Alcohol consumption and epigenetic age acceleration in young adults

Alcohol is a widely consumed substance in the United States, however its effect on aging remains understudied. In this study of young adults, we examined whether cumulative alcohol consumption, i.e., alcohol years of beer, liquor, wine, and total alcohol, and recent binge drinking, were associated with four measures of age-related epigenetic changes via blood DNA methylation. A random subset of study participants in the Coronary Artery Risk Development in Young Adults Study underwent DNA methylation profiling using the Illumina MethylationEPIC Beadchip. Participants with alcohol consumption and methylation data at examination years 15

Marijuana use and DNA methylation-based biological age in young adults

BACKGROUND: Marijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana\u27s effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation. RESULTS: A random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P \u3c 0.001) and a 2.5-month (P \u3c 0.001) higher average in GrimAge acceleration (GAA) using generalized estimating equations, respectively. Recent use and each additional day of recent use were associated with a 20-month (P \u3c 0.001) and a 1-month (P \u3c 0.001) higher GAA, respectively. A statistical interaction between marijuana-years and alcohol consumption on GAA was observed (P = 0.011), with nondrinkers exhibiting a higher GAA (β = 0.21 [95% CI 0.05, 0.36], P = 0.008) compared to heavy drinkers (β = 0.05 [95% CI - 0.09, 0.18], P = 0.500) per each additional marijuana-year. No associations were observed for the remaining EAA estimates. CONCLUSIONS: These findings suggest cumulative and recent marijuana use are associated with age-related epigenetic changes that are related to lifespan. These observed associations may be modified by alcohol consumption. Given the increase in use and legalization, these findings provide novel insight on the effect of marijuana use on the aging process as captured through blood DNA methylation

The Genetics of Ocular Endophenotypes of Primary Open Angle Glaucoma in Latinos

Intraocular pressure (IOP) and vertical cup-disc ratio (VCDR) are two quantitative traits routinely examined during ocular examinations to monitor and diagnose glaucoma, a leading cause of irreversible blindness worldwide. Findings from previous studies have demonstrated genetic factors influence these traits but such studies were conducted in European and Asian populations. The purpose of this dissertation is to address the current gaps in research regarding the genetic factors and biological mechanisms underlying the pathogenesis of glaucoma and related quantitative traits in Latinos. In the first study, we identified a significant association between African ancestry and IOP with increasing proportions of African ancestry associated with increasing IOP in Latinos. This association was modified by a significant interaction between African ancestry and hypertension. For the second study, we identified two genome-wide significant genetic markers associated with VCDR and replicated previously identified genomic regions associated with VCDR. In the third study, we identified several suggestive interactive associations between genetic markers and body mass index on VCDR that are biologically plausible candidate genomic regions for further examination. And for the fourth study, we observed significant associations between VCDR genetic risk scores and VCDR, with a higher genetic risk score associated with larger VCDR. Moreover, the VCDR genetic risk scores were associated with glaucoma and increased the discriminatory ability for glaucoma. These studies represent the first reports to investigate the association between genetic factors and ocular traits in a Latino population. Findings from this dissertation not only furthers our understanding of the genetic architecture of quantitative traits of glaucoma but also sheds new light on the biological mechanisms of glaucoma and may translate into public health prevention strategies

A Genome-Wide Association Study of Intraocular Pressure in Latinos

Intraocular pressure (IOP) is a major, as well as the only modifiable, risk factor for glaucoma. With an expected increase in the number of individuals affected by glaucoma, understanding genetic factors related to IOP may aid in developing screening and prevention strategies for this disease. The purpose of this thesis is to identify genetic variants associated with IOP in Latinos. A genome-wide association study (GWAS) was conducted using data collected from 3,374 Latinos recruited by the Los Angeles Latino Eye Study (LALES). Linear regression analysis was performed adjusting for age, gender, and principal components of genetic ancestry. Results from the analysis yielded five suggestive single nucleotide polymorphisms (SNPs) that were associated with IOP. The top SNP associated with IOP was located at 21q21.2 (P=8.80×10-8) on chromosome 21 between TUBAP and VN2R20P and was associated with a 1.33 mmHg increase in IOP per effect allele. The second most significant SNP, rs12591689 (P=5.23×10-6), was located on chromosome 15 in PCSK6 and was associated with a 0.31 mmHg increase in IOP per effect allele. This study represents the first GWAS of IOP in Latinos, and both replicated previously reported and identified new genetic variants associated with IOP. Further replication studies are needed, and implications for these genetic variants include screening and identifying individuals who harbor these polymorphisms that increase IOP

A Genome-Wide Association Study of Vertical Cup-Disc Ratio in a Latino PopulationGWAS of Vertical Cup-Disc Ratio in Latino Individuals

PurposeVertical cup-disc ratio (VCDR) is used as a clinical assessment measure to identify and monitor glaucomatous damage to the optic nerve. Previous genetic studies conducted in European and Asian populations have identified many loci associated with VCDR. The genetic factors in other ethnic populations, such as Latino, influencing VCDR remain to be determined. Here, we describe the first genome-wide association study (GWAS) on VCDR in Latino individuals.MethodsWe conducted this GWAS on VCDR using 4537 Latino individuals who were genotyped by using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). Study subjects were 40 years of age and older. Linear regression, adjusting for age, sex, and principal components of genetic ancestry, was conducted to assess the associations between single nucleotide polymorphisms (SNPs) and VCDR. We imputed SNPs from the 1000 Genomes Project to integrate additional SNPs not directly genotyped.ResultsWe replicated two previously reported SNPs that reached GWAS significance, rs1900005 and rs7916697, in the ATOH7-PBLD region, as well as identified two suggestive associations in the CDC7-TGFBR3 region on chromosome 1p22.1 and in the ZNF770-DPH6 region on chromosome 15q14. We discovered a novel SNP, rs56238729 (P = 1.22 × 10-13), in the ATOH7-PBLD region that is significantly associated with VCDR in Latino individuals. We replicated eight previously reported regions, including COL8A1, CDKN2B-CDKN2BAS, BMP2, and CHEK2 (P < 2.17 × 10-3).ConclusionsOur results discovered a novel SNP that is significantly associated with VCDR in Latino individuals and confirmed previously reported loci, providing further insight into the genetic architecture of VCDR

Genome-wide association study identifies WNT7B as a novel locus for central corneal thickness in Latinos.

The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P = 6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1 and ZNF469 (P < 1.25E-3). These findings provide further insight into the genetic architecture of CCT and illustrate that the use of minority groups in GWAS will help identify additional loci

Social Determinants, Cardiovascular Disease, and Health Care Cost: A Nationwide Study in the United States Using Machine Learning

Background Existing studies on cardiovascular diseases (CVDs) often focus on individual‐level behavioral risk factors, but research examining social determinants is limited. This study applies a novel machine learning approach to identify the key predictors of county‐level care costs and prevalence of CVDs (including atrial fibrillation, acute myocardial infarction, congestive heart failure, and ischemic heart disease). Methods and Results We applied the extreme gradient boosting machine learning approach to a total of 3137 counties. Data are from the Interactive Atlas of Heart Disease and Stroke and a variety of national data sets. We found that although demographic composition (eg, percentages of Black people and older adults) and risk factors (eg, smoking and physical inactivity) are among the most important predictors for inpatient care costs and CVD prevalence, contextual factors such as social vulnerability and racial and ethnic segregation are particularly important for the total and outpatient care costs. Poverty and income inequality are the major contributors to the total care costs for counties that are in nonmetro areas or have high segregation or social vulnerability levels. Racial and ethnic segregation is particularly important in shaping the total care costs for counties with low poverty rates or social vulnerability level. Demographic composition, education, and social vulnerability are consistently important across different scenarios. Conclusions The findings highlight the differences in predictors for different types of CVD cost outcomes and the importance of social determinants. Interventions directed toward areas that have been economically and socially marginalized may aid in reducing the impact of CVDs

Marijuana use and DNA methylation-based biological age in young adults

BackgroundMarijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.ResultsA random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P < 0.001) and a 2.5-month (P < 0.001) higher average in GrimAge acceleration (GAA) using generalized estimating equations, respectively. Recent use and each additional day of recent use were associated with a 20-month (P < 0.001) and a 1-month (P < 0.001) higher GAA, respectively. A statistical interaction between marijuana-years and alcohol consumption on GAA was observed (P = 0.011), with nondrinkers exhibiting a higher GAA (β = 0.21 [95% CI 0.05, 0.36], P = 0.008) compared to heavy drinkers (β = 0.05 [95% CI - 0.09, 0.18], P = 0.500) per each additional marijuana-year. No associations were observed for the remaining EAA estimates.ConclusionsThese findings suggest cumulative and recent marijuana use are associated with age-related epigenetic changes that are related to lifespan. These observed associations may be modified by alcohol consumption. Given the increase in use and legalization, these findings provide novel insight on the effect of marijuana use on the aging process as captured through blood DNA methylation