Objective
Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging‐associated insulin resistance is due to ...increased adiposity or other age‐related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition.
Methods
Cohorts of mice aged 4 to 8 months (“young”) and 18 to 27 months (“aged”) exhibiting similar body composition were characterized for glucose metabolism on chow and high‐fat diets. Insulin sensitivity was assessed by hyperinsulinemic‐euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic‐euglycemic clamps.
Results
In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic‐euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high‐fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males.
Conclusions
This study demonstrates that in addition to altered body composition, adiposity‐independent mechanisms also contribute to aging‐associated insulin resistance in mice and humans.
Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.
To investigate the genetic regulation of serum E2 and E1 in men.
Genome-wide association study in 11,097 men of European ...origin from nine epidemiological cohorts.
Genetic determinants of serum E2 and E1 levels.
Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.
Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up ...and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the ...pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci ...for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.
Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority ...of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation.
Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic ...insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10
) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
Abstract
Context
Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D).
Objective
To facilitate use of these SNPs in future ...genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans.
Design, Setting, and Participants
A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L–GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans.
Results
Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L–GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method.
Conclusions
Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L–GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.
Diabetes is characterized by metabolic dysregulation. Metabolomics captures interactions of cellular processes and environmental exposures to promote disease and can improve mechanistic understanding ...to identify clinically relevant targets. However, use is limited by cost and sample availability. To facilitate investigation, machine learning approaches were used in the Insulin Resistance Atherosclerosis Family Study (n=943 Mexican Americans) with empiric metabolites (Metabolon HD4) and GWAS data to generate genetically regulated metabolite estimation models for broad application. 950 metabolites were heritable. Ridge and LASSO regression had cross validated correlation >0.1 for 448 metabolites. In an independent set, LASSO (enforcing sparsity) outperformed Ridge (full polygenic architecture) regression. Estimation was extended to the GUARDIAN Consortium (n∼4377) to assess the association of genetically predicted metabolites with glucose homeostasis and adiposity. Multiple associations (FDR P<0.05) were observed. For glucose homeostasis, mannose, which predicts diabetes development, was inversely associated with glucose effectiveness (P=7.1E-3) . For adiposity, urate was positively associated with BMI and waist circumference, capturing lifestyle contributions. In addition, three uncharacterized metabolites were associated with measures of adiposity (P=0.014-3.1E-6) suggesting this approach could contribute to metabolite characterization.
In conclusion, we have developed algorithms for estimating 448 metabolites using genetic data that had good performance in an independent dataset. Estimation models were used to assess association with glucose homeostasis and adiposity highlighting known and novel associations and demonstrating utility. Future work will expand genetic coverage to include rare variants and phenotypic associations to further characterize metabolic dysregulation.
Disclosure
N.Allred: None. L.J.Raffel: None. T.A.Buchanan: None. R.M.Watanabe: None. J.I.Rotter: None. L.E.Wagenknecht: None. C.D.Langefeld: None. H.K.Im: None. H.C.Ainsworth: None. X.Guo: None. A.W.Mackay: None. F.Nyasimi: None. O.Melia: None. Y.Liang: None. D.W.Bowden: None. K.Taylor: None.
Funding
R01DK118062
Objective
Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes ...were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma‐glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome‐wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.
Methods
Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi‐cohort GWAS of individuals of Mexican American ancestry was performed. Single‐nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta‐analysis.
Results
In the PNPLA3 gene, rs4823173 (P = 3.44 × 10−10), rs2896019 (P = 7.29 × 10−9), and rs2281135 (P = 8.73 × 10−9) were significantly associated with AST levels. Although not genome‐wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10−8, P = 1.98 × 10−7, and P = 1.81 × 10−7, respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome‐wide significant associations were found for GGT.
Conclusions
PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.
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