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Context - Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry.
Objective - The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries.
Design - Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL).
Patients or Other Participants - In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study.
Main Outcome Measures - Blood concentrations of 25(OH)D were measured for all participants.
Results - Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.
Conclusions - Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
BACKGROUND - Epistasis and gene-environment interactions are known to contribute significantly to variation of complex phenotypes in model organisms. However, their identification in human association studies remains challenging for myriad reasons. In the case of epistatic interactions, the large number of potential interacting sets of genes presents computational, multiple hypothesis correction, and other statistical power issues. In the case of gene-environment interactions, the lack of consistently measured environmental covariates in most disease studies precludes searching for interactions and creates difficulties for replicating studies.
RESULTS - In this work, we develop a new statistical approach to address these issues that leverages genetic ancestry, defined as the proportion of ancestry derived from each ancestral population (e.g., the fraction of European/African ancestry in African Americans), in admixed populations. We applied our method to gene expression and methylation data from African American and Latino admixed individuals, respectively, identifying nine interactions that were significant at P<5×10-8. We show that two of the interactions in methylation data replicate, and the remaining six are significantly enriched for low P-values (P<1.8×10-6).
CONCLUSION - We show that genetic ancestry can be a useful proxy for unknown and unmeasured covariates in the search for interaction effects. These results have important implications for our understanding of the genetic architecture of complex traits.
© 2017 WILEY PERIODICALS, INC.
Purpose - To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.
Methods - Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.
Results - Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.
Conclusions - This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.
Context - Low 25-hydroxyvitamin D [25(OH)D] is associated with coronary heart disease (CHD) in people who are white and Chinese but not black or Hispanic. Vitamin D binding globulin (VDBG) avidly binds 25(OH)D, reducing its bioavailability, and differs in isoform and concentration by race.
Objective - Evaluate associations of VDBG with CHD and whether accounting for VDBG or estimating bioavailable 25(OH)D explains the heterogeneity of the association of 25(OH)D with CHD.
Design and Setting - We conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis. Participants with an incident CHD event over 12 years of follow-up (n = 538) and a randomly assigned subcohort (n = 999) were included. We measured baseline 25(OH)D, VDBG, and isoforms using mass spectrometry and estimated bioavailable 25(OH)D from published equations.
Results - VDBG was associated with an increased risk of CHD [hazard ratio, 1.77 (95% confidence interval, 1.46 to 2.14) per standard deviation increment, P < 0.0001], without evidence of heterogeneity by race or isoform (each P for interaction > 0.1). Low total 25(OH)D was differentially associated with CHD events, by race, with or without adjustment for VDBG (P for interaction = 0.04 or 0.05, respectively). Associations of 25(OH)D with CHD were strengthened with adjustment for VDBG among participants who were white or Chinese, and bioavailable 25(OH)D was associated with CHD events only among white participants.
Conclusions - High VDBG concentration was associated with CHD events in all racial and ethnic groups. Incorporation of VDBG strengthened existing associations of 25(OH)D with CHD but did not explain racial heterogeneity in associations of 25(OH)D with CHD.
Copyright © 2017 Endocrine Society
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of .
© 2017 by the American Diabetes Association.
BACKGROUND - Human papillomavirus (HPV) infection has been causally linked to six cancers, and many disproportionately affect minorties. This study reports on the development and effectiveness of an intervention aimed at increasing HPV vaccine uptake among African American and Hispanic pediatric patients in safety-net clinics.
METHODS - Formative research, community engagement, and theory guided development of the intervention. A clustered, non-randomized controlled pragmatic trial was conducted in four clinics providing healthcare for the underserved in Tennessee, U.S., with two intervention sites and two usual care sites. Patients aged 9-18 years (N = 408) and their mothers (N = 305) enrolled, with children clustered within families. The intervention consisted of two provider/staff training sessions and provision of patient education materials, consisting of a video/flyer promoting HPV vaccine. Medical records were reviewed before/after the initial visit and after 12 months.
RESULTS - At the initial visit, provision of patient education materials and provider recommendation were higher at intervention sites versus usual care sites, and receipt of HPV vaccine was higher at intervention sites (45.4% versus 32.9%) but not significantly after adjusting for patient's age and mother's education. Provider recommendation, but not education materials, increased the likelihood of vaccine receipt at the initial visit, although over one-third of intervention mothers cited the flyer/video as motivating vaccination. Completion of the 3-dose series at follow-up was lower in the intervention arm.
CONCLUSIONS - Future interventions should combine patient education, intensive provider/staff education, and patient reminders. Research should compare patient education focusing on HPV vaccine only versus all adolescent vaccines.
TRIAL REGISTRATION - Retrospectively registered with ClinicalTrials.gov NCT02808832 , 9/12/16.
BACKGROUND - Obesity prevalence is disproportionately high among Hispanic children.
OBJECTIVES - The Healthy Families Study assessed the efficacy of a culturally targeted, family-based weight gain prevention intervention for Hispanic immigrant families with children ages 5-7 years.
METHODS - The study used a two-group, cluster randomized trial design, assigning 136 families (clusters) to the active intervention (weight gain prevention) and 136 families to attention control (oral health). The active intervention included a 4-month intensive phase (eight classes) and an 8-month reinforcement phase (monthly mail/telephone contact). Children's body mass index z-score (BMI-Z) was the primary outcome.
RESULTS - The BMI-Z growth rate of the active intervention group did not differ from the attention control group at short-term follow-up (median 6 months; 168 families, 206 children) or long-term follow-up (median 16 months; 142 families, 169 children). Dose response analyses indicated a slower increase in BMI-Z at short term among overweight/obese children who attended more intervention classes. Moderate physical activity on weekends increased at short term. Weekend screen time decreased at short term among those attending at least one class session.
CONCLUSION - Low class attendance likely impacted intention-to-treat results. Future interventions targeting this population should test innovative strategies to maximize intervention engagement to produce and sustain effects on weight gain prevention.
© 2016 World Obesity Federation.
The Hispanic population is the United States' largest minority and one of the fastest growing as well. In the next 30 to 40 years, the proportion of open-angle glaucoma patients represented by Hispanics is expected to dramatically rise. Here we examine the unique considerations and challenges of glaucoma care in this population, from demographics to risk factors to treatments and outcomes. Currently, access to care and the under-diagnosis of glaucoma in this population are significant issues that look only to grow in significance as the glaucoma burden continues to grow. Additionally, utilization of medical and surgical therapy remains lower in Hispanics than in many other ethnic groups. Understanding and proactively addressing the unique challenges in the screening and treatment of Hispanics will be of utmost importance to providing effective care to this population.
BACKGROUND & AIMS - A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.
METHODS - We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.
RESULTS - We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.
CONCLUSIONS - In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10(-15), OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.