The prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.

Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10(-7)). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10(-7). Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

In humans, offspring of women who are overweight or obese are more likely to develop metabolic disease later in life. Studies in lower animal species reveal that a calorically-dense maternal diet is associated with alterations in islet cell mass and function. The long-term effects of maternal diet on the structure and function of offspring islets with characteristics similar to humans are unknown. We used a well-established non-human primate (NHP) model to determine the consequences of exposure to Western-Style Diet (WSD) in utero and during lactation on islet cell mass and function in the offspring.

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Collecting social determinants of health in electronic health records is time-consuming. Meanwhile, an Area Deprivation Index (ADI) aggregates sociodemographic information from census data. The objective of this study was to ascertain whether ADI is associated with stage of human papillomavirus (HPV)-related cancer at diagnosis.

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10-9) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.

Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.