Diversity in EWAS: current state, challenges, and solutions

Here, we report a lack of diversity in epigenome-wide association studies (EWAS) and DNA methylation (DNAm) data, discuss current challenges, and propose solutions for EWAS and DNAm research in diverse populations. The strategies we propose include fostering community involvement, new data generation, and cost-effective approaches such as locus-specific analysis and ancestry variable region analysis

Recent Findings in the Genetics of Blood Pressure and Hypertension Traits

We provide an overview of ongoing discovery efforts in the genetics of blood pressure (BP) and hypertension (HTN) traits. Two large genome-wide association meta-analyses of individuals of European descent were recently published, revealing ~13 new loci for BP traits. Only two of these loci harbor genes in a pathway known to affect BP (CYP17A1 and NPPA/NPPB). Functional variants in these loci are still unknown. Few genome-wide association studies (GWAS) of complex diseases have been published from non-European populations. The study of populations with different evolutionary history and linkage disequilibrium (LD) structure, such as individuals of African ancestry, may provide an opportunity to further narrow these regions to identify the causal gene(s). Several collaborative efforts toward discovery of low-frequency variants and copy number variation for BP traits are currently underway. As evidence for new loci for complex diseases accumulates the assessment of the epidemiologic architecture of these variants in populations assumes higher priority. The impact of public health–relevant contexts such as diet, physical activity, psychosocial factors, and aging has not been examined for most common variants associated with BP

Prospective associations of coronary heart disease loci in African Americans using the MetaboChip: The PAGE study

Background Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans. Methods and Results Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women\u27s Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium. Conclusions Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans

Correction: A whole genome association study of mother-to-child transmission of HIV in Malawi

A correction to: Bonnie R Joubert, Ethan M Lange, Nora Franceschini, Victor Mwapasa, Kari E North, Steven R Meshnick andthe NIAID Center for HIV/AIDS Vaccine Immunology. A whole genome association study of mother-to-child transmission of HIV in Malawi. Genome Medicine 2010, 2:17

A whole genome association study of mother-to-child transmission of HIV in Malawi

Abstract: Background: More than 300,000 children are newly infected with HIV each year, predominantly through mother-to-child transmission (HIV MTCT). Identification of host genetic traits associated with transmission may more clearly explain the mechanisms of HIV MTCT and further the development of a vaccine to protect infants from infection. Associations between transmission and a selection of genes or single nucleotide polymorphisms (SNP)s may give an incomplete picture of HIV MTCT etiology. Thus, this study employed a genome-wide association approach to identify novel variants associated with HIV MTCT. Methods: We conducted a nested case-control study of HIV MTCT using infants of HIV(+) mothers, drawn from a cohort study of malaria and HIV in pregnancy in Blantyre, Malawi. Whole genome scans (650,000 SNPs genotyped using Illumina genotyping assays) were obtained for each infant. Logistic regression was used to evaluate the association between each SNP and HIV MTCT. Results: Genotype results were available for 100 HIV(+) infants (at birth, 6, or 12 weeks) and 126 HIV(-) infants (at birth, 6, and 12 weeks). We identified 9 SNPs within 6 genes with a P-value <5 × 10-5 associated with the risk of transmission, in either unadjusted or adjusted by maternal HIV viral load analyses. Carriers of the rs8069770 variant allele were associated with a lower risk of HIV MTCT (odds ratio = 0.27, 95% confidence interval = 0.14, 0.51), where rs8069770 is located within HS3ST3A1, a gene involved in heparan sulfate biosynthesis. Interesting associations for SNPs located within or near genes involved in pregnancy and development, innate immunological response, or HIV protein interactions were also observed. Conclusions: This study used a genome-wide approach to identify novel variants associated with the risk of HIV MTCT in order to gain new insights into HIV MTCT etiology. Replication of this work using a larger sample size will help us to differentiate true positive findings

Naturecultures guidance: steps in our journey

The emergence of cultural landscapes concepts heralded important mindset shifts in heritage practices. These have underpinned development of landscape approaches that recognise larger-scale interactions and the relationships between natural and cultural elements and processes. However, it has become apparent that an enduring nature-culture binary in heritage practices can result in adverse outcomes ‘on the ground’. The ISCCL has provided a forum and a source of global leadership for these issues, including the exploration of the implications of working with naturecultures to achieve conservation outcomes that are effective and inclusive. Naturecultures was coined by Donna Haraway in 2003 to recognise that natural and human environments, including non-human and more-than-human beings (such as spirits, creation ancestors, divinities) are intimately bound or entangled within different places. There is a now a growing desire to move beyond a curious consideration of the conceptual possibilities of naturecultures to implement its meanings in a wide array of everyday heritage management practices. Physically separated by the global pandemic, we are a small group of natural and cultural heritage practitioners and ISCCL members who decided to step briefly away from our organisational and institutional affiliations to connect with each other, reflect on our experiences, and offer guidance to others. This presentation will be our first opportunity to communicate what we’ve been up to, and to share some thoughts that our journey together has afforded. We argue that applying naturecultures in our practices is beneficial for people and places, and can support more effective conservation outcomes. Please join us to think further about these ideas. Français : L\u27émergence des concepts de paysages culturels a annoncé d\u27importants changements de mentalité dans les pratiques patrimoniales. Ceux-ci ont soutenu le développement d\u27approches paysagères qui reconnaissent les interactions à plus grande échelle et les relations entre les éléments et les processus naturels et culturels. Cependant, il est devenu évident qu\u27un binaire nature-culture durable dans les pratiques patrimoniales peut entraîner des résultats négatifs « sur le terrain ». L\u27ISCCL a fourni un forum et une source de leadership mondial pour ces questions, y compris l\u27exploration des implications du travail avec les cultures de la nature pour obtenir des résultats de conservation efficaces et inclusifs. Naturecultures a été inventé par Donna Haraway en 2003 pour reconnaître que les environnements naturels et humains, y compris les êtres non humains et plus qu\u27humains (tels que les esprits, les ancêtres de la création, les divinités) sont intimement liés ou enchevêtrés dans différents endroits. Il y a maintenant un désir croissant d\u27aller au-delà d\u27une curieuse considération des possibilités conceptuelles des cultures de la nature pour mettre en œuvre ses significations dans un large éventail de pratiques quotidiennes de gestion du patrimoine. Physiquement séparés par la pandémie mondiale, nous sommes un petit groupe de praticiens du patrimoine naturel et culturel et de membres de l\u27ISCCL qui ont décidé de s\u27éloigner brièvement de nos affiliations organisationnelles et institutionnelles pour se connecter les uns aux autres, réfléchir à nos expériences et offrir des conseils aux autres. Cette présentation sera notre première occasion de communiquer ce que nous avons fait et de partager quelques réflexions que notre voyage ensemble a permis. Nous soutenons que l\u27application des cultures de la nature dans nos pratiques est bénéfique pour les personnes et les lieux, et peut favoriser des résultats de conservation plus efficaces. Veuillez vous joindre à nous pour approfondir ces idées. Español: La aparición de conceptos de paisajes culturales anunció importantes cambios de mentalidad en las prácticas patrimoniales. Estos han apuntalado el desarrollo de enfoques de paisaje que reconocen interacciones a mayor escala y las relaciones entre elementos y procesos naturales y culturales. Sin embargo, se ha hecho evidente que un binario duradero entre naturaleza y cultura en las prácticas patrimoniales puede dar lugar a resultados adversos sobre el terreno . El ISCCL ha proporcionado un foro y una fuente de liderazgo global para estos temas, incluida la exploración de las implicaciones de trabajar con las culturas de la naturaleza para lograr resultados de conservación que sean efectivos e inclusivos. Naturecultures fue acuñada por Donna Haraway en 2003 para reconocer que los entornos naturales y humanos, incluidos los seres no humanos y más que humanos (como espíritus, antepasados de la creación, divinidades) están íntimamente ligados o enredados en diferentes lugares. Existe ahora un creciente deseo de ir más allá de una consideración curiosa de las posibilidades conceptuales de las culturas de la naturaleza para implementar sus significados en una amplia gama de prácticas cotidianas de gestión del patrimonio. Físicamente separados por la pandemia global, somos un pequeño grupo de practicantes del patrimonio natural y cultural y miembros de ISCCL que decidieron alejarse brevemente de nuestras afiliaciones organizacionales e institucionales para conectarnos unos con otros, reflexionar sobre nuestras experiencias y ofrecer orientación a los demás. Esta presentación será nuestra primera oportunidad para comunicar lo que hemos estado haciendo y compartir algunos pensamientos que nos ha brindado nuestro viaje juntos. Argumentamos que la aplicación de las culturas de la naturaleza en nuestras prácticas es beneficiosa para las personas y los lugares, y puede respaldar resultados de conservación más efectivos. Únase a nosotros para pensar más en estas ideas

Low agreement between modified-Schwartz and CKD-EPI eGFR in young adults: a retrospective longitudinal cohort study.

Background While there is a great deal of research updating methods for estimating renal function, many of these methods are being developed in either adults with CKD or younger children. Currently, there is limited understanding of the agreement between the modified new bedside Schwartz estimated glomerular filtration rate (eGFR) formula and the adult CKD-EPI formula in adolescents and young adults (AYAs) with chronic kidney disease (CKD) measured longitudinally. Methods Longitudinal cohort study of 242 patients (10-30 years) with CKD, followed retrospectively in a single tertiary centre as they transitioned from the paediatric- to adult-focused settings. The study population came from a longitudinal cohort of AYAs undergoing healthcare transition at the STARx Program at the University of North Carolina, in the South-Eastern USA, from 2006 to 2015. We calculated and compared the eGFR using the new bedside Schwartz formula and the CKD-EPI eGFR. Measurements were repeated for each age in years. Agreement was tested using Bland & Altman analysis. Subgroup analysis was performed using the following age groups 10-15, 15-20, 20-25 and 25-30 years, glomerular and non-glomerular causes of CKD and height z-score. Results Using repeated measures, concordance between the new Schwartz and CKD-EPI eGFR was low at 0.74 (95% C.I. 0.67, 0.79) at the lowest age range of 10-15, 0.78 (95% C.I. 0.71, 0.84) at age 15-20, 0.80 (0.70, 0.87) at ages 20-25, and 0.82 (95% C.I. 0.70, 0.90) at age 25-30. Discordance was worse in males and largest in the 10-15 year-old age group, and in patients with stunted growth. Conclusions The Schwartz and CKD-EPI equations exhibit poor agreement in patients before and during the transition period with CKD-EPI consistently yielding higher eGFRs, especially in males. Further studies are required to determine the appropriate age for switching to the CKD-EPI equation after age 18

Genetics, Ancestry, and Hypertension: Implications for Targeted Antihypertensive Therapies

Hypertension is the most common chronic condition seen by physicians in ambulatory care and a condition for which life-long medications are commonly prescribed. There is evidence for genetic factors influencing blood pressure variation in populations and response to medications. This review summarizes recent genetic discoveries that surround blood pressure, hypertension, and antihypertensive drug response from genome-wide association studies, while highlighting ancestry-specific findings and any potential implication for drug therapy targets. Genome-wide association studies have identified several novel loci for inter-individual variation of blood pressure and hypertension risk in the general population. Evidence from pharmacogenetic studies suggests that genes influence the blood pressure response to antihypertensive drugs, although results are somewhat inconsistent across studies. There is still much work that remains to be done to identify genes both for efficacy and adverse events of antihypertensive medications

Incidence and etiology of acute renal failure among ambulatory HIV-infected patients

BACKGROUND: Acute renal failure (ARF) is a cause of renal dysfunction in human immunodeficiency virus (HIV)-infected patients. Its incidence and causes have not been studied since the introduction of highly active antiretroviral therapy (HAART) in HIV ambulatory patients. METHODS: This is a prospective cohort study of 754 HIV patients, 18 years or older, seen at a university-based infectious disease clinic between 2000 and 2002. ARF was identified using proportional increases in serum creatinine from baseline and by chart review. Clinical conditions were assessed at the time of the ARF event. ARF incidence rates (IR) were calculated by dividing the number of events by person time at risk. To compare patients with and without ARF, t test or chi-square test were used. RESULTS: Patient's mean age was 40 years; 68% were male and 61% were black. One hundred-eleven ARF events occurred in 71 subjects (IR 5.9 per 100 person-years; 95% CI 4.9, 7.1). ARF was more common in men, in those with CD4 cell count 10,000 copies/mL. These patients more often had acquired immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), and have received HAART. ARF was mainly community-acquired, due to prerenal causes or acute tubular necrosis, and associated with opportunistic infections and drugs. Liver disease was a cause of ARF in HCV-infected patients. CONCLUSION: ARF is common in ambulatory HIV patients. Immunosuppression, infection, and HCV are important conditions associated with ARF in the post-HAART era

Sequence variation in telomerase reverse transcriptase (TERT) as a determinant of risk of cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study

Abstract Background Telomerase reverse transcriptase (TERT) maintains telomere ends during DNA replication by catalyzing the addition of short telomere repeats. The expression of telomerase is normally repressed in somatic cells leading to a gradual shortening of telomeres and cellular senescence with aging. Interindividual variation in leukocyte telomere length has been previously associated with susceptibility to cardiovascular disease. The aim of the present study was to determine whether six variants in the TERT gene are associated with risk of incident coronary heart disease, incident ischemic stroke, and mortality in participants in the biracial population-based Atherosclerosis Risk in Communities (ARIC) study, including rs2736100 that was found to influence mean telomere length in a genome-wide analysis. Methods ARIC is a prospective study of the etiology and natural history of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline in 1987–1989. Haplotype tagging SNPs in TERT were genotyped using a custom array containing nearly 49,000 SNPs in 2,100 genes associated with cardiovascular and metabolic phenotypes. Cox proportional hazards models were used to assess the association between the TERT polymorphisms and incident cardiovascular disease and mortality over a 20-year follow-up period in 8,907 whites and 3,022 African-Americans with no history of disease at the baseline examination, while individuals with prevalent cardiovascular disease were not excluded from the analyses of mortality. Results After adjustment for age and gender, and assuming an additive genetic model, rs2736122 and rs2853668 were nominally associated with incident coronary heart disease (hazards rate ratio = 1.20, p = 0.02, 95 % confidence interval = 1.03– 1.40) and stroke (hazards rate ratio = 1.17, p = 0.05, 95 % confidence interval = 1.00 - 1.38), respectively, in African-Americans. None of the variants was significantly associated with cardiovascular disease in white study participants or with mortality in either racial group. Conclusions Replication in additional population-based samples combined with genotyping of polymorphisms in other genes involved in maintenance of telomere length may help to determine whether genetic variants associated with telomere homeostasis influence the risk of cardiovascular disease in middle-aged adults