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).

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.

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.

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.

Neurologic disorders following surgery for peptic ulcer disease.

The neurologic status of 2,000 veterans who had had surgery for peptic ulcer between 1952 and 1957 was evaluated. In 1970, a total of 156 of these men were examined, 97 of whom had procedures that disrupted the normal continuity of the upper gastrointestinal tract. Twenty-one had neurologic disorders, including 17 patients with peripheral neuropathies. Procedures bypassing the ampulla of Vater were performed in 15 of these. The only detected factor associated with neurologic manifestations was weight loss since surgery. A mortality study of the total population revealed 865 patients had died by the end of 1973. There were seven deaths attributed to neurologic causes, one in a patient with amyotrophic lateral sclerosis and one in another with spinal paralysis. All seven were among the 70% of the deceased who had had surgery that disrupted the continuity of the upper gastrointestinal tract. Thus, we conclude that the type of surgery influenced the likelihood of neurologic complications, but at least for motor neuron disease, the increased risk was not appreciable.

Familial motor neuron disease. Evidence for at least three different types.

Based on a clinical, pathologic, and genetic study of 14 families, at least three types of familial motor neuron disease can be distinguished, all apparently of autosomal dominant transmission. The first is characterized by rapid, progressive loss of motor function with predominantly lower motor neuron manifestations and a course lasting less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second type is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke's column, and spinocerebellar tracts. The third type is characterized by a much longer survival usually beyond 10 and after more than 20 years in affected family members but is otherwise similar to the second type.

Predicting the duration of Guam amyotrophic lateral sclerosis.

During the years of study of amyotrophic lateral sclerosis on Guam we have observed a wide range in clinical signs and rate of progression of the disease. Some patients died within 6 months of onset, while others have lived for 20 years. It was our assumption that some aspects of the early neurologic involvement would be related to length of survival, and hence be of prognostic value. We found that an early age at onset and male sex were associated with longer survival. The detailed analysis of degree of involvement of four major neurologic components of amyotrophic lateral sclerosis (progressive muscular atrophy, lateral sclerosis, bulbar paralysis, and pseudobulbar palsy) showed no meaningful pattern of association with duration of illness that could be useful in predicting the course.

Twin study of multiple sclerosis: an epidemiologic inquiry.

The National Research Council Twin Registry comprises 16,000 pairs of white male twins, both members of which had been in military service, mainly in World War II. All their available military and Veterans Administration records and their responses to a 1965 to 1970 NRC questionnaire have been coded as to disease. Upon review we found 16 cases of multiple sclerosis (MS) among 15 pairs of twins, for an age-specific prevalence rate of 51 per 100,000 veterans aged 43 to 53--about half the expected frequency. Of the 15 sets, three sets refused cooperation and three were unavailable for study. Nine sets were examined and interviewed together with the mother. One of five monozygotic twin pairs was concordant for MS and in another the co-twin of an MS case had had a solitary episode of retrobulbar neuritis; all others were discordant. There were more definable environmental events (as noted below) among the affected twins than among the unaffected co-twins. The greatest excess was within the 20 years before onset. Summing events across the four 5-year periods before onset, among the 10 MS versus the eight not-MS individuals, there were 5:1 instances of trauma, 8:2 or operation, 7:1 of ether anesthesia, 7:1 of allergy, 10:5 of infection, and 9:0 of animal exposure. Summing these same events within each 5-year period, the MS:control ratios were 9:1, 10:2, 12:3, and 15:4, respectively, for 0 to 4, 5 to 9, 10 to 14, and 15 to 19 years before onset.

Aging and alcohol abuse.

Demographic information suggests that the problems of alcohol abuse among the elderly will increase at least in proportion to the population growth of that sector. While fewer older people drink and average consumption declines, four factors that promote alcohol abuse are noted. These are: 1) retirement, with its attendant boredom, change of role status, and loss of income; 2) deaths occurring among relatives and friends and the awareness that more deaths are coming; 3) poor health and discomfort; and 4) loneliness, a particular problem among elderly women. Surveys in older age groups, in addition to being costly, are of questionable value. Anecdotal evidence and several early studies, however, suggest that a high proportion of elderly (10 to 15 per cent) who seek medical attention for any reason have an alcohol-related problem, and that elderly alcoholics, whether alcoholism is of early or recent onset, are relatively easy to treat. If these findings can be confirmed, then detection during health-seeking encounters could have great potential value. Research in detection and treatment is critical. A prevention strategy involving the cohort 55 to 64 years of age could have the dual effect of preventing subsequent alcohol problems among these people and offering a message that would be heard by those at older and less accessible ages.

Lymphocyte transformation in presumed ocular histoplasmosis.

Lymphocytes from individuals with inactive macular disciform lesions of presumed ocular histoplasmosis challenged with three histoplasmin antigens incorporated tritiated thymidine at a significantly higher rate than histoplasmin-stimulated lymphocytes of matched control and peripheral scar groups. This finding is consistent with the etiologic association of the disciform ocular syndrome and previous systemic infection with Histoplasma capsulatum. The disciform group had a higher mean response than the other two groups to pokeweed mitogen but not to phytohemagglutinin and had higher mean counts per minute to the specific antigens Toxoplasma gondii, Blastomyces dermatitidis, Cryptococcus neoformans, Mycobacterium tuberculosis, M battery, and M gaus, but not to Candida albicans. These data would suggest that individuals with the disciform lesion of presumed ocular histoplasmosis have a hyperreactive cellular immune response; this response may play an important role in the development of the disciform.

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.

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.

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.

Facts, projections, and gaps concerning data on aging.

In 1900, approximately 25 percent of all deaths occurred in people 65 years of age and over, while today the age at death has been pushed back so that, by 1980, 30 percent of deaths occurred in those over age 80. The greatest declines in age-specific mortality for those 65 and over occurred from 1920 to 1945 and since 1970. Illness and disability rise with age, and there is some evidence that rates of disability in all age groups may be increasing. Measurement of morbidity and disability is the area where data are weakest and our needs for data are perhaps greatest. Agreement is needed on the use, limitations, and interpretations of surveys and of data relating to functional status. In a few years, medical students and physicians will be computer literate. We should plan now for a better utilization of the already available Federal data sets as well as implementation of computerized health care information on individual patients. Some modifications of privacy legislation will probably be necessary in order for physicians to give better care to their patients, and to provide epidemiologic research opportunities in critical areas of public health needs. Caution is urged in order to maintain credibility in health promotion by avoiding overstatement of knowledge in areas where scientific evidence is weak or lacking. Better utilization and development of epidemiologic and statistical information as well as basic research in chronic diseases are urged to prepare for the year 2025, when there will be some 60 million Americans age 65 and over--about 20 percent of the total population.

National health and nutrition examination I--epidemiologic follow-up survey.

An epidemiologic follow-up of the first National Health and Nutrition Examination Survey (NHANES I), being conducted from 1982 to 1984, is expected to provide estimates of the risks of certain health conditions for a sample of the U.S. population and to make it possible to relate these conditions to the nutritional, social, demographic, and behavioral characteristics of the sample. As part of the followup study, the baseline data obtained in NHANES I have been reviewed to define hypotheses and to identify pertinent variables that can be used in studying changes over time and the relationships of these variables to outcome measures. Because the followup study provides cohort data on a large sample of the U.S. population, it presents a unique opportunity for epidemiologists.

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.

Alcohol problems among employed men and women in metropolitan Detroit.

A survey of employed adults in metropolitan Detroit showed that more men than women had alcohol problems but this was largely attributable to the higher percentage of alcohol-dependent drinkers among men. There was little difference between the percentages of men and women who could be identified as nondependent problem drinkers.

The impact of fathers' drinking on cognitive loss among social drinkers.

This chapter examines cognitive loss in social drinkers. The question of concern is whether the relationship between increased levels of alcohol consumption and reduced sober cognitive performance is misspecified. In particular, does reduced abstraction performance in social drinkers result from parental heavy drinking rather than, as we have proposed, from social drinkers' current use of alcohol. Because offspring of alcoholics may be at high risk for cognitive deficits even in childhood, these deficits may be transmitted in alcoholic families. Thus, the relationship between increased drinking and sober cognitive loss might be eliminated if parental drinking is controlled. We report here, however, that the effects of current alcohol use on abstraction performance in a representative sample of employed men and women cannot be accounted for by fathers' drinking. Our findings indicate the need for further research on both the cognitive effects of parental drinking and current alcohol use.

Estrogen use and postmenopausal women: a basis for informed decisions. NIH Consensus Development.

A panel of experts convened by the National Institute on Aging, National Institutes of Health, reached the following consensus regarding estrogen use and postmenopausal women. The use of estrogens alleviates vasomotor symptoms and atrophy of the vaginal epithelium and might aid in preventing osteoporosis. However, it increases the incidence of endometrial cancer. The addition of progestins might prevent this complication, but potential risks have not been adequately evaluated. Convincing evidence that postmenopausal estrogen use influences the occurrence of cardiovascular disease and breast cancer does not currently exist. Many aspects of the menopause and its management require further research. Any candidate for postmenopausal estrogen use should be given as much information as possible about both benefits and risks and then, with her physician, reach an individualized decision regarding whether to receive estrogens.

PIP: This National Institutes of Health consensus report of a panel of experts summarizes the currently available information on postmenopausal estrogen use, as presented by the invited speakers, panelists, and members of the audience, and each section published here represents an excerpt of the consensus statement followed by commentary. Reference to 3 background papers, which are published and available, is made for presentation of more detailed discussion. The following consensus was reached concerning estrogen use and postmenopausal women: 1) the use of estrogens alleviates vasomotor symptoms and atrophy of vaginal epithelium and may aid in preventing osteoporosis. The possibility of increased incidence of endometrial cancer with estrogen use is also acknowledged. Combinations of progestin and estrogen may alleviate this increased risk, but potential risks of progestin have not been studied adequately in postmenopausal women with no ovarian function. 2) there is no convincing evidence that postmenopausal estrogen use influences occurrence of cardiovascular disease and breast cancer. Also agreed upon is the patient management of a potential estrogen replacement therapy candidate: she should be given as much information as possible about both benefits and risks and with her physician's help, she should reach an individualized decision about estrogen use.