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Debbie A Lawlor

Publications and source records attributed to Debbie A Lawlor.

At least 19 recordsLinked to original sources
PubMed2007

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Aged↗
PubMed2007

The association of the paraoxonase (PON1) Q192R polymorphism with depression in older women: findings from the British Women's Heart and Health Study.

BACKGROUND: The association between the R allele of PON1 Q192R and symptoms reported by sheep dippers and Gulf War veterans has been used to suggest a biological basis for these symptoms. In the absence of such studies in non-occupational populations, these conclusions may not be valid. OBJECTIVE: To examine the association of paraoxonase (PON1) Q192R with a report of ever being diagnosed with depression among a random sample of 3266 British women, aged 60-79 years. RESULTS: The R allele of PON1 Q192R was associated with depression: per-allele odds ratio 1.22 (95% confidence interval: 1.05 to 1.41) in this population. CONCLUSIONS: These findings suggest that the association of PON1 Q192R with symptoms of depression in occupationally exposed groups may be driven by exposure to toxins that everyone in the general population is exposed to rather than exposure to toxins specifically used by sheep dippers or Gulf War veterans, or that other mechanisms underlie the association. This is because the study population in which we have found an association consisted of British women aged 60-79 years, few of whom were sheep dippers or Gulf War veterans. When using genotype-outcome associations to infer causality with respect to an environmental exposure modified by the genotype, it is important to examine these associations in general populations and in those specifically exposed to the putative agent. The possible role of PON1 Q192R in psychiatric morbidity requires further examination.

Aged↗
PubMed2006

Associations between childhood intelligence and hospital admissions for unintentional injuries in adulthood: the Aberdeen Children of the 1950s cohort study.

OBJECTIVES: We examined associations between childhood intelligence and hospital admissions for injuries in adulthood. METHODS: Data were derived from a cohort study (=11103) involving individuals born in Aberdeen, Scotland, between 1950 and 1956. RESULTS: Overall, 1043 cohort members had at least 1 hospital admission resulting from an unintentional injury over 231152 person-years of risk. There were inverse linear associations between childhood intelligence assessed at the ages of 7, 9, and 11 years and having had a hospital admission stemming from an unintentional injury (gender-adjusted hazard ratio [HR] for a 1-standard-deviation increase in intelligence test score at age 7 years = 0.75; 95% confidence interval [CI]=0.70, 0.80). These associations were not markedly affected by adjustment for childhood socioeconomic status, maternal age or height, birthweight, or childhood growth. However, they were attenuated after adjustment for educational attainment (HR=0.85; 95% CI=0.78, 0.91). CONCLUSIONS: Childhood intelligence is related to hospital admissions for injuries in adulthood, and this relationship is partly explained by educational attainment. The association between childhood intelligence and injury may contribute to the association between childhood intelligence and premature mortality demonstrated in several studies.

Accidents↗
PubMed2006

Cognitive function in childhood and early adulthood and injuries later in life: the Metropolit 1953 male birth cohort.

BACKGROUND: It has been suggested that cognitive function in childhood is a modifiable risk factor for adult injury. This study examines the relationship between cognitive function measured at the age of 12 and 18 years and fatal and non-fatal injuries later in adult life. METHODS: A total of 11 532 males born in Copenhagen, Denmark in 1953 were followed from 1978 until 2001 with outcomes (death from and hospital admission for unintentional injury) obtained from national registers. At the age of 12 years, 7987 of these cohort members had completed a questionnaire, which included information on cognitive performance. In addition, cognitive test scores measured on most (90%) cohort members were retrieved from the conscription board records (18 years). RESULTS: During follow-up, 100 of the men died as a result of and 2123 had been admitted to hospital at least once for injury. Cognitive function measured at both the age of 12 and 18 years was inversely associated with any form of unintentional injury. Adjustment for educational attainment at the age of 18 years attenuated these associations but did not remove them completely. The association was most evident for falls and poisoning, while associations with other injury types were weaker and disappeared after adjustment for educational status. Cognitive function was associated with repeated hospital admissions for injuries as well as length of hospital stay. CONCLUSIONS: We found marked inverse associations between cognitive function measured in ages 12 and 18 years and adult risk of fatal or non-fatal unintentional injury. An overall increase in educational level may result in a reduction in adult injury risk.

Accidental Falls↗
PubMed2006

Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the mater-university study of pregnancy and its outcomes.

The fetal overnutrition hypothesis proposes that greater maternal adiposity results in increased obesity throughout life in the offspring. The authors examined the associations between parental prepregnancy body mass index (BMI; weight (kg)/height (m)(2)), based on height and weight reported by the mother at her first antenatal clinic visit, and offspring BMI (height and weight measured at age 14 years) in 3,340 parent-offspring trios from a birth cohort based in Brisbane, Australia (mothers were recruited in 1981-1984). The maternal-offspring BMI association was stronger than the paternal-offspring BMI association. In the fully adjusted model, the increase in standardized offspring BMI at age 14 for a one-standard-deviation (SD) increase in maternal BMI was 0.362 SD (95% confidence interval: 0.323, 0.402), and the corresponding result for a one-SD increase in paternal BMI was 0.239 SD (95% confidence interval: 0.197, 0.282). There was statistical support for a difference in the magnitude of the association between maternal-offspring BMI and paternal-offspring BMI in all confounder-adjusted models tested (all p's < 0.0001). In sensitivity analyses taking account of different plausible levels of nonpaternity (up to 15%), the greater maternal effect remained. These findings provide some support for the fetal overnutrition hypothesis.

Adolescent↗
PubMed2006

Socio-economic position and the use of preventive health care in older British women: a cross-sectional study using data from the British Women's Heart and Health Study cohort.

BACKGROUND: Socio-economic inequalities in health may be due to differential uptake of preventive and therapeutic medical services. OBJECTIVES: To examine socio-economic position and self-reported use of six preventive services in a cohort of older British women. METHODS: Women randomly selected from general practice age/sex registers in 23 towns were examined from 1998 to 2001. Of all, 3652 women aged 62-83 years completed a questionnaire in 2003 assessing preventive service use. RESULTS: Women from manual social classes were less likely to have recent flu vaccinations [odds ratio (OR) 0.85, 95% confidence interval (CI) 0.74, 0.98] and dental (OR 0.42, 95% CI 0.36, 0.49), eye (OR 0.77, 95% CI 0.67, 0.88) or chiropody examinations (OR 0.88, 95% CI 0.77, 1.01). Manual social class was not related to having recent blood pressure or cholesterol checks. CONCLUSIONS: Among older British women, preventive services for cardiovascular disease are not socially patterned. However, those from lower socio-economic groups are less likely to have recent flu vaccinations and dental, eye and chiropody examinations.

Aged↗
PubMed2006

Is there a fetal origin of depression? Evidence from the Mater University Study of Pregnancy and its outcomes.

It is unclear whether there is a fetal origin of adult depression. In particular, previous studies have been unable to adjust for the potential effect of maternal depression during pregnancy on any association. The association of birth weight with adult symptoms of depression was examined in an Australian prospective birth cohort, the Mater University Study of Pregnancy and its outcomes. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale among 3,719 participants at the 21-year follow-up in 2002-2005. In multivariable analyses, there were a weak inverse association between birth weight and symptoms of depression in the whole cohort and some evidence of sex differences in this association. Among females, there was a graded inverse association: In the fully adjusted model, the odds ratio for a high level of depressive symptoms for a 1-standard deviation increase in birth weight (gestational age-standardized z score) was 0.82 (95% confidence interval: 0.73, 0.92). Among males, there was no association (with sex in all models: p(interaction) < 0.004). Study results provide some support for a fetal origin of adult depression and suggest that the association is not explained by maternal mental health characteristics during pregnancy. Further research is needed to better understand the mechanisms underlying the association.

Adolescent↗
PubMed2006

Social inequalities in antidepressant treatment and mortality: a longitudinal register study.

BACKGROUND: Despite an increased prevalence of depression among people of low socio-economic position, it remains unclear whether their treatment with antidepressants appropriately matches their increased need compared with people from more affluent backgrounds. This study examined socio-economic differences in antidepressant prescriptions and mortality related to depressive disorders. METHOD: A longitudinal register study of 17947 male and 47458 female local government employees with linked information on socio-economic indicators (education and occupational status) and data on antidepressant use and mortality associated with depressive disorder (suicide, alcohol-related deaths) during the years 1994 to 2000. RESULTS: In men, antidepressant treatment was less common among low educational groups than among high educational groups (OR 0.87, 95% CI 0.76-0.99) and a corresponding difference was seen between occupational statuses (OR for manual v. upper non-manual 0.72, 95% CI 0.62-0.84). In women, socio-economic position was not associated with antidepressant use. However, both among the men and women, employees with low socio-economic position had increased risk for mental-health-related mortality, as indicated by suicides, deaths from alcohol-related causes, and all-cause mortality. CONCLUSIONS: These data suggest a mismatch in the treatment of depression relative to apparent clinical need, with the lowest levels of treatment concentrated in the lower socio-economic groups, despite evidence of their increased prevalence of depression and suicide.

Adult↗
PubMed2006

A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

Adult↗
PubMed2006

Association of childhood socioeconomic position with cause-specific mortality in a prospective record linkage study of 1,839,384 individuals.

Previous studies have lacked sufficient power to assess associations between early-life socioeconomic position and adult cause-specific mortality. The authors examined associations of parental social class at age 0-16 years with mortality among 1,824,064 Swedes born in 1944-1960. Females and males from manual compared with nonmanual childhood social classes were more likely to die from smoking-related cancers, stomach cancer, respiratory disease, cardiovascular disease, and diabetes. Males from manual compared with nonmanual social classes were more likely to die from unintentional injury, homicide, and alcoholic cirrhosis. The association with stomach cancer was little affected by adjustment for parental later-life and own adult social class or education. For other outcomes, educational attainment resulted in greater attenuation of associations than did adjustment for adult social class. Early-life social class was not related to suicide or to melanoma, colon, breast, brain, or lymphatic cancers or to leukemia. With the exception of stomach cancer, caused by Helicobacter pylori infection acquired in childhood, poorer social class in early life was associated with diseases largely caused by behavioral risk factors such as smoking, physical inactivity, and an unhealthy diet. Educational attainment may be important in reducing the health inequalities associated with early-life disadvantage.

Cause of Death↗
PubMed2006

Does maternal smoking during pregnancy have a direct effect on future offspring obesity? Evidence from a prospective birth cohort study.

The authors used a population-based birth cohort of 3,253 children (52% males) born in Brisbane, Australia, between 1981 and 1984 to prospectively examine whether maternal smoking during pregnancy was associated with offspring overweight and obesity. The authors compared mean body mass indexes (weight (kg)/height (m)2) and levels of overweight and obesity at age 14 years among offspring by patterns of maternal smoking (never smoked, smoked before and/or after pregnancy but not during pregnancy, or smoked during pregnancy). Adolescent body mass index and prevalences of overweight and obesity were greater in offspring whose mothers had smoked during pregnancy than in those whose mothers had never smoked. Body mass index and levels of overweight and obesity among adolescent offspring whose mothers stopped smoking during pregnancy but smoked at other times in the child's life were similar to those among offspring whose mothers had never smoked. These results were independent of a range of potentially confounding factors and suggest a direct effect of maternal smoking during pregnancy on adolescent overweight and obesity. They provide yet another incentive for pregnant women to be persuaded not to smoke and for young women to be encouraged to never take up smoking.

Adolescent↗
PubMed2006

Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study.

OBJECTIVE: To investigate risk factors, such as heavy alcohol consumption, that might explain any increased risk of haemorrhagic stroke associated with low blood cholesterol. DESIGN: Prospective cohort study. SETTING: Korea. PARTICIPANTS: 787,442 civil servants (661,700 men, 125,742 women) aged 30-64. MAIN OUTCOME MEASURES: Cardiovascular risk factors were assessed at biennial health check. Data on morbidity and mortality were ascertained from 1990 to 2001 using hospital admissions and mortality surveillance systems. RESULTS: 6328 cases of ischaemic stroke (6021 men, 307 women), 3947 cases of haemorrhagic stroke (3748 men, 199 women), 3170 cases of undefined stroke (2902 men, 268 women), and 4417 cases of myocardial infarction (4305 men, 112 women) occurred. Ischaemic stroke and myocardial infarction were strongly and positively associated with blood cholesterol (hazard ratio per 1 mmol/l cholesterol 1.20 (95% confidence 1.16 to 1.24) and 1.48 (1.43 to 1.53), respectively). Haemorrhagic stroke showed an inverse association in fully adjusted models (0.91, 0.87 to 0.95). This inverse association was confined to participants with hypertension. When stratified by concentration of gamma glutamyl transferase (GGT), an indicator of alcohol consumption, the association was not seen in participants with low concentrations of GGT, and it was independent of hypertension in those with high concentrations of GGT (> 80 U/l).

Adult↗
PubMed2006

Family socioeconomic position at birth and future cardiovascular disease risk: findings from the Aberdeen Children of the 1950s cohort study.

OBJECTIVES: We assessed the association of father's social class, recorded at the time of birth, with coronary heart disease and stroke in a British cohort of 11106 individuals born in the 1950s. METHODS: Survival analysis was used to relate social class at birth to the occurrence of either fatal or nonfatal coronary heart disease or stroke. RESULTS: Rates of coronary heart disease and stroke increased across the social class distribution from highest to lowest, and patterns of association were similar for the 2 outcomes. The gender-adjusted hazard ratio of experiencing either coronary heart disease or stroke comparing the manual and nonmanual social class categories was 1.52 (95% confidence interval [CI]=1.14, 2.02). This ratio fell to 1.41 (95% CI = 1.05, 1.88) after adjustment for indicators of intrauterine and childhood growth. Further adjustment for educational attainment reduced the ratio to 1.28 (95% CI=0.94, 1.75). CONCLUSIONS: We found that social class at birth was associated with risk of fatal and nonfatal cardiovascular disease among individuals born in the 1950s, a period of relative prosperity and after the introduction of the welfare state in Britain. This relation appeared to be mediated in part through educational attainment.

Birth Weight↗
PubMed2006

The relation between components of adult height and intimal-medial thickness in middle age: the Atherosclerosis Risk in Communities Study.

The authors aimed to investigate the relation between components of adult height (leg and trunk length) and atherosclerosis in middle age, using data from 12,254 participants (aged 44-65 years) in the Atherosclerosis Risk in Communities (ARIC) Study. Intimal-medial thickness (IMT) as measured by B-mode ultrasound was the outcome, and exposures were trunk and leg lengths as estimated (using sitting height and the difference between sitting and standing height) at the first study examination in 1987-1989. The mean IMT was 0.73 (standard deviation, 0.17) mm. Greater leg length was associated with lower IMT, with the largest difference being for Black men (a 0.045 (95% confidence interval: 0.023, 0.068)-mm lower IMT per 10-cm higher leg length). Greater trunk length was associated with higher IMT, with the largest difference being for White men (a 0.024 (95% confidence interval: 0.005, 0.044)-mm higher IMT per 10-cm higher trunk length). Although the effect sizes were small, leg length was inversely associated with atherosclerosis, consistent with the results of other studies with cardiovascular disease outcomes.

Atherosclerosis↗
PubMed2006

Integrated single-label liquid-phase assay of APOE codons 112 and 158 and a lipoprotein study in British women.

BACKGROUND: Apolipoprotein E (APOE) is an important element of lipid metabolism and, hence, cardiovascular disorders. APOE has 3 main allelic variants: epsilon3, epsilon4, and epsilon2. Of these, epsilon3 is the most common, followed by epsilon4 and epsilon2. The associations of these isoforms with cardiovascular disorders and Alzheimer disease have been widely studied in different populations. Most of the genotyping in these studies has been performed with gel-based methods, which have important limitations, particularly for large epidemiologic studies. We therefore developed an integrated "one-tube" liquid-phase assay. METHODS: To measure APOE isoforms, we developed an integrated single-label liquid-phase fluorescence assay containing 2 PCR primers, 2 probes, and 2 quencher oligonucleotides. We used a 384-well LightTyper, but the assay would be generically applicable for use with any fluorescence detector with thermal ramp control. We validated this method and applied it in the British Women's Heart and Health Study. RESULTS: There were 4 melting peaks, at 41, 56, 61, and 69 degrees C, which generated 6 distinctive patterns representing genotypic combinations of epsilon3, epsilon4, and epsilon2. The magnitude and direction of the associations found with total cholesterol, HDL-cholesterol, triglycerides, and estimated LDL-cholesterol were consistent with previous reports. CONCLUSION: The one-tube LightTyper assay presented here enables accurate, convenient, and economical genotyping of APOE and can be used for large epidemiologic studies.

Aged↗
PubMed2006

Self-reported smoking cessation interventions were not associated with quitting in older women.

OBJECTIVE: To determine the extent to which smoking cessation interventions are used in the community and their relative success in older women. STUDY DESIGN AND SETTING: Prospective cohort study located in 23 general practices in England, Scotland. and Wales and including 3,622 women aged 60 to 79 years at recruitment from the British Women's Heart and Health Study. RESULTS: Of the 370 smokers at baseline, 77 (21%) had stopped smoking at 3 years, reducing the prevalence of smoking from 10.2% to 8.8%. Women who were light smokers (<10 per day) at baseline were more likely to have quit than heavier smokers. The most common interventions reported by women who smoked at baseline were advice from a general practitioner (GP), family or friend's advice, and use of nicotine replacement, but 42% of the women reported having no intervention to help them to stop smoking. None of the individual interventions were associated with increased odds of quitting smoking over the follow-up period. Women reported finding a GP's advice, referral to a clinic, and nicotine replacement more useful than complementary treatments (acupuncture and hypnotherapy) or advice from family and friends. CONCLUSION: Smoking cessation rates in this study were in line with national targets and surveys. Self-reports of ever receiving interventions were not associated with quitting smoking among these older women. Different and innovative approaches to smoking cessation may need to be developed, and evaluated in future randomized clinical trials, for individuals who have smoked for a long period of time and for whom other smoking cessation interventions have not proved successful.

Age Distribution↗