formation of blood vessels to a similar extent as vascular endothelial growth factor., Conclusion: Here we demonstrate for the first time that plasma chemerin levels are significantly heritable and identified a novel role for chemerin as a stimulator of angiogenesis.

Many forensic disciplines require experts to judge whether two complex patterns are sufficiently similar to conclude that both originate from the same source. Studies in this area have revealed that there are a number of factors that affect perception and judgment and that decisions are subjective and susceptible to extraneous influences (such as emotional context, expectation, and motivation). Some studies have shown that the same expert examiner, examining the same prints but within different contexts, may reach different and contradictory decisions. However, such effects are not always present; some examiners seem more susceptible to such influences than do others--especially when the pattern matching is "hard to call" and when the forensic experts are not aware that they are being observed in an experimental study. Studying forensic examiners can contribute to our understanding of expertise and decision making, as well as have implications for forensic science and other areas of expertise.

Chronic kidney disease (CKD) is an important public health problem in American Indian populations. Recent research has identified associations of polymorphisms in the myosin heavy chain type II isoform A (MYH9) gene with hypertensive CKD in African-Americans. Whether these associations are also present among American Indian individuals is unknown. To evaluate the role of genetic polymorphisms in the MYH9 gene on kidney disease in American Indians, we genotyped 25 SNPs in the MYH9 gene region in 1,119 comparatively unrelated individuals. Four SNPs failed, and one SNP was monomorphic We inferred haplotypes using seven SNPs within the region of the previously described E haplotype using Phase v2.1. We studied the association between 20 MYH9 SNPs with kidney function (estimated glomerular filtration rate, eGFR) and CKD (eGFR\60 ml/min/1.73 m(2) or renal replacement therapy or kidney transplant) using age-, sex- and center-adjusted models and measured genotyped within the variance component models. MYH9 SNPs were not significantly associated with kidney traits in additive or recessive genetic adjusted models. MYH9 haplotypes were also not significantly associated with kidney outcomes. In conclusion, common variants in MYH9 polymorphisms may not confer an increased risk of CKD in American Indian populations. Identification of the actual functional genetic variation responsible for the associations seen in African-Americans will likely help to clarify the lack of replication of this gene in our population of American Indians.

Objective: Genome-wide association studies that compare the statistical association between thousands of DNA variations and a human trait have detected 958 loci across 127 different diseases and traits. However, these statistical associations only provide evidence for genomic regions likely to harbor a causal gene(s) and do not directly identify such genes. We combined gene variation and expression data in a human cohort to identify causal genes., Research Design and Methods: Global gene transcription activity was obtained for each individual in a large human cohort (n = 1,240). These quantitative transcript data were tested for correlation with genotype data generated from the same individuals to identify gene expression patterns influenced by the variants., Results: Variant rs8050136 lies within intron 1 of the FTO gene on chromosome 16 and marks a locus strongly associated with type 2 diabetes and obesity and widely replicated across many populations. We report that genetic variation at this locus does not influence FTO gene expression levels (P = 0.38), but is strongly correlated with expression of RBL2 (P = 2.7 x 10(-5)), approximately 270,000 base pairs distant to FTO., Conclusions: These data suggest that variants at FTO influence RBL2 gene expression at large genetic distances. This observation underscores the complexity of human transcriptional regulation and highlights the utility of large human cohorts in which both genetic variation and global gene expression data are available to identify disease genes. Expedient identification of genes mediating the effects of genome-wide association study-identified loci will enable mechanism-of-action studies and accelerate understanding of human disease processes under genetic influence.

Pregnancy is a complex physiological condition, and the growth hormone (GH)-related hormones produced in the placenta, which emerged during the evolution of primates, are thought to play an important metabolic role in pregnancy that is not yet fully understood. The aim of this study was to identify the genes and transcription products of the GH family in baboon (Papio hamadryas) and to assess these in relation to the evolution of this gene family. GH-related transcripts were amplified using total RNA from placental tissue, by reverse transcription coupled to polymerase chain reaction (RT-PCR). Three different GH-related transcripts were identified in baboon placental tissue, with two encoding chorionic somatomammotropins (CSH) and one the placental variant of GH (GH-2). The CSH transcripts showed some minor allelic variation, and a splice variant of CSH-C that retains its in-frame third intron. Gene sequences for GH-1 (probably representing the GH gene expressed primarily in the pituitary gland), GH-2 and the two CSHs were identified in the baboon genomic database, together with a CSH-related pseudogene. Phylogenetic analysis of the baboon GH-related sequences, together with those of a related Old World monkey, macaque, and ape outgroup (human), showed the equivalence of the genes in baboon and macaque, and revealed evidence for several episodes of rapid adaptive evolution. Many of the substitutions seen during the evolution of these placental proteins have occurred in the receptor-binding sites, especially site 2, contrasting with the strong conservation of the hydrophobic core.

Background: Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain., Objective: The aim was to identify and characterize the effects of MC4R variants in Hispanic children., Design: MC4R was resequenced in 376 parents, and the identified single nucleotide polymorphisms (SNPs) were genotyped in 613 parents and 1016 children from the Viva la Familia cohort. Measured genotype analysis (MGA) tested associations between SNPs and phenotypes. Bayesian quantitative trait nucleotide (BQTN) analysis was used to infer the most likely functional polymorphisms influencing obesity-related traits., Results: Seven rare SNPs in coding and 18 SNPs in flanking regions of MC4R were identified. MGA showed suggestive associations between MC4R variants and body size, adiposity, glucose, insulin, leptin, ghrelin, energy expenditure, physical activity, and food intake. BQTN analysis identified SNP 1704 in a predicted micro-RNA target sequence in the downstream flanking region of MC4R as a strong, probable functional variant influencing total, sedentary, and moderate activities with posterior probabilities of 1.0. SNP 2132 was identified as a variant with a high probability (1.0) of exerting a functional effect on total energy expenditure and sleeping metabolic rate. SNP rs34114122 was selected as having likely functional effects on the appetite hormone ghrelin, with a posterior probability of 0.81., Conclusion: This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure.

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.

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.

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.

Hyperuricemia is associated with the metabolic syndrome, gout, renal and cardiovascular disease (CVD). American Indians have high rates of CVD and 25% of individuals in the strong heart family study (SHFS) have high serum uric acid levels. The aim of this study was to investigate the genetic determinants of serum uric acid variation in American Indian participants of the SHFS. A variance component decomposition approach (implemented in SOLAR) was used to conduct univariate genetic analyses in each of three study centers and the combined sample. Serum uric acid was adjusted for age, sex, age x sex, BMI, estimated glomerular filtration rate, alcohol intake, diabetic status and medications. Overall mean +/- SD serum uric acid for all individuals was 5.14 +/- 1.5 mg/dl. Serum uric acid was found to be significantly heritable (0.46 +/- 0.03 in all centers, and 0.39 +/- 0.07, 0.51 +/- 0.05, 0.44 +/- 0.06 in Arizona, Dakotas and Oklahoma, respectively). Multipoint linkage analysis showed significant evidence of linkage for serum uric acid on chromosome 11 in the Dakotas center [logarithm of odds score (LOD) = 3.02] and in the combined sample (LOD = 3.56) and on chromosome 1 (LOD = 3.51) in the combined sample. A strong positional candidate gene in the chromosome 11 region is solute carrier family22, member 12 (SLC22A12) that encodes a major uric acid transporter URAT1. These results show a significant genetic influence and a possible role for one or more genes on chromosomes 1 and 11 on the variation in serum uric acid in American Indian populations.

Objective: Physical inactivity poses a major risk for obesity and chronic disease, and is influenced by both genetic and environmental factors. However, the genetic association between physical activity (PA) level and obesity is not well characterized. Our aims were to: (i) estimate the extent of additive genetic influences on physical activity while adjusting for household effects; and (ii) determine whether physical activity and adiposity measures share common genetic effects., Subjects: The sample included 521 (42 % male) adult relatives, 18-86 years of age, from five large families in the Southwest Ohio Family Study., Design: Sport, leisure and work PA were self-reported (Baecke Questionnaire of Habitual Physical Activity). Total body and trunk adiposity, including percentage body fat (%BF), were measured using dual-energy X-ray absorptiometry. Abdominal visceral and subcutaneous adipose tissue mass were measured using MRI., Results: Heritabilities for adiposity and PA traits, and the genetic, household and environmental correlations among them, were estimated using maximum likelihood variance components methods. Significant genetic effects (P < 0.05) were found for sport (h2 = 0.26) and leisure PA (h2 = 0.17). Significant (P < 0.05) household effects existed for leisure PA (c2 = 0.25). Sport PA had a negative genetic correlation with central adiposity measurements adjusted for height (rhoG > |-0.40|). Sport and leisure PA had negative genetic correlations with %BF (rhoG > |-0.46|)., Conclusions: The results suggest that the association of sport and leisure PA with lower adiposity is due, in part, to a common genetic inheritance of both reduced adiposity and the predisposition to engage in more physical activity.

Background: Population studies have demonstrated an important role of social, behavioral, and environmental factors in blood pressure (BP) levels. Accounting for the genetic interaction of these factors may help to identify common BP susceptibility alleles., Methods and Results: We studied the interaction of additive genetic effects and behavioral (physical activity, smoking, alcohol use) and socioeconomic (education) factors on BP in approximately 3600 American Indian participants of the Strong Heart Family Study, using variance component models. The mean and SD of resting systolic and diastolic BPs were 123 + or - 17 and 76 + or - 11 mm Hg, respectively. We detected evidence for distinct genetic effects on diastolic BP among ever smokers compared with never smokers (P = 0.01). For alcohol intake, we observed significant genotype-by-environment interactions on diastolic (rhog = 0.10, P = 0.0003) and on systolic BPs (rhog = 0.59, P = 0.0008) among current drinkers compared with former or never drinkers. We also detected genotype-by-physical activity interactions on diastolic BP (rhog = 0.35, P = 0.0004). Finally, there was evidence for distinct genetic effects on diastolic BP among individuals with less than high school education compared with those with 12 or more years of education (rhog = 0.41, P = 0.02)., Conclusions: Our findings suggest that behavioral and socioeconomic factors can modify the genetic effects on BP phenotypes. Accounting for context dependent factors may help us to better understand the complexities of the gene effects on BP and other complex phenotypes with high levels of genetic heterogeneity.

American Indians have a higher prevalence of albuminuria than the general population, likely resulting from a combination of environmental and genetic risk factors. To localize gene regions influencing variation in urinary albumin-to-creatinine ratio, we performed a linkage analysis and explored gene-by-diabetes, -hypertension, and -obesity interactions in a large cohort of American Indian families. We recruited >3600 individuals from 13 American Indian tribes from three centers (Arizona, North and South Dakota, and Oklahoma). We performed multipoint variance component linkage analysis in each center as well as in the entire cohort after controlling for center effects. We used two modeling strategies: Model 1 incorporated age, gender, and interaction terms; model 2 also controlled for diabetes, BP, body mass index, HDL, LDL, triglycerides, and smoking status. We evaluated interactions with diabetes, hypertension, and obesity using additive, interaction-specific linkage and stratified analyses. Loci suggestive for linkage to urinary albumin-to-creatinine ratio included 1q, 6p, 9q, 18q, and 20p. Gene-by-diabetes interaction was present with a quantitative trait locus specific to the diabetic stratum in the Dakotas isolated on 18q21.2 to 21.3 using model 1 (logarithm of odds = 3.3). Gene-by-hypertension interaction was present with quantitative trait loci specific to the hypertensive stratum in the Dakotas on 7q21.11 using model 1 (logarithm of odds = 3.4) and 10q25.1 using model 2 (logarithm of odds = 3.3). These loci replicate findings from multiple other genome scans of kidney disease phenotypes with distinct populations and are worthy of further study.

Rhabdomyolysis is a serious, potentially life threatening condition that can develop unexpectedly under supervised training conditions. Here we present a case of exertional rhabdomyolysis occurring in a healthy, fit 18-year-old placekicker following a supervised practice session led by the team's strength and conditioning coach. The day after this session, the player experienced extreme pain and dark urine and sought treatment at a local emergency department. Hospitalization resulted in a diagnosis of rhabdomyolysis based on myoglobinuria, muscle pain, and extremely elevated circulating creatine kinase values (>130,000 IU x L(-1)). Following eight days of hospitalization with intravenous fluids, the patient recovered without complications. This case illustrates that rhabdomyolysis can occur after strenuous exercise in the absence of dehydration in otherwise conditioned and healthy athletes.

Social science scholarship has tended to focus more on the causes than the consequences of miscarriages of justice. Within the literature on consequences, the overwhelming emphasis has been on individual consequences: psychological and material impacts on the wrongly convicted individual and, in some cases, other indirectly impacted individuals such as family members of the wrongly convicted and victims of the true perpetrator's future crimes. Some attention has been devoted to social harms, the impact of miscarriages of justice on the broader society within which they are situated, such as the undermining of the legitimacy of the criminal justice system. This paper focuses on what are called here cultural consequences of miscarriages of justice: the way in which some high-profile miscarriages of justice can shape the public's beliefs about some of the most basic "facts" about crime, such as the nature, prevalence, or even existence of certain categories of crime and the types of individual who tend to perpetrate particular types of crime. In this way, the paper argues, miscarriages of justice may have hitherto underexplored consequences: reshaping, based on false premises, the public's belief about the very nature of crime itself. This paper discusses three cases studies of miscarriages of justice that for varying periods of time created widespread false beliefs about the nature of crime in large segments of the public. The paper concludes by noting that the "righting" of these false beliefs was in most cases fortuitous. This suggests that unexposed miscarriages of justice may still be shaping popular beliefs about the nature of crime, and aspects of the public's current conception of crime may yet be based on false premises., ((c) 2009 John Wiley & Sons, Ltd.)

For a century, the matching of images of fingerprints has been used for forensic identification. Despite that history, there have been no published, peer-reviewed studies directly examining the extent to which people can correctly match fingerprints to one another. The results of three experiments using naïve undergraduates to match images of fingerprints are reported. The results demonstrate that people can identify fingerprints quite well, and that matching accuracy can vary as a function of both source finger type and image similarity.

Background: Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients., Methods: We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors., Results: Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P=0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups., Conclusions: These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies., (2009 Massachusetts Medical Society)