To investigate the associations of serum amyloid A (SAA) protein and soluble tumor necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2) with diabetic retinopathy (DR) in Hispanics.
Prospective, ...nonrandomized, cross-sectional, family-based observational cohort study.
A total of 473 Hispanic type II diabetic subjects in families ascertained via proband with DR.
Levels of SAA, sTNF-R1, and sTNF-R2 were measured with enzyme-linked immunosorbent assay. Diabetic retinopathy was assessed by fundus photography and graded using modified Airlie House classification.
Levels of SAA, sTNF-R1, and sTNF-R2 to severity of DR with and without covariates.
A direct association of sTNF-R1 (2.37±0.13, 2.15±0.09, 3.09±0.24, 3.25±0.46, 5.02±0.61 ng/ml; P < 0.0001) and sTNF-R2 (6.04±0.20, 6.25±0.52, 7.96±0.70, 8.14±1.13, 14.83±1.68 ng/ml; P < 0.0001) was found for no DR, mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR, respectively. These associations remained significant after adjusting for age, gender, body mass index, glycosylated hemoglobin, diabetes duration, systolic blood pressure, and serum creatinine (P < 0.0001 for sTNF-R1 and P=0.0004 for sTNF-R2). A similar pattern was observed when we adjusted for urinary albumin:creatinine ratio in place of serum creatinine (P=0.005 for sTNF-R1 and P=0.02 for sTNF-R2).
Levels of sTNF-R1 and sTNF-R2 are highly correlated with the severity of DR, suggesting that inflammation and insulin resistance may play a critical role in the development of DR. These may be useful biomarkers for DR, aiding in etiologic studies and possibly identifying at-risk patients for active intervention.
Context: Despite the importance of dihydrotestosterone in androgen action, polymorphisms in the genes for the two isoforms of 5α-reductase (SRD5A1 and SRD5A2) have not been evaluated as risk factors ...for polycystic ovary syndrome (PCOS).
Objective: The objective of the study was to test the hypothesis that haplotypes in the SRD5A1 and SRD5A2 genes are risk factors for PCOS and the severity of hirsutism in affected women.
Design: PCOS and control subjects were genotyped for seven single-nucleotide polymorphisms in SRD5A1 and eight single-nucleotide polymorphisms in SRD5A2. Haplotypes were determined and tested for association with PCOS diagnosis and component phenotypes.
Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the general surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles.
Participants: A total of 287 White women with PCOS and 187 controls participated.
Main Measurements: SRD5A1 and SRD5A2 genotype, quantitative hirsutism score, and hormonal and metabolic phenotypes were assessed.
Results: Haplotypes within both genes were associated with PCOS risk. The Leu allele of the Val89Leu variant in SRD5A2 was associated with protection against PCOS; this allele is known to modestly reduce 5α-reductase activity. Haplotypes in SRD5A1 but not SRD5A2 were also associated with the degree of hirsutism in affected women.
Conclusions: This study presents genetic evidence suggesting an important role of both isoforms of 5α-reductase in the pathogenesis of PCOS. That only SRD5A1 haplotypes were associated with hirsutism suggests that only this isoform is important in the hair follicle.
Using ~60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), ...with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By projection of principal components (PCs) of ancestry to samples from the HapMap phase III and the Human Genome Diversity Panel (HGDP), we show the first two PCs quantify the Caucasian, African, and Native American origins, while the third and fourth PCs bring out an axis that aligns with known South-to-North geographic location of HGDP Native American samples and further separates MESA Mexican versus Central/South American samples along the same axis. Using k-means clustering computed from the first four PCs, we define four subgroups of the MESA Hispanic cohort that show close agreement with self-identification, labeling the clusters as primarily Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. To demonstrate our recommendations for genetic analysis in the MESA Hispanic cohort, we present pooled and stratified association analysis of triglycerides for selected SNPs in the LPL and TRIB1 gene regions, previously reported in GWAS of triglycerides in Caucasians but as yet unconfirmed in Hispanic populations. We report statistically significant evidence for genetic association in both genes, and we further demonstrate the importance of considering population substructure and genetic heterogeneity in genetic association studies performed in the United States Hispanic population.
Reduction in insulin clearance plays an important role in the compensatory response to insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding ...of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic clearance rate of insulin (MCRI). We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD) project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004), insulin secretion (P = 0.0002), alanine aminotransferase (P = 0.0045), total fat mass (P = 0.014), and diabetes (P = 0.03). MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035). These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in insulin clearance.
Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide ...polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.
Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined ...the association of genetic variants within ±500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs3782735 variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality.
Although statins are efficacious for lowering low-density lipoprotein cholesterol, there is wide interindividual variation in response. We tested the extent to which combined effects of common ...alleles of LDLR and HMGCR can contribute to this variability.
Haplotypes in the LDLR 3'-untranslated region (3-UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial (335 blacks and 609 whites). LDLR haplotype 5 (LDLR L5) was associated with smaller simvastatin-induced reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (P=0.0002 to 0.03) in blacks but not whites. The combined presence of LDLR L5 and previously described HMGCR haplotypes in blacks was associated with significantly attenuated apolipoprotein B reduction (-22.4+/-1.5%, N=89) compared with both noncarriers (-30.6+/-1.5%, N=78, P=0.0001) and carriers of either individual haplotype (-28.2+/-1.1%, N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of low-density lipoprotein receptor surface expression using lymphoblast cell lines (P=0.03).
We have identified a common LDLR 3-UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by the greater prevalence of these combined haplotypes in blacks.
Context: Hypoadiponectinemia has emerged as an independent risk factor for type 2 diabetes and cardiovascular disease. Although associations of adiponectin with central obesity and insulin resistance ...have been reported, very little data are available from studies using detailed measures of insulin sensitivity (SI) and/or body fat distribution in ethnic groups at high risk for metabolic disease.
Objective: The aim of the study was to identify the correlates of adiponectin in 1636 nondiabetic Hispanics and African-Americans.
Design: A cross-sectional analysis of participants in the Insulin Resistance Atherosclerosis Family Study was conducted. SI was determined from frequently sampled iv glucose tolerance tests with minimal model analysis. Subcutaneous and visceral adipose tissues (SAT, VAT, respectively) were determined with computed tomography. Triglyceride, high-density lipoprotein, C-reactive protein, and adiponectin were measured in fasting samples. Generalized estimating equation (GEE) models were used to identify factors associated with adiponectin concentration.
Setting: A multicenter study using a family-based design was conducted.
Participants: A total of 1636 nondiabetic Hispanic and African-American subjects participated.
Main Outcome Measures: Circulating adiponectin concentration was measured.
Results: Age, female gender, high-density lipoprotein, SAT, and SI were positive independent correlates of adiponectin, whereas glucose, CRP, and VAT were negative independent correlates (all P < 0.05). Ethnicity was not an independent correlate of adiponectin in this model (P = 0.27); however, an ethnicity by VAT interaction term was retained, indicating a stronger negative association of VAT with adiponectin in African-Americans compared with Hispanics.
Conclusion: Directly measured SI, VAT, and SAT were independently correlated with adiponectin in Hispanic and African-American subjects. The inverse association of VAT with adiponectin was stronger in African-Americans compared with Hispanics, a finding that suggests possible ethnic differences in the effects of visceral obesity.
Several processes contribute to variation in fasting insulin concentration, including fasting glucose, insulin resistance, insulin secretion, and insulin clearance. Our goal was to determine the ...relative contribution of each of these insulin-related traits, plus anthropometric parameters, to fasting insulin among 470 Mexican Americans. The euglycemic hyperinsulinemic clamp yielded insulin sensitivity (M value) and metabolic clearance rate of insulin (MCRI). Acute insulin secretion was estimated by the insulinogenic index (IGI30) from the oral glucose tolerance test. Regression (univariate) and generalized estimating equations (multivariate) were used to describe the relationship of insulin-related traits to fasting insulin. Univarate analyses were used to select which traits to include in the multivariate model. In multivariate analysis, MCRI, M, BMI, waist circumference, and fasting glucose were independently associated with fasting insulin. Decreasing M and MCRI were associated with increasing fasting insulin, whereas increasing BMI, waist circumference, and fasting glucose were associated with increasing fasting insulin. Standardized coefficients allowed determination of the relative strength of each trait's association with fasting insulin in the entire cohort (strongest to weakest): MCRI (-0.35, P < 0.0001), M (-0.24, P < 0.0001), BMI (0.20, P = 0.0011), waist circumference (0.16, P = 0.021), and fasting glucose (0.11, P = 0.014). Fasting insulin is a complex phenotype influenced by several independent processes, each of which might have its own environmental and genetic determinants. One of the most associated traits was insulin clearance, which has implications for studies that have used fasting insulin as a surrogate for insulin resistance.
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