Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Age-associated diseases and conditions: implications for decreasing late life morbidity.

We discuss two types of age-associated diseases; aging-dependent such as Alzheimer's disease and congestive heart failure which increase logarithmically with age, versus age-dependent such as multiple sclerosis and amyotrophic lateral sclerosis which occur at proscribed ages, and then occurrence of new cases ceases or diminishes with further aging. Prevention strategies with both types emphasize postponement or delay of onset. The non-fatal aging-dependent diseases and conditions are an accumulating burden as we age, and increase overall morbidity in late years. These include Alzheimer's disease and other dementias, Parkinson's disease, loss of vision and hearing, incontinence, osteoporosis and hip fracture, osteoarthritis and depression. With mortality postponed, we will be living for many years at old and vulnerable ages. Life's quality will be reasonable for most. Still, increasing the chance that all will experience this desirable outcome requires pursuing the means to delay the onset of the physical and social events which we categorize as the non-fatal aging-dependent diseases and conditions. We must recognize that each added year occurs at the tip of an exponential curve where risk is maximal.

State variation in nursing home mortality outcomes according to do-not-resuscitate status.

BACKGROUND: This study compares mortality outcomes of Medicaid-reimbursed nursing home residents with and without do-not-resuscitate (DNR) orders in two diverse states. METHODS: We used 1994 Minimum Data Set Plus (MDS+) information on 3215 nursing home residents from two states. We used Kaplan-Meier analyses to examine unadjusted mortality among those with and without DNR orders across states. We used a proportional hazard regression with main and interaction variables to model the likelihood of survival in the nursing home. RESULTS: Approximately 27% of nursing home residents with DNR orders in State A die within the year, and approximately 40% of nursing home residents with DNR orders in State B die within the year. Regression results indicate that neither having a DNR order nor state of residence were independently associated with mortality. However, residing in State B and having a DNR order was associated with an increased risk of mortality compared with all others in the sample (risk ratio = 1.73; 95% confidence interval = 1.09, 2.75). CONCLUSION: This study demonstrates that DNR orders are associated with varying mortality across states. Future research is needed to identify the reasons why state level differences exist.

Effectiveness of feeding tubes in nursing home residents with swallowing disorders.

BACKGROUND: Among nursing home residents who stop eating, a common decision for residents, caregivers, and families is the decision to begin tube feeding. This study examines the effectiveness of feeding tubes at reducing mortality among nursing home residents with swallowing disorders and feeding disabilities. METHODS: Data from a version of the Minimum Data Set+ (MDS +) encompassing three different states from calendar years 1993 and 1994 were analyzed. Residents were included in the study if they were not totally dependent on staff for eating upon their first assessment but became totally dependent on staff for eating and had a swallowing disorder at some point during their nursing home stay. We used a proportional hazard regression to examine the relationship of feeding tubes with mortality after total eating dependence occurred. RESULTS: Unadjusted Kaplan-Meier curves found that those with feeding tubes were less likely to die than comparable residents without feeding tubes (p < .001). Estimated survival at 1 year was 39% for those without feeding tubes and 50% for those with feeding tubes. The multivariate results indicated that feeding tubes were associated with a reduced risk of death (risk ratio, 0.71; 95% confidence interval, 0.59, 0.86). CONCLUSIONS: This study provides evidence that tube feeding can be life-prolonging, even if the gain in life is not substantial. Such information can be useful to nursing home staff, residents, and families when trying to decide whether to place a feeding tube in a resident with swallowing disorders and eating disabilities.

Reproductive longevity and increased life expectancy.

BACKGROUND: Female life expectancy in developed countries has increased by 30 years in the twentieth century. AIM: To determine if there has been an increase in reproductive longevity. METHODS: We analysed age-specific fertility data from birth statistics for the USA, Canada, Japan, France, Sweden, the UK and Australia. RESULTS: Since 1940, birth rates for women aged 35 and over have declined. Among women aged 50 years and older, there has been no increase in births. Fertility rates in 1990 were 0.0 to 0.044 per 1000 women, with total numbers ranging from 0 to 60 births. CONCLUSION: The fertile years have not been prolonged in the cohort of women whose life expectancy has increased so dramatically this century. This suggests that reproductive senescence is tightly controlled and not extended by factors that enhance female longevity. Other physiological mechanisms may also be fixed within narrow age limits.

Nursing home resident use of care directives.

BACKGROUND: The Patient Self-Determination Act of 1991 requires that nursing homes reimbursed by Medicare or Medicaid inform all residents upon admission of their rights to enact care directives in the event of terminal illness. This study investigated the relationship between care directive use and resident functional status. METHODS: We analyzed a version of the Minimum Data Set (MDS+) from a single state. We selected residents who were admitted to a nursing home in the first half of 1993 and followed them in the nursing home through the end of 1994. We created logistic models to examine independent correlates associated with having an advance directive or a do-not-resuscitate (DNR) order on admission. We then created similar logistic models to examine independent correlates associated with writing an advance directive or DNR order subsequent to admission. RESULTS: Of the 2,780 residents, 11% (292) had advance directives and 17% (466) had DNR orders upon admission. Of those without care directives upon admission, 6% (143) subsequently had an advance directive and 15% (339) subsequently had a DNR order. Cross-sectionally, older individuals and whites were more likely to have a care directive. Having poor cognitive and physical function was associated with having a DNR order upon admission. Longitudinally, longer stayers and whites were more likely to have an advance directive. Residents who lost physical function were more likely to have an advance directive and those who lost cognitive function were more likely to have a DNR order. CONCLUSIONS: Care directive use is influenced by a number of sociodemographic and functional characteristics.

Prior living arrangements and nursing home resident admission ADL characteristics: a study of two states.

OBJECTIVES: This study examines the relationship between prior living arrangements and average activities of daily living (ADL) function upon nursing home admission across two states. METHODS: Minimum Data Set Plus records from 1993 and 1994 on 4,837 Medicaid reimbursed nursing home residents aged 65 years and older from two states were used. Medicaid reimbursed residents were chosen because Medicaid reimbursement policies differ at the state level, and such differences might affect admission characteristics across states. Ordinary least squares models were used to examine the correlates of the number of ADL limitations (range 0-7) upon nursing home admission. RESULTS: Residents in state A had a mean of 5.36 ADL limitations, whereas residents in state B had a mean of 4.83 limitations. Those who lived alone entered the nursing home with 0.61 fewer ADL limitations (p < .001) than those who lived with others. Living alone in state A reduced this association through an increase of 0.31 ADL limitations (p = .012). DISCUSSION: Older Medicaid recipients who live alone enter the nursing home with better physical function than those who live with others. The difference in function between those who live alone and those who live with others varies across the two states.

Time to nursing home admission for persons with Alzheimer's disease: the effect of health care system characteristics.

OBJECTIVE: To study the influence of state health care system characteristics on time to nursing home admission (NHA) for persons with Alzheimer's disease (AD). METHOD: Up to nine years of Consortium to Establish a Registry for Alzheimer's Disease (CERAD) data on 639 non-Latino White individuals were merged with longitudinal data from the 28 states in which the CERAD participants resided. The state variables reflected characteristics of each state's long-term care (LTC) system, including Medicaid LTC spending practices and the supply of LTC providers. Cox Proportional Hazards Models with time-varying covariates were used to evaluate the risk factors associated with time to NHA. RESULTS: There was differential influence of state variables by marital status. For unmarried non-Latino White persons with AD, a higher percentage of Medicaid LTC spending on home and community-based services (HCBS) was significantly associated with a longer time to NHA. For married persons, a greater number of home health agencies was associated with a longer time to NHA. Other associations also varied by marital status. CONCLUSION: Study findings support the utility of targeted continued expanded provision of HCBS by states and provide a basis for future research regarding the impact of changing state health care systems on LTC utilization for persons with AD.

Hip fracture incidence among elderly Hispanics.

OBJECTIVES: This study estimated hip fracture incidence for elderly Hispanics in the United States. METHODS: A cohort of Spanish-surnamed 1992 Medicare enrollees was followed for 2 years. Hip fractures were identified by inpatient diagnostic code. RESULTS: For Hispanic women, the national age-adjusted hip fracture rate was 7.3 per 1000 person-years; for men, the rate was 3.3. Rates varied markedly, with higher rates for the predominantly Mexican-American southwestern states than for Puerto Ricans. CONCLUSIONS: Nationally, the Hispanic population is at intermediate risk of hip fracture between Blacks and Whites, but geographic variation suggests that Mexican Americans are at higher risk than Puerto Ricans.

Gastrostomy placement and mortality among hospitalized Medicare beneficiaries.

CONTEXT: Although the use of feeding tubes among older individuals stirs considerable controversy, population-based descriptive data regarding patient outcomes are scarce. OBJECTIVE: To describe hospitalized Medicare beneficiaries having gastrostomies placed and their associated mortality rates. DESIGN: Retrospective cohort study. SETTING AND PATIENTS: Hospitalized Medicare beneficiaries aged 65 years or older discharged in 1991 following gastrostomy placement (excluding individuals in health maintenance organizations). MAIN OUTCOME MEASURES: Mortality at 30 days, 1 year, and 3 years following gastrostomy and characteristics of individuals undergoing gastrostomy placement. RESULTS: In 1991, claims reflecting gastrostomy insertion were submitted for 81105 older Medicare beneficiaries following hospital discharge. The in-hospital mortality rate was 15.3%. Cerebrovascular disease, neoplasms, fluid and electrolyte disorders, and aspiration pneumonia were the most common primary diagnoses. The overall mortality rate at 30 days was 23.9% (95% confidence interval [CI], 23.65%-24.2%), reaching 63.0% (95% CI, 62.7%-63.4%) at 1 year and 81.3% (95% CI, 81.0%-81.5%) by 3 years. One in 131 white and 1 in 58 black Medicare beneficiaries aged 85 years or older was discharged alive or deceased from a hospital in 1991 following gastrostomy placement. CONCLUSIONS: Gastrostomies are frequently placed in older individuals and more often in blacks; mortality rates following placement are substantial.

Hip fracture incidence among elderly Asian-American populations.

This study estimated national age- and sex-specific nontraumatic hip fracture incidence rates for elderly Chinese Americans, Japanese Americans, and Korean Americans. Based on a 50 percent sample of 1992 Medicare enrollees with the race/ethnicity code "Asian" and "other," cohorts of persons with distinctive Chinese (n = 24,366), Japanese (n = 28,762), and Korean (n = 5,470) names were followed passively for 2 years for a hospitalization with a diagnostic code indicating hip fracture. Cohorts of whites and blacks were followed for comparison. Year of immigration was deduced from the year of issuance of the Social Security number. Age-adjusted hip fracture incidence was lower for all three Asian-American groups than for whites. For females, the standardized fracture ratio relative to whites was 30.1 for Chinese, 73.2 for Japanese, and 52.8 for Koreans; for males, the standardized fracture ratio was 41.9 for Chinese, 58.1 for Japanese, and 90.7 for Koreans. Persons whose Social Security numbers were issued after the immigration Act of 1965 had an adjusted relative risk of 1.37 (95% confidence interval 1.05-1.78) compared with those in the US before that year, after adjustment for age, sex, and ethnic group.

Race and sex differences in mortality following fracture of the hip.

This paper describes the all-cause mortality experience, following a fracture of the hip, of 712,027 persons covered by the Medicare program from 1984 through 1987. White women experienced the lowest mortality rate (17.2 per 1000 person-months), followed by Black women (22.9 per 1000 person-months), Black men (33.5 per 1000 person-months), and White men (33.7 per 1000 person-months). The observed race-sex differences in survival were found at all ages and regardless of the number of comorbid conditions listed with the discharge diagnosis. While these data demonstrate marked race-sex differences in survival following hip fracture, the cause of these differences is not immediately apparent and demands further investigation.