Showing papers by "George Davey Smith published in 2008"
TL;DR: The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies and can be considered as analogous to randomized controlled trials.
Abstract: Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.
2,364 citations
University of Michigan1, National Institutes of Health2, University of Virginia3, University of Maryland, Baltimore4, University of Bristol5, Broad Institute6, Johns Hopkins University7, University of London8, University of Southern California9, National Institute for Health and Welfare10, University of Helsinki11, Veterans Health Administration12, University of Texas Health Science Center at Houston13, University of North Carolina at Chapel Hill14
TL;DR: It is shown that common variants in the osteoarthritis-associated locus GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm (overall P < 10−15).
Abstract: Identifying genetic variants that influence human height will advance our understanding of skeletal growth and development. Several rare genetic variants have been convincingly and reproducibly associated with height in mendelian syndromes, and common variants in the transcription factor gene HMGA2 are associated with variation in height in the general population. Here we report genome-wide association analyses, using genotyped and imputed markers, of 6,669 individuals from Finland and Sardinia, and follow-up analyses in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated locus GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm (overall P < 10(-15)). Our results indicate that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.
399 citations
TL;DR: Objective measures of physical activity can be incorporated into large longitudinal studies of children and were different from those who did not, but the differences were modest.
Abstract: Background: Objective methods can improve accuracy of physical activity measurement in field studies but uncertainties remain about their use. Methods: Children age 11 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), were asked to wear a uni-axial accelerometer (MTI Actigraph) for 7 days. Results: Of 7159 children who attended for assessment, 5595 (78%) provided valid measures. The reliability coefficient for 3 days of recording was .7 and the power to detect a difference of 0.07 SDs (P ≤ .05) was > 90%. Measures tended to be higher on the first day of recording (17 counts/min; 95% CI, 10–24) and if children wore the monitor for fewer days, but these differences were small. The children who provided valid measures of activity were different from those who did not, but the differences were modest. Conclusion: Objective measures of physical activity can be incorporated into large longitudinal studies of children.
378 citations
TL;DR: The new studies confirmed that mortality risk for all causes was higher among those who experienced poorer socioeconomic circumstances during childhood and show that this association persists among younger birth cohorts, despite temporal general improvements in childhood conditions across successive birth cohorts.
Abstract: Objective: To update a systematic review on the association between childhood socioeconomic circumstances and cause-specific mortality. Studies published since 2003 include a far greater number of deaths than was previously available justifying an update of the previous systematic review. Methods: Individual-level studies examining childhood socioeconomic circumstances and adult overall and cause-specific mortality published between 2003 and April 2007. Results and conclusions: The new studies confirmed that mortality risk for all causes was higher among those who experienced poorer socioeconomic circumstances during childhood. As already suggested in the original systematic review, not all causes of death were equally related to childhood socioeconomic circumstances. A greater proportion of new studies included women and showed that a similar pattern is valid for both genders. In addition, the new studies show that this association persists among younger birth cohorts, despite temporal general improvements in childhood conditions across successive birth cohorts. The difficulties of establishing a particular life-course model were highlighted.
353 citations
TL;DR: FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of ecZema, and atopic sensitization, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations.
Abstract: Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10 −8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10 −11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10 −27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the "eczema plus early wheeze" and "eczema plus asthma" phenotypes.
338 citations
TL;DR: Adolescent obesity was related to increased mortality in middle age from several important causes, and risk of death from endocrine, nutritional, and metabolic diseases and from circulatory system diseases was increased in the two highest BMI categories for both sexes.
Abstract: The prevalence of obesity in childhood and adolescence has increased worldwide. Long-term effects of adolescent obesity on cause-specific mortality are not well specified. The authors studied 227,000 adolescents (aged 14-19 years) measured (height and weight) in Norwegian health surveys in 1963-1975. During follow-up (8 million person-years), 9,650 deaths were observed. Cox proportional hazards regression was used to compare cause-specific mortality among individuals whose baseline body mass index (BMI) was below the 25th percentile, between the 75th and 84th percentiles, and above the 85th percentile in a US reference population with that of individuals whose BMI was between the 25th and 75th percentiles. Risk of death from endocrine, nutritional, and metabolic diseases and from circulatory system diseases was increased in the two highest BMI categories for both sexes. Relative risks of ischemic heart disease death were 2.9 (95% confidence interval (CI): 2.3, 3.6) for males and 3.7 (95% CI: 2.3, 5.7) for females in the highest BMI category compared with the reference. There was also an increased risk of death from colon cancer (males: 2.1, 95% CI: 1.1, 4.1; females: 2.0, 95% CI: 1.2, 3.5), respiratory system diseases (males: 2.7, 95% CI: 1.4, 5.2; females: 2.5, 95% CI: 1.4, 4.8), and sudden death (males: 2.2, 95% CI: 1.2, 4.3; females: 2.7, 95% CI: 1.1, 6.6). Adolescent obesity was related to increased mortality in middle age from several important causes.
327 citations
TL;DR: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI, and the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions is highlighted.
Abstract: Objective: Common variation in the FTO gene is associated with body mass index (BMI) and type 2 diabetes. Increased BMI is associated with diabetes risk factors including raised insulin, glucose and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. Research design and methods: We tested the association between FTO genotype and ten metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO -BMI and BMI-trait associations. Results: Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039SD [95%CI:0.013-0.064]; P =0.003), glucose (0.024SD [0.001-0.048]; P =0.044), and triglycerides (0.028SD [0.003-0.052]; P =0.025), and lower HDL-cholesterol (0.032SD [0.008-0.057]; P =0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine-aminotransferase, gamma-glutamyl-transferase and LDL-cholesterol, HbA1c and systolic and diastolic blood pressure were in the expected direction but did not reach P FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio:1.17 [95%CI:1.10-1.25]; P =3×10 −6 ). Conclusions: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of greater than 12,000 individuals were needed to detect associations at P
310 citations
TL;DR: The hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension is supported.
Abstract: Background Alcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2 )a s a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wildtype homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour.
304 citations
TL;DR: If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.
Abstract: Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of-that is randomized with respect to-the inheritance of other traits, according to Mendel's law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers' compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.
296 citations
TL;DR: It is concluded that the naïve acceptance of findings utilizing conventional epidemiological methods in this setting is misplaced.
Abstract: The influence of factors acting during the intrauterine period on health outcomes of offspring is of considerable research and public health interest. There are, however, methodological challenges in establishing robust causal links, because exposures often act many decades before outcomes of interest, may act before it is evident that women are pregnant and would enter pregnancy birth cohorts, and may also be strongly related to other factors, generating considerable degrees of potential confounding. The degree of confounding can sometimes be estimated by comparing the association between exposures experienced by the mother during pregnancy and outcomes among the offspring with the association of exposures experienced by the father during the pregnancy period and offspring outcomes. If the effects are due to an intrauterine exposure, then maternal exposure during pregnancy should have a clearly greater influence than paternal exposure. A different approach is that of Mendelian randomization, which utilizes genetic variants of known functional effect that can proxy for modifiable exposures. If carried by the mother, these variants would influence the intrauterine environment experienced by her offspring. These genetic variants are stable over time and can be assessed after pregnancy is complete or even after outcomes in the offspring have been observed. The variants would also not generally be related to potential confounding factors. Other epidemiological strategies are briefly reviewed. It is concluded that the naive acceptance of findings utilizing conventional epidemiological methods in this setting is misplaced.
250 citations
TL;DR: In this paper, a region of chromosome 16 containing the fat mass-and obesity-associated gene (FTO) is reproducibly associated with fat mass and body mass index (BMI), risk of obesity and adiposity.
TL;DR: Initial breastfeeding (particularly when exclusive) may be associated with lower blood cholesterol concentrations in later life, and moves to reduce the cholesterol content of formula feeds below those of breast milk should be treated with caution.
17 Mar 2008
TL;DR: Neither the parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9–11 y, which is unlikely to have driven the recent obesity epidemic.
Abstract: Background
The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.
University of Virginia1, National Institutes of Health2, University of Michigan3, Broad Institute4, National Research Council5, University of Maryland, Baltimore6, University of Bristol7, Novo Nordisk8, University of Eastern Finland9, University of London10, University of Copenhagen11, University of Helsinki12, National Institute for Health and Welfare13, University of Southern California14, Aarhus University15, University of North Carolina at Chapel Hill16
TL;DR: The results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
Abstract: Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
TL;DR: Higher levels of PA were associated with lower BP, and results suggested that the volume of activity may be more important than the intensity.
Abstract: The pathological processes associated with development of cardiovascular disease begin early in life. For example, elevated blood pressure (BP) can be seen in childhood and tracks into adulthood. The relationship between physical activity (PA) and BP in adults is well-established, but findings in children have been inconsistent, with few studies measuring PA mechanically. Children aged 11 to 12 years were recruited from the Avon Longitudinal Study of Parents and Children. 5505 had systolic and diastolic BP measurements, plus valid (at least 10 hours for at least 3 days) accelerometer measures of PA; total PA recorded as average counts per minute (cpm) over the period of valid recording, and minutes per day spent in moderate to vigorous PA (MVPA). Data on a number of possible confounders were also available. Small inverse associations were observed; for systolic BP, beta=-0.44 (95% confidence interval -0.59, -0.28) mm Hg per 100 cpm, and beta=-0.66 (95% CI -0.92, -0.39) mm Hg per 15 minutes/d MVPA, adjusting for child's age and gender. After adjustment for potential confounders, associations were weakened but remained. When PA variables were modeled together, associations with total PA were only a little weaker, whereas those with MVPA were substantially reduced; for systolic BP, beta=-0.42 (95% CI -0.71, -0.13) mm Hg per 100 cpm, and beta=-0.03 (95% CI -0.54, 0.48) mm Hg per 15 minutes/d MVPA. In conclusion, higher levels of PA were associated with lower BP, and results suggested that the volume of activity may be more important than the intensity.
TL;DR: Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal and inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Abstract: Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
TL;DR: How often the log odds, risk, or hazard ratio per unit increase in exposure, and its standard error, can be estimated from results reported from observational studies of diet and prostate or bladder cancer so that results are usable in meta-analyses estimating dose-response associations is examined.
Abstract: Epidemiologic investigations often report dose-response associations, which may be combined in meta-analyses. The authors examined how often the log odds, risk, or hazard ratio per unit increase in exposure, and its standard error, can be estimated from results reported from observational studies of diet and prostate or bladder cancer so that results are usable in meta-analyses estimating dose-response associations. Eight electronic databases were searched for studies reporting on the association of diet, nutrition, or physical activity with these cancers. A total of 767 papers reported 3,284 results; 1,999 (61%) results, reported in 545 (71%) papers, were usable in dose-response meta-analyses. The most important reason that results were not usable was the absence of sufficient information on exposure levels in the different groups. The proportion of results usable in "high-low" meta-analyses (comparisons of extreme categories) was similar (62%). Results that showed evidence of an association were more likely to be usable than results that found no such evidence. Insufficient detail in reporting of results of observational studies can lead to exclusion of these results from meta-analyses and is an important threat to the validity of systematic reviews of such research. Results providing evidence of associations may be overrepresented in meta-analyses of observational studies.
TL;DR: In this paper, the associations of menarcheal age with BMI and other cardiovascular risk factors in adolescence and adulthood in a population-based sample of 794 female adolescents aged 9-18 y at baseline and again 3 and 6 y later.
TL;DR: The results suggest that current best-practice interventions to reduce classic coronary risk factors, if successfully implemented in both high and low socioeconomic groups, could eliminate most of the socioeconomic differences in coronary heart disease mortality.
01 Jan 2008
TL;DR: Findings suggest that early menarche is only a risk marker, and greater childhood BMI seems to contribute to earlier age at menarches and, because of tracking, greater adult BMI and associated cardiovascular risk.
Abstract: Background: It is unclear whether age at menarche is an independent determinant of future cardiovascular risk. Objective: We aimed to determine whether menarcheal age is an independentpredictorofbodymassindex(BMI)andawiderangeof cardiovascular risk factors in adolescence and adulthood. Design:WeexaminedtheassociationsofmenarchealagewithBMI (in kg/m 2 ) and other cardiovascular risk factors in adolescence and adulthood in a population-based sample of 794 female adolescents aged 9–18 y at baseline. Their age at first menstruation was requested at baseline and again 3 and 6 y later. Cardiovascular risk factors were assessed at baseline and at age 30–39 y. Results:A1-ydecreaseinmenarchealagewasassociatedwith0.81 (95% CI: 0.53, 1.08) higher adult BMI as well as greater waist circumference and waist-to-hip ratio, elevated systolic blood pressure, higher insulin resistance, and greater risk of metabolic syndrome (P 0.05 for all). In multivariable analysis in which these adult risk factors were mutually adjusted for, only the inverse associationbetweenageatmenarcheandadultBMIremained.However, this inverse association was lost after adjustment for premenarcheal BMI (: 0.16; 95% CI 0.55, 0.23; P 0.42). Higher premenarcheal BMI predicted earlier menarche, and the strong association between premenarcheal BMI and adult BMI was robust to adjustment for age at menarche. Conclusions: These findings suggest that early menarche is only a risk marker. Greater childhood BMI seems to contribute to earlier age at menarche and, because of tracking, greater adult BMI and associated cardiovascular risk. An independent effect of early menarche on adult adiposity cannot be excluded, but it is likely to be small at best. Am J Clin Nutr 2008;87:1876–82.
TL;DR: This pragmatic study provides the most robust evidence to date on this important hypothesis for which classic trials are unlikely that improved maternal and child nutrition may have a role in reducing the burden of cardiovascular disease in low income and middle income countries.
Abstract: Objective To determine whether integration of nutritional supplementation with other public health programmes in early life reduces the risk of cardiovascular disease in undernourished populations. Design Approximately 15 years’ follow-up of participants born within an earlier controlled, community trial of nutritional supplementation integrated with other public health programmes. Setting 29 villages (15 intervention, 14 control) near Hyderabad city, south India. Participants 1165 adolescents aged 13-18 years. Intervention Balanced protein-calorie supplementation (2.51 MJ, 20 g protein) offered daily to pregnant women and preschool children aged under 6 years, coupled with integrated delivery of vertical public health programmes. Main outcome measures Height, adiposity, blood pressures, lipids, insulin resistance (homoeostasis model assessment (HOMA) score), and arterial stiffness (augmentation index). Results The participants from the intervention villages were 14 mm (95% confidence interval 4 to 23; P=0.007) taller than controls but had similar body composition. The participants from the intervention villages had more favourable measures of insulin resistance and arterial stiffness: 20% (3% to 39%; P=0.02) lower HOMA score and 3.3% (1% to 5.7%; P=0.008) lower augmentation index. No strong evidence existed for differences in blood pressures and serum lipids. Conclusions In this undernourished population, integrated delivery of supplemental nutrition with other public health programmes in pregnancy and early childhood was associated with a more favourable profile of cardiovascular disease risk factors in adolescence. This pragmatic study provides the most robust evidence to date on this important hypothesis for which classic trials are unlikely. Improved maternal and child nutrition may have a role in reducing the burden of cardiovascular disease in low income and middle income countries.
TL;DR: This is the first study to demonstrate that only immediate postnatal growth predicts diastolic blood pressure in term births, whereas it adds further evidence that both birth weight andPostnatal growth are associated with systolic blood Pressure in support of both the fetal origins and growth acceleration hypotheses.
Abstract: There is a consistent inverse association between birth weight and systolic blood pressure; however, few studies have been able to examine the immediate postnatal period. We have examined whether accelerated postnatal growth predicts adult systolic and diastolic blood pressure. We followed up participants from the Barry Caerphilly Growth Study. Blood pressure data were obtained on 679 of the original 951 subjects (73%) aged ≈25 years. Both multivariable linear regression and spline models were used to examine the association among weight, length, and growth velocities with systolic blood pressure and diastolic blood pressure. Both statistical approaches showed that birth weight was inversely associated with systolic blood pressure. Only the spline models found that immediate (0 to 5 months) weight gain (β coefficient: 1.29 mm Hg; 95% CI: 0.36 to 2.23; P =0.007) and weight gain between 1 year and 9 months to 5 years (β coefficient: 1.44 mm Hg; 95% CI: 0.31 to 2.57; P =0.01) were independently associated with systolic blood pressure, whereas only immediate weight gain (β coefficient: 0.74 mm Hg; 95% CI: 0.08 to 1.41; P =0.03) was associated with diastolic blood pressure. This is the first study to demonstrate that only immediate postnatal growth predicts diastolic blood pressure in term births, whereas it adds further evidence that both birth weight and postnatal growth are associated with systolic blood pressure in support of both the fetal origins and growth acceleration hypotheses.
TL;DR: The findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.
Abstract: Background: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C.T (rs1130864) and CHD risk in the largest study to date of this association. Methods and Results: We estimated the association of CRP genetic variant +1444C.T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N=18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was1.07 (95%CI: 1.02, 1.13).Genotype (rs1130864) wasassociated with circulating CRP;the pooledratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I 2 =0%, p.0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I 2 ,7.5%, p.0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80). Conclusions: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.
TL;DR: In this paper, the authors reviewed epidemiology studies of modifiable maternal exposures and offspring blood pressure (BP) and found no strong evidence that any component of maternal diet during pregnancy (maternal protein, energy, calcium, and various other nutrients) influences offspring BP.
Abstract: Prenatal programming of adult disease is well established in animals. In humans the impact of common in utero exposures on long-term offspring health is less clear. We reviewed epidemiology studies of modifiable maternal exposures and offspring blood pressure (BP). Three maternal exposures were identified for review and meta-analyzed where possible: smoking during pregnancy, diet, and age at childbirth. Meta-analysis suggested there was a modest association between higher offspring BP and prenatal exposure to smoke (confounder-adjusted β = 0.62 mm Hg, 95% confidence interval: 0.19–1.05, I2 = 16.4%). However, the level of confounder adjustment varied between studies, which in some studies attenuated the association to the null. There was no strong evidence that any component of maternal diet during pregnancy (maternal protein, energy, calcium, and various other nutrients) influences offspring BP. The results of studies of maternal age varied and there was strong evidence of heterogeneity in the pooled analysis. The association with maternal age, if present, was modest (confounder-adjusted β = 0.09 mm Hg/y, 95% confidence interval: −0.03 to 0.21, I2 = 89.8%). In sum, there is little empirical evidence that the maternal exposures reviewed program offspring BP. Other components of offspring health may be more susceptible to effects of programming in utero.
TL;DR: It is suggested that BDNF genotype does not exert a major influence on the development of depression, following a systematic review and meta‐analysis of all association studies of these two BDNF polymorphisms and depression.
Abstract: Depression is common and a major cause of morbidity and mortality and is also known to have serious effects on quality of life. Both clinical and pharmacologic studies have implicated the role of brain-derived neurotrophic factor (BDNF) as a susceptibility locus for the development of mental illness, including depression, bipolar disorder, and schizophrenia. Population-based genetic studies have examined the association between BDNF and a variety of depression outcomes, but the results have not clearly established the role of BDNF in the development of this complex disorder. The aim of this study was to test for associations between two genetic variants in BDNF, Val66Met (rs6265) and -270 C > T, and depression measured in two independent samples. In this analysis we included 3,548 participants from British Women's Heart and Health Study (BWHHS) and 6,836 mothers from Avon Longitudinal Study of Parents and Children (ALSPAC) who had complete data on genotype and depression outcomes. We did not detect any strong evidence of associations between any of the two polymorphisms and indicators of depression in either BWHHS or ALSPAC samples. Further, we carried out a systematic review and meta-analysis of all association studies of these two BDNF polymorphisms and depression. The meta-analysis of Val66Met in depression obtained an overall summary OR of 1.06 (95% CI: 0.89-1.26, P = 0.537) comparing MM with VV genotypes and an OR of 0.97 (95% CI: 0.89-1.05, P = 0.403) comparing MV with VV genotypes. Our findings suggest that BDNF genotype does not exert a major influence on the development of depression.
TL;DR: A μ‐opioid receptor‐mediated activation of phospholipase C is demonstrated, via a pertussis toxin‐sensitive G protein, that is Ca2+‐dependent, that could play a part in the cellular mechanisms of opioid action.
Abstract: The cellular mechanisms underlying opioid action remain to be fully determined, although there is now growing indirect evidence that some opioid receptors may be coupled to phospholipase C. Using SH-SY5Y human neuroblastoma cells (expressing both mu- and delta-opioid receptors), we demonstrated that fentanyl, a mu-preferring opioid, caused a dose-dependent (EC50 = 16 nM) monophasic increase in inositol (1,4,5)trisphosphate mass formation that peaked at 15 s and returned to basal within 1-2 min. This response was of similar magnitude (25.4 +/- 0.8 pmol/mg of protein for 0.1 microM fentanyl) to that found in the plateau phase (5 min) following stimulation with 1 mM carbachol (18.3 +/- 1.4 pmol/mg of protein), and was naloxone-, but not naltrindole- (a delta antagonist), reversible. Further studies using [D-Ala2, MePhe4, Gly(ol)5]enkephalin and [D-Pen2,5]enkephalin confirmed that the response was specific for the mu receptor. Incubation with Ni2+ (2.5 mM) or in Ca(2+)-free buffer abolished the response, as did pretreatment (100 ng/ml for 24 h) with pertussis toxin (control plus 0.1 microM fentanyl, 26.9 +/- 1.5 pmol/mg of protein; pertussis-treated plus 0.1 microM fentanyl, 5.1 +/- 1.3 pmol/mg of protein). In summary, we have demonstrated a mu-opioid receptor-mediated activation of phospholipase C, via a pertussis toxin-sensitive G protein, that is Ca(2+)-dependent. This stimulatory effect of opioids on phospholipase C, and the potential inositol (1,4,5)trisphosphate-mediated rises in intracellular Ca2+, could play a part in the cellular mechanisms of opioid action.
TL;DR: This work presents examples of the use of the Mendelian randomization approach and discusses both the limitations and potentials of this strategy.
Abstract: Observational studies have contributed in a major way to understanding modifiable determinants of cardiovascular disease risk, but several examples exist of factors that were identified in observational studies as potentially protecting against coronary heart disease, that in randomized controlled trials had no such effect. The likely reason for misleading findings from observational epidemiological studies is that associations are influenced by confounding, bias, and reverse causation--where disease influences a risk factor, rather than vice versa. Mendelian randomization utilizes genetic variants that serve as proxy measures for modifiable risk factors to allow estimation of the causal influence of the modifiable risk factor in question. We present examples of the use of the Mendelian randomization approach and discuss both the limitations and potentials of this strategy.
TL;DR: In fully adjusted models, there was no strong statistical evidence that maternal alcohol and tobacco consumption during pregnancy were associated with childhood IQ with any greater magnitude than paternal alcohol and Tobacco consumption (also assessed during their partners' pregnancy).
Abstract: This study aims to test the hypothesis that moderate maternal alcohol and tobacco use in pregnancy is associated with intelligent quotient (IQ) scores in childhood through intrauterine mechanisms. We conducted parental-offspring comparisons between the associations of tobacco and alcohol consumption with child's IQ in the Avon Longitudinal Study of Parents and Children. Analyses were conducted on 4332 participants with complete data on maternal and paternal use of alcohol and tobacco at 18 wk gestation, child's IQ and a range of confounders. IQ was measured at child age 8 with the Weschler Intelligence Scale for Children (WISC-III). We used multivariable linear and logistic regression to estimate mean differences and 95% confidence intervals in IQ scores across the exposure categories and computed f statistics to compare maternal and paternal associations. In fully adjusted models, there was no strong statistical evidence that maternal alcohol and tobacco consumption during pregnancy were associated with childhood IQ with any greater magnitude than paternal alcohol and tobacco consumption (also assessed during their partners' pregnancy). Our findings suggest that the relationship between maternal moderate alcohol and tobacco use in early pregnancy and childhood IQ may not be explained by intrauterine mechanisms.
TL;DR: The SPINK5 420LysSer mutation confers a risk of ecZema when maternally inherited but is not a major eczema risk factor, and the KLK7 insertion appears to confer no risk of Eczema.
Abstract: Background Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK5) and the serine protease kallikrein-related peptidase 7 gene (KLK7) appear to confer risk to eczema in some cohorts, but these findings have not been widely replicated These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG) , the strongest identified genetic risk factor for eczema to date Objectives We sought to clarify the individual risk of eczema conferred by the SPINK5 polymorphism rs2303067 (Glu420Lys) and a previously described insertion in the 3′ untranslated region of KLK7 and to examine potential epistatic effects between these variants and FLG mutations Methods Initially, we examined the effects of these polymorphisms and FLG in 486 unrelated patients from a German family-based study, an additional 287 German patients, and 418 unrelated Irish/English patients with eczema (n for 3 genes studied=1191 vs 4544 control subjects) We then additionally studied the SPINK5 polymorphism and FLG mutations in 1583 patients with eczema from the Avon Longitudinal Study of Parents and Children cohort (sample size for 2 genes studied=2774 vs 10,607 control subjects) Results No association was seen with the SPINK5 or KLK7 variants in the case-control analysis; however, a weaker effect was observed for the SPINK5 variant with maternal transmission in the family-based study No interactions were seen between the polymorphisms in KLK7 , SPINK5 , and FLG Conclusion The SPINK5 420LysSer mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor The KLK7 insertion appears to confer no risk of eczema We found no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations