Duodenal adipose tissue is associated with obesity in baboons (Papio sp) : a novel site of ectopic fat deposition in non-human primates

AimsEctopic fat is a recognized contributor to insulin resistance and metabolic dysfunction, while the role of fat deposition inside intestinal wall tissue remains understudied. We undertook this study to directly quantify and localize intramural fat deposition in duodenal tissue and determine its association with adiposity.MethodsDuodenal tissues were collected from aged (21.21.3years, 19.53.1kg, n=39) female baboons (Papio sp.). Fasted blood was collected for metabolic profiling and abdominal circumference (AC) measurements were taken. Primary tissue samples were collected at the major duodenal papilla at necropsy: one full cross section was processed for hematoxylin and eosin staining and evaluated; a second full cross section was processed for direct chemical lipid analysis on which percentage duodenal fat content was calculated.Results Duodenal fat content obtained by direct tissue quantification showed considerable variability (11.95 +/- 6.93%) and was correlated with AC (r=0.60, p<0.001), weight (r=0.38, p=0.02), leptin (r=0.63, p<0.001), adiponectin (r=-0.32, p<0.05), and triglyceride (r=0.41, p=0.01). The relationship between duodenal fat content and leptin remained after adjusting for body weight and abdominal circumference. Intramural adipocytes were found in duodenal sections from all animals and were localized to the submucosa. Consistent with the variation in tissue fat content, the submucosal adipocytes were non-uniformly distributed in clusters of varying size. Duodenal adipocytes were larger in obese vs. lean animals (106.9 vs. 66.7 mu m(2), p=0.02).Conclusions Fat accumulation inside the duodenal wall is strongly associated with adiposity and adiposity related circulating biomarkers in baboons. Duodenal tissue fat represents a novel and potentially metabolically active site of ectopic fat deposition

Genetic variation and urine cadmium levels: ABCC1 effects in the Strong Heart Family Study

Genetic effects are suspected to influence cadmium internal dose. Our objective was to assess genetic determinants of urine cadmium in American Indian adults participating in the Strong Heart Family Study (SHFS). Urine cadmium levels and genotyped short tandem repeat (STR) markers were available on 1936 SHFS participants. We investigated heritability, including gene-by-sex and smoking interactions, and STR-based quantitative trait locus (QTL) linkage, using a variance-component decomposition approach, which incorporates the genetic information contained in the pedigrees. We also used available single nucleotide polymorphisms (SNPs) from Illumina's Metabochip and custom panel to assess whether promising QTLs associated regions could be attributed to SNPs annotated to specific genes. Median urine cadmium levels were 0.44 μg/g creatinine. The heritability of urine cadmium concentrations was 28%, with no evidence of gene-by-sex or -smoking interaction. We found strong statistical evidence for a genetic locus at chromosome 16 determining urine cadmium concentrations (Logarithm of odds score [LOD] = 3.8). Among the top 20 associated SNPs in this locus, 17 were annotated to ABCC1 (p-values from 0.0002 to 0.02), and attenuated the maximum linkage peak by a ∼40%. Suggestive QTL signals (LOD>1.9) in chromosomes 2, 6, 11, 14, and 19, showed associated SNPs in the genes NDUFA10, PDE10A, PLEKHA7, BAZ1A and CHAF1A, respectively. Our findings support that urinary cadmium levels are heritable and influenced by a QTL on chromosome 16, which was explained by genetic variation in ABCC1. Studies with extended sets of genome-wide markers are needed to confirm these findings and to identify additional metabolism and toxicity pathways for cadmium

Genetic variants and physical activity interact to affect bone density in Hispanic children

Background: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. Methods: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. Results: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p < 0.05). Higher PRS was associated with a lower total body BMD (β = − 0.040 ± 0.009, p = 1.1 × 10− 5) and lumbar spine BMD (β = − 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (β = − 0.015 ± 0.006, p = 0.02; β = 0.008 ± 0.01, p = 0.4, respectively). Discussion: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed. Conclusions: Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children

Arsenic-gene interactions and beta-cell function in the Strong Heart Family Study

We explored arsenic-gene interactions influencing pancreatic beta-cell activity in the Strong Heart Family Study (SHFS). We considered 42 variants selected for associations with either beta-cell function (31 variants) or arsenic metabolism (11 variants) in the SHFS. Beta-cell function was calculated as homeostatic model - beta corrected for insulin resistance (cHOMA-B) by regressing homeostatic model – insulin resistance (HOMA-IR) on HOMA-B and adding mean HOMA-B. Arsenic exposure was dichotomized at the median of the sum of creatinine-corrected inorganic and organic arsenic species measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). Additive GxE models for cHOMA-B were adjusted for age and ancestry, and accounted for family relationships. Models were stratified by center (Arizona, Oklahoma, North Dakota and South Dakota) and meta-analyzed. The two interactions between higher vs. lower arsenic and SNPs for cHOMA-B that were nominally significant at P < 0.05 were with rs10738708 (SNP overall effect −3.91, P = 0.56; interaction effect with arsenic −31.14, P = 0.02) and rs4607517 (SNP overall effect +16.61, P = 0.03; interaction effect with arsenic +27.02, P = 0.03). The corresponding genes GCK and TUSC1 suggest oxidative stress and apoptosis as possible mechanisms for arsenic impacts on beta-cell function. No interactions were Bonferroni-significant (1.16 × 10−3). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic β-cell endocrine function, but were not Bonferroni-significant

Genetic analysis of hsCRP in American Indians: The Strong heart family study

Background Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations. Methods The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses. Results CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10−20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10−7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10−4. Conclusion In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children

Context: Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. Objective: We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. Methods: We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4–19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry. Results: Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 10− 9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 × 10− 8), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 10− 8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P < 9 × 10− 7). Conclusions: We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P < 3 × 10−14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10−9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10−6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10−10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation

Genome-wide association study identifying novel variant for fasting insulin and allelic heterogeneity in known glycemic loci in Chilean adolescents: The Santiago Longitudinal Study

Background: The genetic underpinnings of glycemic traits have been understudied in adolescent and Hispanic/Latino (H/L) populations in comparison to adults and populations of European ancestry. Objective: To identify genetic factors underlying glycemic traits in an adolescent H/L population. Methods: We conducted a genome-wide association study (GWAS) of fasting glucose (FG) and fasting insulin (FI) in H/L adolescents from the Santiago Longitudinal Study. Results: We identified one novel variant positioned in the CSMD1 gene on chromosome 8 (rs77465890, effect allele frequency = 0.10) that was associated with FI (β = −0.299, SE = 0.054, p = 2.72×10−8) and was only slightly attenuated after adjusting for body mass index z-scores (β = −0.252, SE = 0.047, p = 1.03×10−7). We demonstrated directionally consistent, but not statistically significant results in African and Hispanic adults of the Population Architecture Using Genomics and Epidemiology Consortium. We also identified secondary signals for two FG loci after conditioning on known variants, which demonstrate allelic heterogeneity in well-known glucose loci. Conclusion: Our results exemplify the importance of including populations with diverse ancestral origin and adolescent participants in GWAS of glycemic traits to uncover novel risk loci and expand our understanding of disease aetiology

Genetic determinants of metabolic biomarkers and their associations with cardiometabolic traits in Hispanic/Latino adolescents

Background: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers—adiponectin, leptin, ghrelin, and orexin—and their associations with CMD risk factors. Methods: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. Results: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. Conclusions: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers. Impact: This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents.Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts.Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits — The Hispanic/Latino Anthropometry Consortium

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification