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BackgroundGenetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.MethodsWe combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.FindingsWhen testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.InterpretationThis study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Objective: Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole‐exome sequence data from 6803 longitudinally studied individuals. Methods: Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays. Results: The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function. Conclusions: In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers. [ABSTRACT FROM AUTHOR]

Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate. Article Highlights: The genetic determinants of interindividual differences in energy expenditure (EE) are not well established. Sphingolipids have been proposed to influence EE by altering mitochondrial function. Association analysis of genetic variants in genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in CERS2 associated with higher sleeping EE assessed by whole-room indirect calorimetry. The rs267738 variant was associated with increased glucose production under basal and insulin-stimulated conditions and with decreased basal mitochondrial respiration. The rs267738 missense variant may affect the expression of key gluconeogenic genes G6PC1 and PCK1. [ABSTRACT FROM AUTHOR]

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Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p

BackgroundThe presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample.ResultsA fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy.ConclusionsThe identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) in an indigenous American community by genotyping all study participants for both high-resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test. We defined the risk protection haplotype of SLC16A11 , T-C-G-T-T , as allele 2 of a diallelic genetic model with three genotypes, SLC16A11*11 , *12 , and *22 , where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB1*16:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [ *22 ] and 0.78 [ *12 ]); an added interaction term was statistically significant (OR 0.49 [ *12 ]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30–41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes. Article Highlights: This study enlarged our sample of high-resolution HLA-DRB1 alleles and 5 individually typed mutations for the SLC16A11 locus and used these to test for protection, risk, and interaction for type 2 diabetes. We confirmed our earlier reports of protection (DRB1*16:02) and risk (SLC16A11) and used all genotypes in a sensitivity analysis for BMI. HLA-DRB1*16:02 was found to be protective, and sensitivity analysis demonstrated that SLC16A11 is a risk in lower BMI strata and protective in higher ones. Epistasis for individuals with DRB1*16:02 and T-C-G-T-T reduces the odds for type 2 diabetes in a BMI range of 30–41 kg/m2, and binding studies implicate core peptide FSAFASGLL. [ABSTRACT FROM AUTHOR]

Aim: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. Materials and Methods: Baseline body composition, insulin sensitivity by hyperinsulinaemic‐euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M‐low and M‐high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow‐up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin‐to‐creatinine ratio ≥30 mg/g). Separate associations of M‐low, M‐high and AIR (per 1‐SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). Results: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M‐low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p =.03; M‐high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p =.02; mg/kg‐metabolic body size/min (log)]. In separate adjusted models, lower M‐low and M‐high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p =.004; HR 1.31, 95% CI 1.06, 1.63, p =.01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p =.3). Conclusions: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria. [ABSTRACT FROM AUTHOR]

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10(-28)) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits.

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Aims/hypothesisKidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes.MethodsBiomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP.ResultsDuring follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p

Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10(-5), LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.

OBJECTIVE: To examine the role of glycemic measures performed during childhood in predicting future diabetes-related nephropathy and retinopathy in a high-risk indigenous American cohort. RESEARCH DESIGN AND METHODS: We studied associations between glycated hemoglobin (HbA1c) and 2-h plasma glucose (PG), measured during childhood (age 5 to <20 years) in a longitudinal observational study of diabetes and its complications (1965–2007), and future albuminuria (albumin creatinine ratio [ACR] ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), and retinopathy (at least one microaneurysm or hemorrhage or proliferative retinopathy on direct ophthalmoscopy). Areas under the receiver operating characteristic curve (AUCs) for childhood glycemic measures when predicting nephropathy and retinopathy were compared. RESULTS: Higher baseline levels of HbA1c and 2-h PG significantly increased the risk of future severe albuminuria (HbA1c: hazard ratio [HR] 1.45 per %; 95% CI 1.02–2.05 and 2-h PG: HR 1.21 per mmol/L; 95% CI 1.16–1.27). When categorized by baseline HbA1c, children with prediabetes had a higher incidence of albuminuria (29.7 cases per 1,000 person-years [PY]), severe albuminuria (3.8 cases per 1,000 PY), and retinopathy (7.1 cases per 1,000 PY) than children with normal HbA1c levels (23.8, 2.4, and 1.7 cases per 1,000 PY, respectively); children with diabetes at baseline had the highest incidence of the three complications. No significant differences were observed between AUCs for models with HbA1c, 2-h PG, and fasting PG when predicting albuminuria, severe albuminuria, or retinopathy. CONCLUSIONS: In this study, higher glycemia levels ascertained by HbA1c and 2-h PG during childhood were associated with future microvascular complications; this demonstrates the potential utility of screening tests performed in high-risk children in predicting long-term health outcomes. [ABSTRACT FROM AUTHOR]

Early puberty onset is associated with higher risk of diabetes, but most studies have not accounted for childhood factors that may confound the association. Using data from a study conducted in an Indigenous community in Arizona (1965–2007), we examined associations of timing and velocity of the adolescent growth spurt with type 2 diabetes, and whether these associations are mediated by childhood body mass index and insulinemia. Adolescent growth parameters were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, for 861 participants with height measurements spanning the whole period of growth. In males, older age at take-off, age at peak velocity, and age at maturation were associated with decreased prevalence of diabetes (odds ratio (OR) = 0.43 per year, 95% confidence interval (CI): 0.27, 0.69; OR = 0.50, 95% CI: 0.35, 0.72; OR = 0.58, 95% CI: 0.41, 0.83, respectively), while higher velocity at take-off was associated with increased risk (OR = 3.47 per cm/year, 95% CI: 1.87, 6.42) adjusting for age, birth year, and maternal diabetes. Similar results were observed with incident diabetes. Our findings suggest that an early and accelerated adolescent growth spurt is a risk factor for diabetes, at least in males. These associations are only partially explained by measures of adiposity and insulinemia. [ABSTRACT FROM AUTHOR]

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 10−9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10−12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = −7.55 [95% CI −9.88, −5.22]; P = 3.2 × 10−10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10−4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy. [ABSTRACT FROM AUTHOR]