Maternal plasma cortisol's effect on offspring birth weight: a Mendelian Randomisation study.

BACKGROUND: Observational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. METHODS: We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant's effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects. RESULTS: The estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. CONCLUSIONS: Our findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Associations between aggressive behaviour scores and cardiovascular risk factors in childhood.

OBJECTIVE: To examine the influence of aggressive behaviour scores on cardiovascular disease (CVD) risk factors throughout childhood. METHODS: This study utilized cross-sectional and longitudinal data from the Western Australian Pregnancy Cohort (Raine) Study (n = 2900). Aggressive behaviour scores were derived from the Child Behavior Checklist/4-18(CBCL), Youth Self-Report/11-18 (YSR) and Teacher Report Form/6-18 (TRF). CVD risk factors included body mass index (BMI), blood pressure, fasting lipids and homeostasis model of insulin resistance (HOMA-IR). RESULTS: Girls with higher aggressive behaviour scores had higher BMI from 10 years of age (P ≤ 0.001), higher BMI trajectories throughout childhood (P = 0.0003) and at 14 years higher HOMA-IR (P = 0.008). At the 14-year survey, this equated to a difference of 1.7 kg/m2 in the predicted BMI between the extreme CBCL scores in girls (top 5% (CBCL ≥ 17) vs. CBCL score = 0). Boys with higher aggressive behaviour scores had higher BMI at 5 years (P = 0.002), lower diastolic pressure at 14 years (P = 0.002) and lower systolic blood pressure trajectories throughout childhood (P = 0.016). CONCLUSION: Aggressive behaviour influences BMI from early childhood in girls but not boys. If this association is causal, childhood offers the opportunity for early behavioural intervention for obesity prevention.

Genetic variation in the beta-2 adrenergic receptor is associated with chronic musculoskeletal complaints in adolescents.

BACKGROUND: There is significant evidence to suggest that psychological and stress-related factors are important predictors of the onset of chronic widespread pain (CWP) and fibromyalgia (FM). The hypothalamic-pituitary-adrenal axis, together with the efferent sympathetic/adrenomedullary system, influence all body organs (including muscles) during short- and long-term threatening stimuli. The aim of this study was to investigate the relationship between genetic variants in adrenergic candidate genes and chronic musculoskeletal complaints (MSCs) in adolescents. METHODS: Adolescents from the Western Australian Pregnancy (Raine) Cohort attending the 17-year cohort review completed a questionnaire containing a broad range of psychosocial factors and pain assessment (n = 1004). Blood samples were collected for DNA extraction and genotyping. Genotype data was obtained for 14 single nucleotide polymorphisms (SNPs) in two candidate genes - beta-2 adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT). Haplotypes were reconstructed for all individuals with genotype data. RESULTS AND CONCLUSION: Both female gender and poor mental health were associated with (1) an increased risk for chronic, disabling comorbid neck and low back pain (CDCP); and (2) an increase in the number of areas of pain. Of the 14 SNPs evaluated, only SNP rs2053044 (ADRB2, recessive model) displayed an association with CDCP [odds ratio (OR) = 2.49; 95% confidence interval (CI) = 1.25, 4.98; p = 0.01] and pain in three to four pain areas in the last month (OR = 1.86; 95% CI = 1.13, 3.06; p = 0.02). These data suggest that genetic variants in ADRB2 may be involved in chronic MSCs.

Fat mass and obesity-associated obesity-risk genotype is associated with lower foetal growth: an effect that is reversed in the offspring of smoking mothers.

Fat mass and obesity-associated (FTO) gene variants are associated with childhood and adult obesity; however, the influence of FTO polymorphisms on foetal growth is unknown. Associations between the FTO variant rs9939609 and the foetal growth trajectories, maternal pregnancy weight gain, anthropometric measures at birth and body mass index (BMI) at age 14 years were assessed in 1079 singleton-birth Australian Caucasians. Analyses were repeated in 3512 singleton-birth Dutch Caucasians. The rs9939609 obesity-risk AA genotype was associated with symmetrical intrauterine growth restriction; an effect reversed in mothers who smoked during pregnancy. The effect increased over time and was modified by maternal smoking for head circumference (P = 0.007), abdominal circumference (P = 0.007), femur length (P = 0.02) and estimated foetal weight (P = 0.001). The modification of the association between the AA genotype and birth anthropometrics by maternal smoking was consistent across birth weight (P = 0.01) and birth length (P = 0.04) and neonatal day 2 anthropometry. Consistent associations were replicated in the Generation R cohort. Maternal pregnancy weight gain matched the pattern of birth weight and was independent of placental weight. In adolescents, the AA genotype was associated with increased BMI-adjusted-for-age in males (P = 0.00009), but no effect was detected in females. A variant in the FTO gene influences foetal growth trajectories in the third trimester, early postnatal growth and adiposity in adolescence. Maternal smoking during pregnancy reversed the direction of association of rs9939609 on foetal growth, which was probably mediated by maternal energy intake. The detection of genetic variants associated with foetal growth has the potential to identify novel molecular mechanisms underlying growth and targeted early life intervention.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

Matrix metalloproteinase-2 gene variants and abdominal aortic aneurysm.

OBJECTIVE: To investigate associations between two polymorphisms of the matrix metalloproteinase-2 gene (MMP2) and the incidence and progression of abdominal aortic aneurysm (AAA). METHODS: Cases and controls were recruited from a trial of screening for AAAs. The association between two variants of MMP2 (-1360C>T, and +649C>T) in men with AAA (n=678) and in controls (n=659) was examined using multivariate analyses. The association with AAA expansion (n=638) was also assessed. RESULTS: In multivariate analyses with adjustments for multiple testing, no association between either SNP and AAA presence or expansion was detected. CONCLUSION: MMP2 -1360C>T and +649C>T variants are not risk factors for AAA.

The PHF11 gene is not associated with asthma or asthma phenotypes in two independent populations.

BACKGROUND: Numerous areas of the human genome have previously been associated with asthma and asthma-related phenotypes, but few positive findings have been successfully replicated in independent populations. Initial studies have reported strong associations of variants in the plant homeodomain zinc finger protein 11 (PHF11) gene with serum IgE levels, asthma, airway hyper-responsiveness and childhood atopic dermatitis. OBJECTIVES: To investigate the association of variants in the PHF11 gene with asthma and associated intermediate phenotypes in two independent Western Australian population-based samples. METHODS: A linkage-disequilibrium (LD)-tagging set of 20 single nucleotide polymorphisms (SNPs) was genotyped in PHF11 in two separate populations (total n = 2315), a family-based twin study consisting of 230 families (n = 992 subjects) and a population-based nested case-control study consisting of 617 asthma cases and 706 controls. Information regarding asthma, respiratory physiology, atopy and environmental exposures was collected. Transmission disequilibrium tests, variance components models and generalised linear models were used to test for association between PHF11 SNPs and selected asthma outcomes (including longitudinal change in lung function). RESULTS: After correction for multiple testing, no statistically significant (p < 0.05) associations were found between PHF11 and either asthma or total serum IgE levels in either population. No statistically significant associations were found with any other asthma-associated phenotypes in either population. CONCLUSIONS: Previously reported associations of PHF11 with asthma outcomes were not replicated in this study. This study suggests that PHF11 is unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our populations.

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits.

AIMS/HYPOTHESIS: Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. METHODS: The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS: The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007). CONCLUSIONS/INTERPRETATION: The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.

Polymorphisms of the matrix metalloproteinase 9 gene and abdominal aortic aneurysm.

BACKGROUND: Increased matrix metalloproteinase (MMP) 9 activity has been implicated in the formation of abdominal aortic aneurysm (AAA). The aim was to explore the association between potentially functional variants of the MMP-9 gene and AAA. METHODS: The -1562C > T and -1811A > T variants of the MMP-9 gene were genotyped in 678 men with an AAA (at least 30 mm in diameter) and 659 control subjects (aortic diameter 19-22 mm) recruited from a population-based trial of screening for AAA. Levels of MMP-9 were measured in a random subset of 300 cases and 84 controls. The association between genetic variants (including haplotypes) and AAA was assessed by multivariable logistic regression. RESULTS: There was no association between the MMP-9-1562C > T (odds ratio (OR) 0.70 (95 per cent confidence interval (c.i.) 0.27 to 1.82)) or -1811A > T (OR 0.71 (95 per cent c.i. 0.28 to 1.85)) genotypes, or the most common haplotype (OR 0.81 (95 per cent c.i. 0.62 to 1.05)) and AAA. The serum MMP-9 concentration was higher in cases than controls, and in minor allele carriers in cases and controls, although the differences were not statistically significant. CONCLUSION: In this study, the genetic tendency to higher levels of circulating MMP-9 was not associated with AAA.

Polymorphisms of the interleukin-6 gene promoter and abdominal aortic aneurysm.

BACKGROUND: Elevated levels of circulating interleukin-6 (IL-6) have been reported in patients with abdominal aortic aneurysms (AAAs). Although this implicates inflammation as a cause of AAAs, there is also evidence that the aneurysmal aorta may secrete IL-6 into the circulation as a result of aortic proteolysis. Genetic association studies are one means of trying to clarify the role of specific mediators in the causal pathway. The aim of the present study was to examine the association between variants of the IL-6 gene and AAAs. METHODS: An association study involving 677 men with screen-detected AAAs and 656 age-matched controls was performed. Three variants in the IL-6 promoter region were analysed: IL-6-174G>C (rs1800795), IL-6-572G>C (rs1800796) and IL-6-597G>A (rs1800797). Univariate regression of SNP genotype on AAA as a binary outcome was initially performed under a range of genetic models (additive, dominant and recessive). This was followed by multivariate analyses, testing the same models but including risk factors known to be associated with AAAs. All analyses and haplotype estimation were performed under a generalized linear model framework. RESULTS: IL-6-572G>C polymorphism (frequency 1.5% in cases) was identified as an independent risk factor for AAA with an odds ratio (OR) of 6.00 (95%CI: 1.22, 29.41) when applied to the recessive model. No association was seen in the additive or dominant models. In a multivariate analysis using the most common haplotype (h.111, frequency 48.7%) as a reference, h.211 (frequency 4.4%) was an independent risk factor for AAA (OR 1.56, 95%CI: 1.02, 2.39). CONCLUSION: The IL-6 572G>C polymorphism (and h.211 haplotype) is associated with AAA, however it is too rare to be an important cause of most AAAs. This does not support the concept that the elevated level of IL-6 reported in patients with AAAs is a primary cause of the aneurysmal process.