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HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
BACKGROUND & AIMS - There are marked racial and ethnic differences in non-cardia gastric cancer prevalence within the United States. Although gastric cancer screening is recommended in some regions of high prevalence, screening is not routinely performed in the United States. Our objective was to determine whether selected non-cardia gastric cancer screening for high-risk races and ethnicities within the United States is cost effective.
METHODS - We developed a decision analytic Markov model with the base case of a 50-year-old person of non-Hispanic white, non-Hispanic black, Hispanic, or Asian race or ethnicity. The cost effectiveness of a no-screening strategy (current standard) for non-cardia gastric cancer was compared with that of 2 endoscopic screening modalities initiated at the time of screening colonoscopy for colorectal cancer: upper esophagogastroduodenoscopy with biopsy examinations and continued surveillance only if intestinal metaplasia or more severe pathology is identified or esophagogastroduodenoscopy with biopsy examinations continued every 2 years even in the absence of identified pathology. We used prevalence rates, transition probabilities, costs, and quality-adjusted life years (QALYs) from publications and public data sources. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay threshold of $100,000/QALY.
RESULTS - Compared with biennial and no screening, screening esophagogastroduodenoscopy with continued surveillance only when indicated was cost effective for non-Hispanic blacks ($80,278/QALY), Hispanics ($76,070/QALY), and Asians ($71,451/QALY), but not for non-Hispanic whites ($122,428/QALY). The model was sensitive to intestinal metaplasia prevalence, transition rates from intestinal metaplasia to dysplasia to local and regional cancer, cost of endoscopy, and cost of resection (endoscopic or surgical).
CONCLUSIONS - Based on a decision analytic Markov model, endoscopic non-cardia gastric cancer screening for high-risk races and ethnicities could be cost effective in the United States.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
OBJECTIVE - To investigate race-sex associations with risk among whites and blacks in the southeastern United States. The relationship between race, sex, and kidney stone risk is poorly understood.
METHODS - Participants were 42,136 black and white adults enrolled in the Southern Community Cohort Study between 2002 and 2009, with no history of kidney stones and receiving Medicare or Medicaid services. Incident kidney stone diagnoses through December 2014 were determined via linkage with Centers for Medicare and Medicaid Services research files. Hazard ratios (HRs) for associations with race and sex were computed from multivariable Cox proportional hazards models adjusting for baseline characteristics, comorbid diseases, and dietary intakes.
RESULTS - During 116,931 and 270,917 person-years of follow-up for whites and blacks, respectively, age-adjusted incidence rates (95% confidence interval [CI]) were 5.98 (4.73-7.23) and 4.50 (3.86-5.14) per 1000 person-years for white men and women, respectively, while corresponding rates among blacks were 2.19 (1.71-2.67) and 2.47 (2.19-2.75) per 1000 person-years. Risk was higher among whites compared to blacks (HR = 2.23, 95% CI 1.97-2.53). Male sex was significantly associated with risk among whites (HR = 1.45, 95% CI 1.20-1.75), but not among blacks (HR = 0.90, 95% CI 0.75-1.07). Formal tests of interaction by race and sex were statistically significant for all models (P = .01 for fully adjusted model).
CONCLUSION - The association of incident kidney stones with sex differs between whites and blacks. White men have the highest risk, while no difference in risk is observed between black men and women.
Copyright © 2018 Elsevier Inc. All rights reserved.
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Copyright © 2018 American Society of Human Genetics. All rights reserved.
Background - We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States.
Methods - Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates.
Results - Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication.
Conclusions - Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.
Natriuretic peptides (NP) are cardiac-derived hormones with favorable cardiometabolic actions. Low NP levels are associated with increased risks of hypertension and diabetes mellitus, conditions with variable prevalence by race and ethnicity. Heritable factors underlie a significant proportion of the interindividual variation in NP concentrations, but the specific influences of race and ancestry are unknown. In 5597 individuals (40% white, 24% black, 23% Hispanic, and 13% Chinese) without prevalent cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis, multivariable linear regression and restricted cubic splines were used to estimate differences in serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels according to, ethnicity, and ancestry. Ancestry was determined using genetic ancestry informative markers. NT-proBNP concentrations differed significantly by race and ethnicity (black, median 43 pg/ml [interquartile range 17 to 94], Chinese 43 [17 to 90], Hispanic 53 [23 to 107], white 68 [34 to 136]; p = 0.0001). In multivariable models, NT-proBNP was 44% lower (95% confidence interval -48 to -40) in black and 46% lower (-50 to -41) in Chinese, compared with white individuals. Hispanic individuals had intermediate concentrations. Self-identified blacks and Hispanics were the most genetically admixed. Among self-identified black individuals, a 20% increase in genetic European ancestry was associated with 12% higher (1% to 23%) NT-proBNP. Among Hispanic individuals, genetic European and African ancestry were positively and negatively associated with NT-proBNP levels, respectively. In conclusion, NT-proBNP levels differ according to race and ethnicity, with the lowest concentrations in black and Chinese individuals. Racial and ethnic differences in NT-proBNP may have a genetic basis, with European and African ancestry associated with higher and lower NT-proBNP concentrations, respectively.
Copyright © 2017 Elsevier Inc. All rights reserved.
Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at <5.0 × 10 Of these, rs9980 at replicated in stage 2 meta-analysis (=3.1 × 10), with combined stages 1 and 2 genome-wide significance of =5.6 × 10 Transethnic meta-analysis further supported the association at rs9980 (=5.9 × 10). Additionally, rs16846053 at showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (=6.7 × 10). encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for and are expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in and expression and function in the central nervous system may affect the regulation of systemic water balance.
Copyright © 2017 by the American Society of Nephrology.
Illumina genotyping arrays have powered thousands of large-scale genome-wide association studies over the past decade. Yet, because of the tremendous volume and complicated genetic assumptions of Illumina genotyping data, processing and quality control (QC) of these data remain a challenge. Thorough QC ensures the accurate identification of single-nucleotide polymorphisms and is required for the correct interpretation of genetic association results. By processing genotyping data on > 100 000 subjects from >10 major Illumina genotyping arrays, we have accumulated extensive experience in handling some of the most peculiar scenarios related to the processing and QC of Illumina genotyping data. Here, we describe strategies for processing Illumina genotyping data from the raw data to an analysis ready format, and we elaborate on the necessary QC procedures required at each processing step. High-quality Illumina genotyping data sets can be obtained by following our detailed QC strategies.
BACKGROUND - Although the incidence of cervical cancer has been decreasing in the United States over the last decade, Hispanic and African American women have substantially higher rates than Caucasian women. The human papillomavirus (HPV) is a necessary, although insufficient, cause of cervical cancer. In the United States in 2013, only 37.6% of girls 13 to 17 years of age received the recommended 3 doses of a vaccine that is almost 100% efficacious for preventing infection with viruses that are responsible for 70% of cervical cancers. Implementation research has been underutilized in interventions for increasing vaccine uptake. The Consolidated Framework for Implementation Research (CFIR), an approach for designing effective implementation strategies, integrates 5 domains that may include barriers and facilitators of HPV vaccination. These include the innovative practice (Intervention), communities where youth and parents live (Outer Setting), agencies offering vaccination (Inner Setting), health care staff (Providers), and planned execution and evaluation of intervention delivery (Implementation Process).
METHODS - Secondary qualitative analysis of transcripts of interviews with 30 community health care providers was conducted using the CFIR to code potential barriers and facilitators of HPV vaccination implementation.
RESULTS - All CFIR domains except Implementation Process were well represented in providers' statements about challenges and supports for HPV vaccination.
CONCLUSION - A comprehensive implementation framework for promoting HPV vaccination may increase vaccination rates in ethnically diverse communities. This study suggests that the CFIR can be used to guide clinicians in planning implementation of new approaches to increasing HPV vaccine uptake in their settings. Further research is needed to determine whether identifying implementation barriers and facilitators in all 5 CFIR domains as part of developing an intervention contributes to improved HPV vaccination rates.
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
Copyright © 2016 American Society of Human Genetics. All rights reserved.