Early-life exposure to ambient air pollutants and kidney function in adolescents: a cohort study based on the 'Children of 1997' Hong Kong birth cohort.

OBJECTIVES: Air pollution is increasingly linked to impaired kidney function in adults. However, little is known about how early-life exposure to air pollutants affects kidney function in adolescents. STUDY DESIGN: Cohort study. METHODS: We leveraged data from the 'Children of 1997' Hong Kong population-representative birth cohort (N = 8327). Residential exposure to average ambient levels of four air pollutants, including inhalable particle (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and nitrogen monoxide (NO), during in utero, infancy, and childhood periods was estimated using the inverse distance weighting. Kidney function was assessed using estimated glomerular filtration rate (eGFR) calculated from age-adjusted equations for adolescents. Generalized linear regression was used to examine the association of air pollutant exposure in each period with kidney function at 17.6 years. Two-pollutant models tested the robustness of the association. RESULTS: Of the 3350 participants included, 51.4% were boys. Exposure to PM10 was associated with poorer kidney function. Each interquartile range increment in PM10 was inversely associated with eGFR (ß: -2.933, 95% confidence interval -4.677 to -1.189) in utero, -2.362 (-3.992 to -0.732) infancy, -2.708 (-4.370 to -1.047) childhood, and -2.828 (-4.409 to -1.247) overall. Exposure to PM10 and SO2in utero had a stronger inverse association with kidney function in males. The associations were robust to PM10 exposure in two-pollutant models. CONCLUSIONS: Our findings suggest that early-life exposure to ambient PM10 and SO2 is associated with reduced kidney function in adolescents, especially exposure in utero.

Insights into Causal Cardiovascular Risk Factors from Mendelian Randomization.

PURPOSE OF THE REVIEW: This review summarizes major insights into causal risk factors for cardiovascular disease (CVD) by using Mendelian randomization (MR) to obtain unconfounded estimates, contextualized within its strengths and weaknesses. RECENT FINDINGS: MR studies have confirmed the role of major CVD risk factors, including alcohol, smoking, adiposity, blood pressure, type 2 diabetes, lipids, and possibly inflammation, but added that the relation with alcohol is likely linear, confirmed the role of diastolic blood pressure, identified apolipoprotein B as the major target lipid, and foreshadowed results of some trials concerning anti-inflammatories. Identifying a healthy diet and the role of early life influences, such as birth weight, has proved more difficult. Use of MR has winnowed empirically driven hypotheses about CVD into a set of genetically validated targets of intervention. Greater inclusion of global diversity in genetic studies and the use of an overarching framework would enable even more informative MR studies.

A phenome-wide association study of genetically mimicked statins.

BACKGROUND: Beyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c). METHODS: We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c. RESULTS: As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition. CONCLUSIONS: Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice.

Interleukin-18 and COVID-19.

Vulnerability to coronavirus disease (COVID)-19 varies due to differences in interferon gamma (IFNγ) immunity. We investigated whether a key modifiable interferon precursor, interleukin-18, was related to COVID-19, overall and by severity, using Mendelian randomisation. We used four established genome-wide significant genetic predictors of interleukin-18 applied to the most recent genome-wide association study of COVID-19 (June 2021) to obtain Mendelian randomisation inverse variance weighted estimates by severity, i.e. any (cases = 112 612, non-cases = 2 474 079), hospitalised (cases = 24 274, non-cases = 2 061 529) and very severe (cases = 8779, non-cases = 1 001 875) COVID-19. To be comprehensive, we also conducted an exploratory analysis for IFNγ and two related cytokines with less well-established genetic predictors, i.e. interleukin-12 and interleukin-23. Genetically predicted interleukin-18 was associated with lower risk of any COVID-19 (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (0.94-0.99, P-value 0.004)) and of very severe COVID-19 (OR 0.88, 95% CI 0.78-0.999, P-value 0.048). Sensitivity analysis and a more liberal genetic instrument selection gave largely similar results. Few genome-wide significant genetic predictors were available for IFNγ, interleukin-12 or interleukin-23, and no associations with COVID-19 were evident. Interleukin-18 could be a modifiable target to prevent COVID-19 and should be further explored in an experimental design.

A phenome-wide association study of ABO blood groups.

BACKGROUND: ABO blood group is associated with differences in lifespan, cardiovascular disease, and some cancers, for reasons which are incompletely understood. To gain sex-specific additional insight about potential mechanisms driving these common conditions for future interventions, we characterized associations of ABO blood group antigen across the phenotype sex-specifically. METHODS: We performed a phenome-wide association study (PheWAS) assessing the association of tag single nucleotide polymorphisms (SNPs) for ABO blood group antigens (O, B, A1, and A2) with 3873 phenotypes. RESULTS: The tag SNP for the O antigen was inversely associated with diseases of the circulatory system (particularly deep vein thrombosis (DVT)), total cholesterol, low-density lipoprotein cholesterol (LDL-C), and ovarian cancer, and positively associated with erythrocyte traits, leukocyte counts, diastolic blood pressure (DBP), and healthy body composition; the tag SNP for the A1 antigen tended to have associations in reverse to O. Stronger associations were more apparent for men than women for DVT, DBP, leukocyte traits, and some body composition traits, whereas larger effect sizes were found for women than men for some erythrocyte and lipid traits. CONCLUSION: Blood group has a complex association with cardiovascular diseases and its major risk factors, including blood pressure and lipids, as well as with blood cell traits and body composition, with some differences by sex. Lower LDL-C may underlie some of the benefits of blood group O, but the complexity of associations with blood group antigen suggests overlooked drivers of common chronic diseases.

Correction to: In utero exposure to gestational diabetes and adiposity: does breastfeeding make a difference?

In the original version of this article, the Publisher incorrectly listed the affiliation of the author, G.M. Leung. The correct affiliation for this author should be: School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

In utero exposure to gestational diabetes and adiposity: does breastfeeding make a difference?

BACKGROUND/OBJECTIVES: Short-term breastfeeding from mothers with gestational diabetes (GDM) may programme metabolism and increase offspring diabetes risk. We examined the association of in utero GDM exposure with adiposity from infancy to adolescence, and whether any association was modified by breastfeeding during early infancy. METHODS: In the prospective Chinese birth cohort "Children of 1997" (n = 7342, 88% follow-up rate), generalised estimate equations with multiple imputation were used to assess associations of in utero GDM exposure with age- and sex-specific body mass index (BMI) z-score during infancy (3 and 9 months), childhood (2- < 8 years) and adolescence (8-16 years), adjusted for sex, parity, maternal age, birth place, preeclampisa, smoking, and family socio-economic position. We also tested whether the associations differed by mode of infant feeding (always formula-fed, mixed, always breastfed) during the first three months of life. RESULTS: In utero GDM exposure (7.5%) was associated with a lower BMI z-score during infancy (-0.13, 95% confidence interval (CI) -0.22, -0.05) but higher BMI z-scores during childhood (0.14, 95% CI 0.03, 0.25) and adolescence (0.25 95% CI 0.11, 0.38). Breastfeeding for the first three months did not modify the association of in utero GDM status with subsequent BMI (all p values for interaction >0.4). CONCLUSIONS: In utero GDM exposure was associated with greater adiposity during childhood and adolescence. Breastfeeding in early infancy from mothers with GDM was not associated with greater adiposity in children and thus should still be encouraged.

Migrant status and childhood hospitalizations for asthma and other wheezing disorders.

BACKGROUND: In developed Western settings, asthma is more prevalent among second-generation compared to first-generation migrants. However, these studies are difficult to interpret as they include migrants of various ethnicities and countries of origin. OBJECTIVE: We assessed the association of parental migrant status with wheezing disorders among children born in Hong Kong, a developed non-Western setting, where many children have migrant parents from mainland China of the same ethnicity. METHODS: We used Cox regression to examine the adjusted associations of parental migrant status with time to first public hospital admission for asthma, bronchitis and bronchiolitis (International Classification of Diseases, Ninth Version Clinical Modification 466, 490 and 493) from 9 days to 12 years in a population-representative birth cohort of 8327 Chinese children in Hong Kong. RESULTS: Having both parents as migrants was associated with higher risk of hospitalization for asthma and other wheezing disorders, compared to both parents being Hong Kong born (hazard ratio 1.30, 95% confidence interval 1.05-1.60 from 9 days to 6 years), adjusted for type of hospital at birth, parental history of allergies, mother's age at birth, father's age at birth and highest parental education. CONCLUSIONS AND CLINICAL RELEVANCE: In the unique, non-Western context of Hong Kong, second-generation migrants had higher risk of hospitalization for childhood wheezing disorders compared to the native population, particularly before 6 years of age. Further study is required to clarify the underlying mechanisms involved.

Duration of puberty in preterm girls.

OBJECTIVES: Preterm birth is associated with altered pubertal timing, but the effect on pubertal duration has rarely been assessed. Here, we tested the hypothesis that preterm birth is associated with shorter duration of puberty among girls in Hong Kong where preterm birth has little social patterning. METHODS: In the population-representative Chinese birth cohort "Children of 1997", we used multivariable linear regression to assess the association of preterm status (≤36 completed gestational weeks, n = 170; term birth 37-42 gestational weeks, n = 3476) with duration of puberty, adjusted for parent's highest education, mother's place of birth, maternal smoking during pregnancy, gestational diabetes, preeclampsia, and mother's age of menarche. RESULTS: The mean duration from thelarche to menarche was 2.53 years. Preterm girls had a shorter duration from thelarche to menarche by 2.6 months, 95% confidence interval 0.5-4.7 months. Age of menarche did not differ by preterm status but preterm girls had later thelarche. Preterm birth was not associated with a shorter duration from pubarche to menarche. CONCLUSIONS: Preterm births may be associated with shorter duration of puberty from thelarche to menarche, possibly through effects of in utero estrogen exposure, the drivers of thelarche, or the drivers of pubertal duration/progression, with potential implications for subsequent risk of cardiovascular disease and hormonal cancers.

The effect of hematocrit and hemoglobin on the risk of ischemic heart disease: A Mendelian randomization study.

Hematocrit and hemoglobin affect viscosity, and have been considered as risk factors for ischemic heart disease (IHD), although observations are inconsistent; randomized controlled trials targeting hematocrit or hemoglobin have not been definitive. To clarify their role, the risk of IHD was assessed according to genetically determined hematocrit and hemoglobin. We applied single nucleotide polymorphisms (SNPs) strongly determining hematocrit and hemoglobin, from a genome wide association study, to a large case (64,746) control (130,681) study of coronary artery disease, CARDIoGRAMplusC4D, to obtain unconfounded estimates using instrumental variable analysis by combining the Wald estimators for each SNP taking into account any correlation between SNPs using weighted generalized linear regression. Hematocrit was positively associated with IHD, odds ratio (OR) 1.07 per %, 95% confidence interval (CI) 1.03 to 1.11, before and after excluding SNPs from gene regions directly functionally relevant to IHD. However, hematocrit was not associated with IHD (OR 0.99, 0.94 to 1.04) after also excluding SNPs associated with lipids at genome wide significance. Hemoglobin was not associated with IHD (OR 1.06 per g/dL, 0.97 to 1.15) which was similar (OR 1.02, 0.94 to 1.11) after excluding SNPs from gene regions directly functionally relevant to IHD. Hemoglobin was negatively associated with IHD after also excluding SNPs associated with lipids at genome wide significance (OR 0.86, 0.78 to 0.94). In conclusion, hematocrit shares genetic determinants with IHD, but whether the genes contribute to IHD via hematocrit or other mechanisms is not entirely clear. Higher Hemoglobin is unlikely to cause IHD.

Breast cancer incidence and mortality in a transitioning Chinese population: current and future trends.

BACKGROUND: Projections of future trends in cancer incidence and mortality are important for public health planning. METHODS: By using 1976-2010 data in Hong Kong, we fitted Poisson age-period-cohort models and made projections for future breast cancer incidence and mortality to 2025. RESULTS: Age-standardised breast cancer incidence (/mortality) is projected to increase (/decline) from 56.7 (/9.3) in 2011-2015 to 62.5 (/8.6) per 100,000 women in 2021-2025. CONCLUSIONS: The incidence pattern may relate to Hong Kong's socio-economic developmental history, while falling mortality trends are, most likely, due to improvements in survival from treatment advancement and improved health service delivery.

Mode of delivery and childhood hospitalizations for asthma and other wheezing disorders.

BACKGROUND: Observationally, delivery by Caesarean section is associated with higher risk of childhood asthma and wheeze in developed Western settings, but associations are less consistent in other settings. OBJECTIVE: To examine the association of mode of delivery with hospitalizations for asthma and other wheezing disorders in a developed non-Western setting with high rates of Caesarean section. METHODS: Using Cox regression, we examined the adjusted association of mode of delivery with public hospital admissions for asthma, bronchitis, and bronchiolitis (International Classification of Diseases, Ninth Version Clinical Modification 466, 490 and 493) from 9 days to 12 years of age in a population-representative prospective birth cohort of 8327 Chinese children in Hong Kong. Confounders included sex, birth and parental characteristics, and socio-economic position (SEP). RESULTS: Delivery by Caesarean section accounted for 27% of all births and was not clearly associated with hospitalizations for asthma and other wheezing disorders to 12 years [hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.91 to 1.36] compared to vaginal delivery. Similarly, there were no clear associations to 2 years (HR 1.07, 95% CI 0.83 to 1.38) or 6 years (HR 1.12, 95% CI 0.91 to 1.37), although we cannot rule out residual confounding by SEP. CONCLUSIONS AND CLINICAL RELEVANCE: We cannot rule out an association, but our findings suggest that the observed associations of delivery by Caesarean section with childhood wheezing disorders may vary with setting and may not be biologically mediated. Further studies with different designs are needed to clarify the role of the microbiome and mode of delivery in the aetiology of asthma and other childhood wheezing disorders.

Adolescent testosterone, muscle mass and glucose metabolism: evidence from the 'Children of 1997' birth cohort in Hong Kong.

AIMS: Diabetes rates are high in Asia despite relatively low rates of obesity, which might be related to lower muscle mass. Muscle mass plays an important role in glucose metabolism. Peak muscle mass is obtained in late adolescence. We tested the hypothesis that pubertal testosterone is negatively associated with glucose metabolism mediated by muscle mass. METHODS: Participants aged 15 years (278 boys and 223 girls) were recruited from the Hong Kong's 'Children of 1997' birth cohort in 2012. Multivariable linear regression with multiple imputation and inverse probability weighting was used to examine the adjusted associations of pubertal testosterone with skeletal muscle index, body fat percentage, fasting glucose, insulin and homeostasis model of assessment - insulin resistance. RESULTS: Total testosterone was negatively associated with fasting glucose (-0.008, 95% confidence interval -0.015 to -0.002), insulin (-0.43, 95% confidence interval -0.56 to -0.30) and insulin and homeostasis model of assessment - insulin resistance (-0.09, 95% confidence interval -0.12 to -0.06) adjusted for sex, birth weight, highest parental education, mother's place of birth and physical activity. These associations were attenuated by additional adjustment for skeletal mass index or body fat percentage. CONCLUSIONS: Adolescent glucose metabolism may be influenced by testosterone, perhaps partially via skeletal muscle mass.

The Association of Infant Growth Patterns with Adiposity in Adolescence: Prospective Observations from Hong Kong's 'Children of 1997' Birth Cohort.

BACKGROUND: The role of infant growth in adiposity remains unclear. METHODS: We used multivariable linear regression, with inverse probability weighting and multiple imputation to account for loss to follow-up, in a population-representative Chinese birth cohort, 'Children of 1997' in Hong Kong, to examine, in terms births, the adjusted association of infant (birth to 12 months) weight growth trajectories with body mass index (BMI) (n = 6861, 88% follow-up), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) (n = 5398, 69% follow-up) at ∼ 14 years. RESULTS: Infant weight growth trajectories had graded associations with adolescent BMI and WHtR but not with WHR, such that compared with adolescents born light with slow infant growth, adolescents born heavy with fast infant growth had higher BMI z-score [0.60, 95% confidence interval (CI) 0.49, 0.70], higher WHtR z-score (0.17, 95% CI 0.08, 0.26) but similar WHR z-score (-0.02, 95% CI -0.11, 0.08), adjusted for sex, gestational age, parental education, parental BMI, parental height, and parental place of birth. CONCLUSIONS: Varying associations of infant growth with different adiposity measures suggest a complex role of infant growth in long-term health, perhaps because infant growth, or its underlying drivers, influences build and body composition as well as adiposity.