Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study.

BACKGROUND: With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics. METHODS: A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong's "Children of 1997" birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the "Children of 1997" birth cohort and coronary artery disease from Biobank Japan. RESULTS: Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], - 1.06 [- 1.52 to - 0.60]; PCSK9: - 0.93 [- 1.56 to - 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid - 0.79 [- 1.25 to - 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed. CONCLUSIONS: Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.

Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data.

Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait loci (eQTL or mQTL) data and genetic variant-disease associations from genome-wide association studies (GWAS of MDD). We also assessed drug exposure using gene expression and DNAm levels of NSAID targets as proxies. Genetic variants were robustly adjusted for multiple comparisons related to gene expression, DNAm was used as MR instrumental variables and GWAS statistics of MDD as the outcome. A 1-standard deviation (SD) lower expression of NEU1 in blood was related to lower C-reactive protein (CRP) levels of -0.215 mg/L (95% confidence interval (CI): 0.128-0.426) and a decreased risk of MDD (odds ratio [OR] = 0.806; 95% CI: 0.735-0.885; p = 5.36 × 10-6). A concordant direction of association was also observed for NEU1 DNAm levels in blood and a risk of MDD (OR = 0.886; 95% CI: 0.836-0.939; p = 4.71 × 10-5). Further, the genetic variants associated with MDD were mediated by NEU1 expression via DNAm (ß = -0.519; 95% CI: -0.717 to -0.320256; p = 3.16 × 10-7). We did not observe causal relationships between inflammatory genetic marker estimations and MDD risk. Yet, we identified a concordant association of NEU1 messenger RNA and an adverse direction of association of higher NEU1 DNAm with MDD risk. These results warrant increased pharmacovigilance and further in vivo or in vitro studies to investigate NEU1 inhibitors or supplements for MDD.

The influence of growth and sex hormones on risk of alzheimer's disease: a mendelian randomization study.

Alzheimer's disease is more prevalent in women, possibly due to sex or growth hormones but existing evidence is inconclusive. We investigated whether genetically predicted sex and growth hormones are associated with risk of Alzheimer's disease. Genetic variants strongly and independently predicting insulin-like growth factor 1 (IGF-1), testosterone and sex hormone-binding globulin (SHBG) were obtained from large, published genome wide associations studies (GWAS) and applied to GWAS of Alzheimer's disease based on clinical diagnosis (cases = 21,982, control = 41,944) from the International Genomics of Alzheimer's Project and the UK Biobank parental (maternal cases = 27,696; paternal cases = 14,338) and siblings' diagnosis (cases = 2,171) as proxy cases. Published GWAS summary statistics were used in our analyses. Estimates were obtained from inverse variance weighting with sensitivity analysis (i.e., MR-Egger, weighted median and MR-PRESSO). Multivariable analyses adjusted for pleiotropic effects and possible sources of selection bias were also performed. Genetically predicted higher total testosterone may reduce the risk of paternal Alzheimer's disease (odds ratio (OR) 0.86, 95% confidence interval (CI) 0.76 to 0.97, per SD increase in testosterone) and in meta-analysis for women (OR 0.92, 95% CI 0.87, 0.98) with directionally similar results from other analyses. SHBG were not associated with Alzheimer's disease. IGF-1 in women was inversely associated with risk of clinical Alzheimer's disease in sensitivity analysis but not in the main analysis. These results suggest genetically predicted higher total testosterone may lower risk of Alzheimer's disease. The role of testosterone and the immune system in Alzheimer's disease could be further investigated.

Breastfeeding and ApoB in late adolescence: a Hong Kong birth cohort study.

Breastfeeding is widely promoted. Experimental evidence concerning long-term benefits is limited. Observational studies are open to bias from confounding by socio-economic position. We assessed the association of breastfeeding with late adolescent lipid sub-fractions, particularly apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (non-HDL-c), overall and by sex. We took advantage of a setting where breastfeeding has little association with higher socio-economic position and where several results from randomized controlled trials of breastfeeding promotion have been replicated. We used the population-representative "Children of 1997" birth cohort comprising 88% of births in Hong Kong in April and May 1997. Associations of breastfeeding in the first 3 months of life (never, mixed, exclusive) with lipid sub-fractions were obtained using linear regression adjusted for potential confounders including parental socio-economic position, maternal place of birth, type of delivery, gestational age, and birth weight. Differences by sex were assessed. Multiple imputation and inverse probability weighting were used to recover the original sample. Of the 3462 participants included, mean age was 17.6 years and 48.8% were girls. Mean ApoB was 0.74 g/L (standard deviation 0.15). Exclusive versus never breastfeeding was associated with lower ApoB (-0.027 g/L, 95% confidence interval (CI)-0.046 to-0.007, p = 0.007) and lower non-HDL-c (-0.143 mmol/L, 95% CI-0.237 to-0.048) with similar estimates by sex. CONCLUSION: Breastfeeding may provide some population-level lifelong protection against cardiovascular disease. This study supports policies promoting breastfeeding as a modifiable exposure that contributes to a healthy start in life as an investment for lifelong cardiovascular disease prevention. WHAT IS KNOWN: • Apolipoprotein B (ApoB) is a recognized risk factor for cardiovascular disease, but whether breastfeeding affects ApoB in later life overall and by sex is unknown. WHAT IS NEW: • Exclusive breastfeeding in the first 3 months of life was associated with lower ApoB in late adolescence, with similar estimates for both sexes. • The inverse association of breastfeeding with ApoB suggests that breastfeeding could reduce cardiovascular disease and overall mortality over the lifespan.

Blood pressure and risk of cancer: a Mendelian randomization study.

BACKGROUND: Previous large observational cohort studies showed higher blood pressure (BP) positively associated with cancer. We used Mendelian randomization (MR) to obtain less confounded estimates of BP on total and site-specific cancers. METHODS: We applied replicated genetic instruments for systolic and diastolic BP to summary genetic associations with total cancer (37387 cases, 367856 non-cases) from the UK Biobank, and 17 site-specific cancers (663-17881 cases) from a meta-analysis of the UK Biobank and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging. We used inverse-variance weighting with multiplicative random effects as the main analysis, and sensitivity analyses including the weighted median, MR-Egger and multivariable MR adjusted for body mass index and for smoking. For validation, we included breast (Breast Cancer Association Consortium: 133384 cases, 113789 non-cases), prostate (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium: 79194 cases, 61112 non-cases) and lung (International Lung and Cancer Consortium: 10246 cases, 38295 non-cases) cancer from large consortia. We used asthma as a negative control outcome. RESULTS: Systolic and diastolic BP were unrelated to total cancer (OR 0.98 per standard deviation higher [95% confidence interval (CI) 0.89, 1.07] and OR 1.00 [95% CI 0.92, 1.08]) and to site-specific cancers after accounting for multiple testing, with consistent findings from consortia. BP was nominally associated with melanoma and possibly kidney cancer, and as expected, not associated with asthma. Sensitivity analyses using other MR methods gave similar results. CONCLUSIONS: In contrast to previous observational evidence, BP does not appear to be a risk factor for cancer, although an effect on melanoma and kidney cancer cannot be excluded. Other targets for cancer prevention might be more relevant.

Genetic Evidence on the Association of Interleukin (IL)-1-Mediated Chronic Inflammation with Airflow Obstruction: A Mendelian Randomization Study.

Preclinical studies suggest interleukin (IL)-1α/ß is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, recent trials of anti-IL-1 therapies showed limited benefit for COPD. To clarify, we primarily examined total and direct effects of IL-1 and its receptors/coreceptors/receptor antagonists (IL-1/IL-1Rs) on airflow obstruction (AO) using Mendelian randomization (MR), and secondarily explored reverse causation using bidirectional MR. We selected independent cis protein quantitative trait loci (cis-pQTLs) as genetic instruments for IL-1/IL-1Rs from two proteomic genome-wide association studies (n = 11,594) of European ancestry (mean age ∼47 years). We applied those cis-pQTLs to the International COPD Genetics Consortium (n = 15,256 cases, 47,936 controls) of ∼81.9% European descent (∼57 years). No IL-1/IL-1Rs were significantly associated with AO after correction for multiple testing. However, a higher genetically predicted IL-1 receptor antagonist (IL-1Ra) was nominally associated with a 20% reduction in AO risk using univariable MR, with a larger direct effect (∼31%, i.e. not via IL-1α/ß) using multivariable MR. Furthermore, higher total IL-18 binding protein (IL-18BP) was nominally associated with lower AO. Nominal total effects were also noted for higher IL-1α with lower AO and higher IL-1R1 with higher AO. Higher IL-1Ra and IL-18BP might have a role in preventing AO, but need to be contextualized.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1955848 .

The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study.

BACKGROUND: Cortisol, a steroid hormone frequently used as a biomarker of stress, is associated with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). To clarify whether cortisol causes these outcomes, we assessed the role of cortisol in ischemic heart disease (IHD), ischemic stroke, T2DM, and CVD risk factors using a bi-directional Mendelian randomization (MR) study. METHODS: Single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) and independently (r2 < 0.001) predicting cortisol were obtained from the CORtisol NETwork (CORNET) consortium (n = 12,597) and two metabolomics genome-wide association studies (GWAS) (n = 7824 and n = 2049). They were applied to GWAS of the primary outcomes (IHD, ischemic stroke and T2DM) and secondary outcomes (adiposity, glycemic traits, blood pressure and lipids) to obtain estimates using inverse variance weighting, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, SNPs predicting IHD, ischemic stroke, and T2DM were applied to the cortisol GWAS. RESULTS: Genetically predicted cortisol (based on 6 SNPs from CORNET; F-statistic = 28.3) was not associated with IHD (odds ratio (OR) 0.98 per 1 unit increase in log-transformed cortisol, 95% confidence interval (CI) 0.93-1.03), ischemic stroke (0.99, 95% CI 0.91-1.08), T2DM (1.00, 95% CI 0.96-1.04), or CVD risk factors. Genetically predicted IHD, ischemic stroke, and T2DM were not associated with cortisol. CONCLUSIONS: Contrary to observational studies, genetically predicted cortisol was unrelated to IHD, ischemic stroke, T2DM, or CVD risk factors, or vice versa. Our MR results find no evidence that cortisol plays a role in cardiovascular risk, casting doubts on the cortisol-related pathway, although replication is warranted.

Age-period-cohort projection of trends in blood pressure and body mass index in children and adolescents in Hong Kong.

BACKGROUND: Blood pressure (BP) and body mass index (BMI) trends during childhood and adolescence are complex, making context-specific projections necessary to inform prevention and presage changes. OBJECTIVE: This study aimed to project BP and BMI in Hong Kong Chinese children and adolescents from 2015 to 2024 based on trends in BP and BMI observed from 1996/99 to 2014. METHODS: We decomposed recent trends into sex-specific contributions of age, period and cohort using age-period-cohort linear regression with Bayesian inference and autoregressive priors based on BP in children and adolescents aged 9-18 years from 1999 to 2014 and BMI in those aged 6-18 years from 1996 to 2014. We then used the resultant models to project BP and BMI from 2015 to 2024. RESULTS: During the study period, systolic BP decreased from 1999 to 2004/5 before gradually increasing to 2014 during childhood (for boys: from 104.6 to 101.9 and then to 103.4 mmHg) and during adolescence. Similar patterns were observed for diastolic BP. BMI generally increased from 1996 to 2009 before falling to 2014 during childhood (e.g. for boys: from 17.2 to 18.0 and then to 17.1 kg/m2). From 2015 onwards, systolic BP was projected to increase in girls, but remain stable in boys. For both sexes, diastolic BP was projected to increase, whereas BMI was projected to decrease to 2024. CONCLUSIONS: In this economically developed Chinese setting, future trends in BP and BMI in children and adolescents are predicted to be divergent, consistent with prior discordant trends in BP and BMI.

Sleep duration and risk of diabetes: Observational and Mendelian randomization studies.

Inadequate sleep could contribute to type 2 diabetes, but observational studies are inconsistent and open to biases, particularly from confounding. We used Mendelian randomization (MR) to obtain an unconfounded estimate of the effect of sleep duration on diabetes, fasting glucose (FG) and hemoglobin A1c (HbA1c), and an observation study to assess differences by sex. Using MR, we assessed the effects of genetically instrumented sleep on diabetes, based on 68 single nucleotide polymorphisms (SNPs), applied to the DIAbetes Genetics Replication and meta-analysis case (n = 26,676)-control (n = 132,532) study and on FG and HbA1c, based on 55 SNPs, applied to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) study of FG (n = 122,743) and HbA1c (n = 123,665). In the population-representative Hong Kong Chinese "Children of 1997" birth cohort we assessed whether associations of sleep duration at ~17.5 years with FG and HbA1c differed by sex. Using inverse variance weighting with multiplicative random effects, sleep duration was not associated with diabetes (odds ratio (OR) 0.85 per hour of sleep, 95% confidence interval (CI) 0.64 to 1.13), FG (-0.032 mmol/l per hour of sleep, 95% CI -0.126 to 0.063) or HbA1c (-0.022% per hour of sleep, 95% CI -0.069 to 0.024). In "Children of 1997", the associations of sleep duration with FG differed by sex (p for interaction 0.05) but not with HbA1c. Overall sleep duration does not appear to be related to diabetes, FG or HbA1c, but the possibility of sex differences merits investigation.

Associations of growth from birth to puberty with glycemic indicators at ~17.5 years: Evidence from Hong Kong's "Children of 1997" birth cohort.

BACKGROUND: From an evolutionary biology perspective, where growth and reproduction trade-off against longevity, we assessed the associations of growth from birth to puberty by phase with later glycemic indicators and any differences by sex. METHODS: In the population-representative Hong Kong Chinese "Children of 1997" birth cohort (n = 8327), the relation of initial size (weight-for-age z score (WAZ) at birth, length/height-for-age z score (LAZ) at 3 months or body-mass-index-for-age z score (BAZ) at 3 months based on the World Health Organization growth standards/references) and growth at different phases (WAZ gains from 0 to 2 and 2 to 8 years, LAZ or BAZ gains from 3 months to 3 years, 3 to 8 years and 8 to 14 years) with fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) at ~17.5 years, was assessed using adjusted partial least squares regression. Additional analyses further considered growth in late and early infancy. RESULTS: This study included 3276 of the cohort participants. Higher WAZ gain from 2 to 8 years, LAZ and BAZ gains from 3 to 8 years were consistently associated with higher FPG, adjusted for maternal and infant characteristics, family history of diabetes and household income. Also, higher BAZ gain from 3 to 8 years was associated with higher HbA1c. These associations did not differ by sex. CONCLUSIONS: Our findings suggest different mechanisms could underlie the pathogenesis of glucose intolerance. Factors that drive specific growth at different phases need to be evaluated to better inform child growth management for long-term health outcomes.

The Roles of 27 Genera of Human Gut Microbiota in Ischemic Heart Disease, Type 2 Diabetes Mellitus, and Their Risk Factors: A Mendelian Randomization Study.

Manipulation of the gut microbiota presents a new opportunity to combat chronic diseases. Randomized controlled trials of probiotics suggest some associations with adiposity, lipids, and insulin resistance, but to our knowledge no trials with "hard" outcomes have been conducted. We used separate-sample Mendelian randomization to obtain estimates of the associations of 27 genera of gut microbiota with ischemic heart disease, type 2 diabetes mellitus, adiposity, lipid levels, and insulin resistance, based on summary data from CARDIoGRAAMplusC4D and other consortia. Among the 27 genera, a 1-allele increase in single nucleotide polymorphisms related to greater abundance of Bifidobacterium was associated with lower risk of ischemic heart disease (odds ratio = 0.985, 95% confidence interval (CI): 0.971, 1.000; P = 0.04), a 0.011-standard-deviation lower body mass index (95% CI: -0.017, -0.005), and a 0.026-standard-deviation higher low-density lipoprotein cholesterol level (95% CI: 0.019, 0.033), but the findings were not robust to exclusion of potential pleiotropy. We also identified Acidaminococcus, Aggregatibacter, Anaerostipes, Blautia, Desulfovibrio, Dorea, and Faecalibacterium as being nominally associated with type 2 diabetes mellitus or other risk factors. Results from our study indicate that these 8 genera of gut microbiota should be given priority in future research relating the gut microbiome to ischemic heart disease and its risk factors.

Opposite associations of household income with adolescent body mass index according to migrant status: Hong Kong's "Children of 1997" birth cohort.

BACKGROUND/OBJECTIVES: In economically developed settings, household income is usually inversely associated with child and adolescent adiposity, but this association may not extend to migrants. Hong Kong is a unique developed setting to study how household income and adolescent adiposity vary by migrant status given many Hong Kong-born Chinese children were born to parents who migrated from neighboring provinces of Mainland China. SUBJECTS/METHODS: We examined differences between the associations of absolute household income vs. relative household income on adolescent body mass index (BMI) z-score or overweight (including obesity) status using a linear or logistic model in a Chinese birth cohort (n = 5613, 68% follow-up). We focused on whether the associations differed by mother's or father's migrant status (birthplace). RESULTS: No association was found between absolute household income and BMI z-score among adolescents with either native or migrant mothers. However, the association of relative household income with BMI z-score varied by mother's migrant status (P-values for interaction <0.0005). In adolescents of native born mothers, greater relative household income deprivation was associated with higher BMI z-score (0.03 z-score per USD 128 difference in Yitzhaki index, 95% confidence interval (CI) 0.01 to 0.05). However, in adolescents of migrant mothers, greater relative household income deprivation was associated with lower BMI z-score (-0.05, 95% CI -0.09 to -0.01). Similar association of relative household income with overweight (including obesity) status was found in adolescents of native born mothers but not in adolescents of migrant mothers. CONCLUSIONS: Relative income (mediated by social comparisons with others in society) appears to be relevant to adolescent adiposity, but the association depends on the interplay between individual characteristics (migrant background) and societal context.

Birth weight, gestational age and late adolescent liver function using twin status as instrumental variable in a Hong Kong Chinese birth cohort: "Children of 1997".

Birth weight (BW) is inversely associated with diabetes and liver function in Mendelian Randomization studies. Observationally, lower BW is usually also associated with poorer liver function. However, these studies could be confounded by socioeconomic position. Here we assessed if BW is associated with liver function in a unique population with little socio-economic patterning of BW, using both instrumental variable and an observational analysis. We used instrumental variable analysis (IVA) to assess the association of BW with liver function (alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin) at ~17 years with twin status as an instrumental variable in the prospective population-representative "Children of 1997" birth cohort (n = 8327). We also conducted an observational analysis adjusted for sex, maternal age, maternal migrant status, smoking and parental socio-economic position. A generalized linear model with gamma family was used for ALT, ALP, and bilirubin because they are not normally distributed. Using IVA, BW was not associated with ALT, ALP or bilirubin, but was possibly negatively associated with albumin (-1.12 g/L, 95% confidence interval (CI) -2.08 to -0.16). Observationally, BW was negatively associated with ALT (-1.23 IU/L, 95% CI -2.16 to -0.30), ALP (-1.72 IU/L, 95% CI -3.43 to -0.01) and higher albumin (-0.23 g/L, 95% CI -0.40 to -0.06). Poor liver function may be a pathway by which the risks of lower BW are actuated. This insight might help identify post-natal targets of intervention to mitigate the adverse health effects of lower birth weight.

The Associations of Breast Feeding with Infant Growth and Body Mass Index to 16 years: 'Children of 1997'.

BACKGROUND: Controversial findings concerning associations of breast feeding with growth have been reported. This study examined whether the associations of breast feeding with early growth trajectories and body mass index to 16 years differed by sex or age. METHODS: In Hong Kong's 'Children of 1997' population-representative birth cohort, contemporaneously reported breast-feeding status in the first 3 months was classified as exclusive breast feeding (BF) (n = 470), mixed feeding (MF) (n = 2693), and formula feeding (FF) (n = 4204). Adjusted sex- and age-specific associations of breast feeding with infant growth (gains in weight-for-age z scores (WAZ), length/height-for-age z scores (LAZ), and body-mass-index-for-age z score (BAZ) based on the World Health Organization standards/references from birth to 36 months) were assessed using linear regression and mixed modelling, respectively. Adjusted sex-specific associations of breast feeding with average BAZ from 3 months to 16 years were assessed using generalized estimating equation. Potential confounders were maternal and infant characteristics, and household income. RESULTS: Among 7367 children, associations of breast feeding with infant growth did not vary by sex, but WAZ gains varied by age. Greater WAZ gains were observed in BF than FF infants from 0 to 3 months but in FF than BF infants from 3 to 9 months. Breast feeding was not associated with overall BAZ from 3 months to 16 years, with no differences by sex. CONCLUSIONS: Our findings suggest that breast feeding may only have short-term effects on growth. Further studies of the role of breast feeding in other metabolic diseases may be needed.

The association of breastfeeding with insulin resistance at 17 years: Prospective observations from Hong Kong's "Children of 1997" birth cohort.

Breastfeeding has many benefits for mother and infant. Whether breastfeeding also protects against type 2 diabetes is unclear. To clarify the role of breastfeeding in type 2 diabetes, we assessed the association of breastfeeding with insulin resistance in late adolescence in a birth cohort from a non-Western setting where breastfeeding was not associated with higher socio-economic position. We used multivariable linear regression, with multiple imputation and inverse probability weighting, to examine the adjusted associations of contemporaneously reported feeding in the first 3 months of life (exclusively breastfed, mixed feeding, or always formula-fed) with fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) at 17 years in a subset (n = 710, 8.6% of entire cohort) of the Hong Kong Chinese birth cohort "Children of 1997." We found a graded association of breastfeeding exclusivity in the first 3 months of life with lower fasting insulin and HOMA-IR (p-for-trend < .05), but not fasting glucose, at 17 years. Exclusively breastfed adolescents (7%) had nonsignificantly lowest fasting insulin and HOMA-IR, adjusted for sex, birth weight, parity, length of gestation, pregnancy characteristics, parents' education, and mother's place of birth. Exclusively breastfeeding for 3 months may be causally associated with lower insulin resistance in late adolescence. Further follow-up studies into adulthood are required to clarify the long-term protection of breastfeeding from type 2 diabetes.

Pubertal testis volume, age at pubertal onset, and adolescent blood pressure: Evidence from Hong Kong's "Children of 1997" birth cohort.

OBJECTIVES: A warning from Health Canada suggests that testosterone increases blood pressure (BP). No evidence from large randomized controlled trials is available, and observational studies are confounded by ill-health lowering serum testosterone. To address the evidence gap, we assessed the association of pubertal testicular volume, as a reflection of testosterone production, with BP. METHODS: We examined whether testicular volume was associated with sex-, age-, and height-standardized BP z-score at ∼13 years in a population-representative Chinese birth cohort (n = 5195, 63% follow-up). We used age at pubertal onset, determined as the earliest age when Tanner stage II for genitalia, breast, or pubic hair, or testicular volume of 4 mL occurred, as control exposures. These exposures were expected to produce findings different from testicular volume because they are not direct measures of testosterone. They were used to ascertain specificity of exposure and to detect residual confounding. RESULTS: Greater testicular volume was associated with higher systolic BP by 0.03 z-score, which is equivalent to 1.40 mm Hg per standard deviation of testicular volume (95% CI 0.02-0.04), adjusted for infant characteristics, socioeconomic position, and childhood body mass index. Similarly adjusted, earlier pubertal onset was not associated with higher systolic BP z-score in boys or girls. CONCLUSIONS: Greater pubertal testicular volume is related to higher BP, consistent with a potential role of androgens in the higher BP in boys than girls that emerges during puberty. Our finding provides preliminary evidence supportive of more definitive studies to clarify the warning on testosterone from Health Canada.

Grandparental education, parental education and adolescent blood pressure.

BACKGROUND: Maternal and paternal education could affect childhood blood pressure differently. Grandparental education might also play a role. Disentangling their contribution to childhood blood pressure may shed light on the persistence of disparities and potential windows of intervention. METHODS: Using 5604 participants from a Chinese birth cohort born in 1997 and followed-up until ~13years (68% of follow-up), we examined the associations of parental education and grandparental education with age-, sex, and height-specific blood pressure z-scores or prehypertension status. RESULTS: Parental education was inversely associated with adolescent systolic (-0.11 z-score, equivalent to -1.17mmHg, 95% confidence interval (CI) -0.19 to -0.04 for grade ≥12 compared with grade ≤9) and diastolic blood pressure (-0.07 z-score, equivalent to -0.79mmHg, 95% CI -0.11 to -0.04). The magnitude of association was similar for maternal or paternal education. Grandparental education was not associated with adolescent blood pressure. No association with prehypertension was found. CONCLUSIONS: In an economically developed non-Western setting, both maternal and paternal, but not grandparental, education was associated with adolescent blood pressure. Blood pressure may be responsive to contemporary family socioeconomic conditions that may be scrutinized for suitable interventions.

Birth weight and adult cardiovascular risk factors using multiple birth status as an instrumental variable in the 1958 British Birth Cohort.

BACKGROUND: Birth weight is classified as a risk factor for cardiovascular disease by the World Health Organization, but appropriate preventive interventions remain unclear because the observations have not been confirmed in experiments and appear to be contextually specific. METHODS: Using 9452 participants of the 1958 British Birth Cohort at age 42years in 2000 (58% follow-up), we examined the credibility of multiple birth status as an instrumental variable (IV) for birth weight and, if appropriate, use it to obtain less confounded estimates of the associations of birth weight with cardiovascular disease risk factors including self-reported height, body mass index and hypertension than conventional regression in 2014. RESULTS: Multiple birth (203 twins and 6 triplets) was associated with older maternal age, but not with paternal occupation or maternal smoking. Multiple births had lower birth weight-for-gestational age z-score. Multiple birth status was not directly associated with height, BMI or hypertension. Using IV estimates birth weight-for-gestational age z-score was not clearly associated with height (0.99cm, 95% confidence interval (CI) -0.27, 2.25), body mass index (BMI) (0.42kg/m(2), 95% CI -0.17, 1.01) or hypertension (risk ratio 0.82, 95% CI 0.54, 1.23) adjusted for maternal age, with a first-stage F statistic of 145.3 from IV analysis. CONCLUSIONS: Multiple birth status is a credible IV for obtaining a less confounded estimate of the association of birth weight with height, BMI and blood pressure. Such analysis suggests that birth weight may be spuriously related to height, BMI and blood pressure, and thus not an effective target for intervention.

Identifying potentially depressed older Chinese adults in the community: Hong Kong's Elderly Health Service cohort.

BACKGROUND: Depression is common at older ages, but is under-recognized due to stigma, misperception, and under-diagnosis; its manifestations may vary by setting. Identifying older adults at risk of depression in the community is urgently needed for timely support and early interventions. We assessed the performance of an existing risk prediction model developed in a European setting (i.e., Depression Risk Assessment Tool (DRAT-up)), and developed a new model (i.e., EHS-Depress model) to predict 2-year risk of the onset of later life depressive symptoms in older Chinese adults. METHODS: Among 185,538 participants aged ≥65 years from Hong Kong's Elderly Health Service (EHS) cohort, 174,806 without depressive symptoms at baseline were included. Two-thirds were randomly sampled for recalibration and new model development using Cox proportional-hazards models with backward elimination. Overall predictive performance, discrimination, and calibration were assessed using the remaining. RESULTS: The original DRAT-up model underestimated the risk of developing depressive symptoms in older Chinese adults; recalibrating it improved calibration. The new EHS-Depress model had better discrimination (Harrell's C statistic 0.68 and D statistic 2.74) and similarly good calibration (calibration slope 1.18 and intercept -0.002) probably due to the inclusion of more specific health measures, socio-demographics, lifestyle factors, and regular social contact as predictors. LIMITATIONS: Predictors of depressive symptoms included in our models depend on the data availability. CONCLUSIONS: The EHS-Depress model predicted 2-year risk of developing depressive symptoms better than the original and recalibrated DRAT-up models. The setting-specific risk prediction model is more applicable to older Chinese adults in primary care settings.

Association of childhood food consumption and dietary pattern with cardiometabolic risk factors and metabolomics in late adolescence: prospective evidence from 'Children of 1997' birth cohort.

BACKGROUND: Healthy diet might protect against cardiometabolic diseases, but uncertainty exists about its definition and role in adolescence. METHOD: In a subset of Hong Kong's 'Children of 1997' birth cohort (n=2844 out of 8327), we prospectively examined sex-specific associations of food consumption and dietary pattern, proxied by the Global Diet Quality Score (GDQS) at~12.0 years, with cardiometabolic risk factors and metabolomics at~17.6 years. RESULT: Higher vegetable (-0.04 SD, 95% CIs: -0.09 to 0.00) and soy consumption (-0.05 SD, 95% CI: -0.09 to -0.01) were associated with lower waist-to-hip ratio. Higher fruit and vegetable consumption were associated with lower fasting glucose (p<0.05). Higher fish consumption was associated with 0.06 SD (95% CI: 0.01 to 0.10) high-density lipoprotein cholesterol and -0.07 SD (95% CI: -0.11 to -0.02) triglycerides. After correcting for multiple comparisons (p<0.001), higher fish, fruit and vegetable consumption were associated with higher fatty acid unsaturation, higher concentration and percentage of omega-3 and a lower ratio of omega-6/omega-3. At nominal significance (p<0.05), higher fish consumption was associated with lower very-low-density lipoprotein and triglycerides relevant metabolomics. Higher vegetable and fruit consumption were associated with lower glycolysis-related metabolomics. Lower sugar-sweetened beverages (SSBs) consumption was associated with lower branched-chain amino acids. Similar associations with adiposity and metabolomics biomarkers were observed for GDQS. CONCLUSIONS: Higher consumption of fruit, vegetables and fish and lower ice cream and SSBs consumption were associated with lower cardiometabolic risk in adolescents.