Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

STUDY QUESTION: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Variability in sleep disturbance, physical activity and quality of life by level of depressive symptoms in women with Type 2 diabetes.

AIMS: To examine (1) the prevalence of depressive symptoms in women with Type 2 diabetes, (2) the associations between depressive symptoms and the following dependent variables: sleep disturbance; physical activity; physical health-related; and global quality of life, and (3) the potential moderating effects of antidepressants and optimism on the relationship between depressive symptoms and dependent variables. METHODS: Participants in the Women's Health Initiative who had Type 2 diabetes and data on depressive symptoms (N=8895) were included in the analyses. In multivariable linear regression models controlling for sociodemographic, medical and psychosocial covariates, we examined the main effect of depressive symptoms, as well as the interactions between depressive symptoms and antidepressant use, and between depressive symptoms and optimism, on sleep disturbance, physical activity, physical health-related quality of life; and global quality of life. RESULTS: In all, 16% of women with Type 2 diabetes reported elevated depressive symptoms. In multivariable analyses, women with depressive symptoms had greater sleep disturbance (P<0.0001) and lower global quality of life (P<.0001). We found evidence of significant statistical interaction in the models for quality-of-life outcomes: the increased risk of poor physical health-related quality of life associated with antidepressant use was stronger in women without vs with depressive symptoms, and the association between greater optimism and higher global quality of life was stronger in women with vs without depressive symptoms. CONCLUSIONS: To improve health behaviours and quality of life in women with Type 2 diabetes, sociodemographic and medical characteristics may identify at-risk populations, while psychosocial factors including depression and optimism may be important targets for non-pharmacological intervention.

The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

An immunodominant epitope present in multiple class I MHC molecules and recognized by cytotoxic T lymphocytes.

CTL derived from (C3H x B6.K1)F1 animals were sensitized against L cells that express the transfected gene product Q10d/Ld. These CTL were highly crossreactive against three other class I molecules, H-2Kbm1, H-2Ld, and H-2Kd. In an attempt to define this crossreactive epitope it was noted that between 25 and 39% of amino acids in the alpha helices and central beta strands of these three molecules vary from Q10d. These amino acids represent residues that have been proposed to potentially interact with a peptide antigen or TCR (21). However, all four molecules share the amino acid tyrosine at positions 155 and 156. Additionally, Q10d, H-2Kbm1, and H-2Ld share alanine at position 152, while H-2Kd has an aspartic acid. We showed that these residues were important in controlling this epitope by the finding that anti-Q10d CTL did not recognize H-2Kbm1 revertant molecules that had either the position 152 alanine changed back to the wild-type H-2Kb residue (glutamic acid) or position 155 and 156 tyrosines changed back to wild-type residues arginine and leucine. Further evidence that these molecules share a crossreactive epitope was noted by the failure of (C3H x H-2Kbm1)F1 animals to generate CTL that recognized H-2Ld or H-2Kd, and the inability of (C3H x BALB/c)F1 animals to generate CTL reactive against H-2Kbm1. CTL from these mice were still able to recognize Q10d/Ld indicating that other epitopes could be detected if natural tolerance prevented recognition of the crossreactive epitope. To further define the epitope, CTL clones were generated against Q10d/Ld and maintained on either H-2Kbm1 or BALB/c feeder cells. In addition to testing these clones on the target cells described above, mutant molecules derived from H-2Ld, which have amino acid substitutions in their alpha 1 domain, were analyzed. It was noted that some anti-Q10 clones that did not crossreact on H-2Ld did react against H-2Ld mutant antigens that had H-2Dd amino acid substitutions in the alpha 1 domain at positions 63, 65, 66, and 70. Other clones had differential reactivities on these H-2Ld mutants further substantiating that alpha 1 domain amino acids play a role in controlling the expression of the crossreactive epitope. Thus, four class I molecules with multiple amino acid differences in their alpha 1 and alpha 2 domains share a crossreactive epitope readily recognized by alloreactive CTL.(ABSTRACT TRUNCATED AT 250 WORDS)

Selection of mammalian cells resistant to a chloramphenicol analog.

This study describes the selection and preliminary characterization of mammalian cells resistant to 100 mug Tevenel/ml. Tevenel, the sulfamoyl analog of chloramphenicol, is a specific inhibitor of mitochondrial protein synthesis. After growth in suspension culture for 5 days in 100 mug Tevenel/ml and subsequent plating in 100 mug Tevenel/ml, LMTK- cells yielded resistant clones. As a control, L cells treated identically yielded no clones. Three resistant clones were chosen for study. Each resistant cell line had an identical growth rate in the presence and absence of 100 mug Tevenel/ml. By plating efficiency analysis, the resistant cells were found to be cross-resistant to D-chloramphenicol. The change responsible for resistance was found to be stable for at least 100 generations in the absence of the drug. Protein synthesis by isolated mitochondria of resistant cells was found to be less inhibited by concentrations of both Tevenel and D-chloramphenicol up to 200 mug/ml than the protein synthesis by LMTK- mitochondria. This resistance in vitro was not changed by incubation of the mitochondria in 0.01% Triton X-100.

Localization of the globin gene in the template active fraction of chromatin of Friend leukemia cells.

Friend leukemia cell chromatin has been fractionated into template active and inactive components. The globin gene sequence is associated with the template active component both prior to and after the cells are induced with dimethyl sulfoxide to synthesize hemoglobin and therefore appears to be in an active configuration in uninduced as well as in induced Friend leukemia cells. In cells which have lost the ability to produce hemoglobin, the globin gene sequence is not associated with the template active fraction of chromatin. These results demonstrate the success of the fractionation procedure.

Directed deletion of a yeast transfer RNA intervening sequence.

Many eukaryotic genes contain intevening sequences, segments of DNA that interrupt the continuity of the gene. They are removed from RNA transcripts of the gene by a process known as splicing. The intervening sequence in a yeast tyrosine transfer RNA (tRNA Tyr) suppressor gene was deleted in order to test its role in the expression of the gene. The altered gene and its parent were introduced into yeast by transformation. Both genes exhibited suppressor function, showing that the intervening sequence is not absolutely essential for the expression of this gene.

Participatory planning of interventions to mitigate human-wildlife conflicts.

Conservation of wildlife is especially challenging when the targeted species damage crops or livestock, attack humans, or take fish or game. Affected communities may retaliate and destroy wildlife or their habitats. We summarize recommendations from the literature for 13 distinct types of interventions to mitigate these human-wildlife conflicts. We classified eight types as direct (reducing the severity or frequency of encounters with wildlife) and five as indirect (raising human tolerance for encounters with wildlife) interventions. We analyzed general cause-and-effect relationships underlying human-wildlife conflicts to clarify the focal point of intervention for each type. To organize the recommendations on interventions we used three standard criteria for feasibility: cost-effective design, wildlife specificity and selectivity, and sociopolitical acceptability. The literature review and the feasibility criteria were integrated as decision support tools in three multistakeholder workshops. The workshops validated and refined our criteria and helped the participants select interventions. Our approach to planning interventions is systematic, uses standard criteria, and optimizes the participation of experts, policy makers, and affected communities. We argue that conservation action generally will be more effective if the relative merits of alternative interventions are evaluated in an explicit, systematic, and participatory manner.

Videometric analysis of regional left ventricular function before and after aortocoronary artery bypass surgery: correlation of peak rate of myocardial wall thickening with late postoperative graft flows.

The peak rate of systolic wall thickening (pdTw/dt) in regions of the left ventricle was determined by biplane roentgen videometry in 60 patients before and a median of 14 mo after aorto-coronary bypass graft surgery. The left ventricular ejection fraction, stroke volume, and end-diastolic volume and pressure did not change significantly after surgery in the presence of patent or occluded grafts (P greater than 0.05). Statistically significant increases occurred in the peak rate of systolic wall thickening regions supplied by patent bypass grafts, and significant decreases occurred in regions with occluded grafts (P less than 0.01). Of 42 preoperatively hypokinetic regions (pdTw/dt greater than 0 less than 5.0 cm/s) supplied by a patent graft, 30 improved by an average of 2.6 cm/s after operation; 18 returned to normal. Failure of 24 hypokinetic regions to improve to normal was associated with myocardial infarction in 11 or with late postoperative graft blood flows of less than 60 ml/min measured by videodensitometry, in 10. All seven preoperatively akinetic (pdTw/dt=0) or dyskinetic (pdTw/dt less than 0) regions did not improve after the operation despite the fact that, in five of the seven, coronary bypass flows were over 60 ml/min. All eight preoperatively hypokinetic regions supplied by coronary artery graft flows of less than or equal 40 ml/min failed to improve to normal after operation. All nine preoperatively hypokinetic regions supplied by coronary artery graft flows of over 60 ml/min improved to normal after surgery. Late postoperative coronary artery bypass graft flows, the functional status of the myocardium, the status and distribution of the native coronary circulation, and decreased regional function elsewhere in the ventricle must all be considered when regional left ventricular function is interpreted.

Prevalence of dementia in the United States: the aging, demographics, and memory study.

AIM: To estimate the prevalence of Alzheimer's disease (AD) and other dementias in the USA using a nationally representative sample. METHODS: The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. RESULTS: The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71-79 years to 37.4% of those aged 90 and older. CONCLUSIONS: Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.

Liver-specific expression of a Qa-encoded class I gene is associated with DNA hypomethylation.

DNA methylation of two murine major histocompatibility complex (H-2) class I genes was examined in hybridizations to MspI and HpaII chromosomal DNA restriction digests. Q10, which exhibits liver-specific expression, and H-2Kb, a transplantation antigen gene, were examined in liver, spleen, thymus, and cell-line DNAs. Unmethylated Q10 gene sequences were detected only in the liver, whereas the H-2Kb gene was unmethylated in all tissues examined.

Identification of the cloned gene for the murine transplantation antigen H-2Kb by hybridization with synthetic oligonucleotides.

The H-2K(b) gene is a member of the large major histocompatibility complex class I gene family. Since many members of this family cross-hybridize with class I cDNA probes, the cloned H-2K(b) gene was identified by hybridization with specific oligonucleotide probes. This clone was definitively shown to encode the H-2K(b) polypeptide by partial DNA sequencing and by serological and tryptic peptide analyses of the expressed product.

Cancer incidence in humans: relationship to plasma lipids and relative weight.

Surveillance was done on cancers in subjects in rural Iowa for 6 years after they participated in a cardiovascular risk factor-screening program. Among 5,565 men and women 20-94 years old at screening, 131 persons were identified as having cancers. Each cancer patient was matched to a control without cancer, and differences in antecedent plasma cholesterol and triglyceride levels and relative weight were sought. Mean relative weight at screening was lower among cancer patients of both sexes than among controls. Plasma cholesterol levels were lower among male patients and higher among female patients than among controls, with the differences more prominent for those less than 60 years old at screening. In males, the lower cholesterol levels occurred only in those with neoplasms developing within 24 months of screening. The higher cholesterol levels among female patients with cancers limited to gonadal hormone-related sites were not time-dependent. Triglyceride levels were not significantly different between cancer patients and controls in any analytic group, but triglyceride levels did closely parallel cholesterol alterations. A minimum of 1% of the cohort had diagnosed cancers before the screening program.

Chronically depressed mood and cancer risk in older persons.

BACKGROUND: Depression has been proposed as a predisposing factor for cancer, but prospective studies have been inconclusive. We examined whether a high level of depressive symptoms, present for a long time, is associated with increased risk of cancer in the elderly. METHODS: Data were obtained and analyzed from persons who lived in three communities (Massachusetts, Iowa, and Connecticut) of the Established Populations for Epidemiologic Studies of the Elderly, a prospective cohort study with a mean follow-up of 3.8 years that included 4825 persons (1708 men and 3117 women) aged 71 years and older. Chronically depressed mood was defined as present when the number of depressive symptoms exceeded specific cut points on the Center for Epidemiologic Studies-Depression scale at baseline (1988) and 3 and 6 years before baseline. New cases of cancer were identified from Medicare hospitalization records and death certificates. RESULTS: Of the 4825 persons studied, 146 (3.0%) were chronically depressed. The incidence rate of cancer was 30.5 per 1000 person-years for the 146 persons with chronic depression and 21.9 per 1000 person-years for the 4679 nonchronically depressed persons. After adjustment for age, sex, race, disability, hospital admissions, alcohol intake, and smoking, the hazard ratio for cancer associated with chronically depressed mood was 1.88 (95% confidence interval = 1.13-3.14). The excess risk of cancer associated with chronic depression was consistent for most types of cancer and was not specific to cigarette smokers. CONCLUSION: When present for at least 6 years, depression was associated with a generally increased risk of cancer.

Medical history risk factors for non-Hodgkin's lymphoma in older women.

BACKGROUND: It has been suggested that certain medical conditions and drug exposures might suppress the immune system and increase the risk of developing non-Hodgkin's lymphoma (NHL). PURPOSE: We investigated whether specific medical conditions and drug exposures were associated with the risk of NHL in a cohort of older women who were enrolled in the Iowa Women's Health Study. METHODS: A cohort of 41837 women, 55-69 years of age at baseline, was followed prospectively for the development of cancer from 1986 through 1992. These women had completed a baseline questionnaire in January 1986 that inquired about the occurrence and age at onset of specific medical conditions, about family history of cancer, and about the use of selected medications. Follow-up questionnaires were mailed to the women in 1987, 1989, and 1992. Incident cancers and deaths were ascertained through linkages to state and national databases. For most analyses, women with a self-reported history of cancer at baseline (n = 3903) were excluded. Relative risks (RRs) and 95% confidence intervals (CIs), adjusted for age or for age and other variables, were used as a measure of the association between NHL and medical history factors. Reported P values are two-sided. RESULTS: One hundred fourteen incident cases of NHL were identified in the cohort during follow-up. A history of adult-onset diabetes mellitus (i.e., first diagnosed after the age of 30 years) was associated with an increased risk of developing NHL (age-adjusted RR = 2.18; 95% CI = 1.22-3.90). In addition, there was an association between the duration of adult-onset diabetes and increasing risk of NHL (P for trend = .004), with an age-adjusted RR of 2.90 (95% CI = 1.07-7.90) for women with a diagnosis of diabetes for 15 or more years compared with women with no diagnosis of diabetes. Women with a history of blood transfusion were also at increased risk for the development of NHL (age-adjusted RR = 1.95; 95% CI = 1.33-2.85). The risk estimates for diabetes and transfusion history were independent of each other and were not changed substantially after adjustment for other risk factors. History of a previous cancer (excluding hematopoietic and lymphatic cancers) was associated with an increased risk of NHL (age-adjusted RR = 1.92; 95% CI = 1.21-3.06); this risk estimate was attenuated somewhat after adjustment for a history of diabetes, transfusion history, and other major risk factors (RR = 1.66; 95% CI = 1.02-2.69). No statistically significant associations were found between NHL and a history of chronic colitis, nonestrogen steroid use, use of exogenous estrogens, or use of thyroid medications. CONCLUSIONS AND IMPLICATIONS: A history of adult-onset diabetes mellitus, blood transfusion, and a history of cancer (or its treatment) appear to be independent risk factors for NHL in older women.

Cyclic ovarian function and breast cancer.

We postulated previously that systematic differences in menstrual cycle length and/or variability might be used as indicators of underlying hormonal abnormalities that could help explain the endocrine biology of some breast cancer risk factors. In the present study, we prospectively and retrospectively analyzed menstrual cycle patterns in breast cancer cases and controls in two populations. No significant differences were found. This and previous studies emphasize that contemporary women have a long reproductive experience characterized by uninterrupted, regular menses, which is a condition of maximum ovulation potential and which contributes to estrogen stimulation over time.

Menstrual cycle patterns and breast cancer risk factors.

Using a data set of women who longitudinally recorded menstrual and reproductive events, we examined menstrual cycle characteristics in relationship to early and late menarche, early and late menopause, and deferred parity, three variables epidemiologically related to breast cancer incidence. Women with late onset of menarche had longer and more variable cycles in the 10 years after menarche than did those with early onset. Women with late onset of menopause had longer and more variable cycles in the premenopausal interval than did those with early onset. Cumulative fertility in women after marriage did not differ according to cycle length and variance. Late menopause may be a breast cancer risk factor due to relative estrogen excess and progesterone lack as reflected in longer, more varied cycle patterns. Observed cycle differences between women with early and late menarche await further study of the endocrine physiology of the menstrual cycle in those groups.

Chemical and physical properties of mammalian mitochondrial aminoacyl-transfer RNAs. I. Molecular weights of mitochondrial leucyl- and methionyl-transfer RNAs.

The sedimentation and electrophoretic properties of Syrian hamster cytosolix and mitochondrial methionyl- and leucyl- +RNAs have been compared under denaturing conditions. Mitochondrial leucyl-tRNA could be separated into three species by chromatography on RPC-5. Their apparent molecule weights as determined by polyacrylamide slab gel elecltrophoresis were 23 000 for one species and 24 000 for the other two compared to the five cytosolic leucyl-tRNA species whose apparent molecular weights ranged from 26 000 to 28 000. Mitochondrial leucyl-tRNAs sedimented more slowly than their cytosolic counterparts, again indicating a lower molecular weight. The apparent molecular weights of the mitochondrial methionyl-tRNAs were identical or only slightly lower than their cytosolic counterparts as determined by polyacrylamide slab gel electrophoresis but both mitochondrial methionyl-tRNA and formylmethionyl-tRNA sedimented slightly more slowly than cytolsolic methionyl-tRNA. It is suggested that mitochondrial tRNAs fall into the size range of other t RNAs and might be uniform in size.

Chemical and physical properties of mammalian mitochondrial aminoacyl-transfer RNAs. II. Analysis of 7-methylguanosine in mitochondrial and cytosolic aminoacyl-transfer RNAs.

The 7-methylguanosine (m7G) content of two individual mitochondrial tRNAs, labelled in the aminoacyl moiety was assayed by the specific cleavage of the tRNA at this nucleotide followed by electrophoretic analysis to identify the 3'-terminal fragment of the tRNA. Neither Syriam hamster mitochondrial tRNALeu nor tRNAMet were found to contain m7G. In contrast, cytosolic tRNAMetS were cleaved indicating the presence of m7G, apparently 27--28 and 29 nucleotides from their 3' terminus. Cystolic tRNALeu was not cleaved. These results are discussed in relationship to the reported low content of methylated nucleosides in mitochondrial 4 S RNA.