A two-sample Mendelian randomization study explores metabolic profiling of different glycemic traits.

We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management.

Early-life exposure to ambient air pollution with cardiovascular risk factors in adolescents: Findings from the "Children of 1997" Hong Kong birth cohort.

BACKGROUND: Long-term exposure to ambient air pollution is associated with cardiovascular disease (CVD) risk. Little is known about the impact of early-life exposure to air pollutants on CVD risk factors in late adolescence, which may track into adulthood. To clarify, we examined this question in a unique setting with high air pollution and a high level of economic development. METHODS: This study leveraged the "Children of 1997" Hong Kong birth cohort (N = 8327), including here 3350 participants. We estimated ambient air pollutant exposure including inhalable particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2) and nitrogen monoxide (NO) by growth phase (in utero, infancy, childhood) and overall based on residential address. Generalized linear regression was used to assess the associations of air pollutants exposure by growth phase and sex with CVD risk factors (fasting blood glucose, glycosylated hemoglobin, lipid profile, blood pressure, and body mass index) at 17.6 years. We also assessed whether associations varied by sex. RESULTS: Early life exposed had little association with glucose metabolism, blood pressure or body mass index, but after considering multiple comparisons early exposure to PM10 was associated with low density lipoprotein (LDL) in boys, with ß and 95 % confidence intervals (95 % CI) of 0.184 (0.069 to 0.298) mmol/l, 0.151 (0.056 to 0.248) mmol/l, and 0.157 (0.063 to 0.252) mmol/l by per interquartile range (IQR) increment of PM10 for in utero, infancy, and overall, respectively. No such associations were evident for girls, differences by sex were evident. CONCLUSIONS: Our study suggested sex-specific associations of early-life PM10 exposure with elevated LDL in adolescence, especially exposure in utero and infancy.

Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality.

Importance: Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. Objectives: To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. Design, Setting, and Participants: This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Exposures: Genetically predicted apoB, LDL-C, and TG. Main Outcomes and Measures: The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. Results: This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. Conclusions and relevance: In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.

Unraveling Potential Sex-Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization.

BACKGROUND: Establishing the sex-specific efficacy of cardiovascular medications is pivotal to evidence-based clinical practice, potentially closing the gender gap in longevity. Trials large enough to establish sex differences are unavailable. This study evaluated sex-specific effects of commonly prescribed cardiovascular medications on lifespan. METHODS AND RESULTS: In a two-sample Mendelian randomization study, established genetic variants mimicking effects of lipid-lowering drugs, antihypertensives, and diabetes drugs were applied to genetic associations with lifespan proxied by UK Biobank maternal (n=412 937) and paternal (n=415 311) attained age. Estimates were obtained using inverse variance weighting, with sensitivity analyses where possible. For lipid-lowering drugs, genetically mimicked PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors were associated with longer lifespan, particularly in men (2.39 years per SD low-density lipoprotein cholesterol reduction [95% CI, 0.42-4.36], P for interaction=0.14). Genetically mimicked treatments targeting APOC3, LPL, or possibly LDLR were associated with longer lifespan in both sexes. For antihypertensives, genetically mimicked ß-blockers and calcium channel blockers were associated with longer lifespan, particularly in men (P for interaction=0.17 for ß-blockers and 0.31 for calcium channel blockers). For diabetes drugs, genetically mimicked metformin was associated with longer lifespan in both sexes. No associations were found for genetically mimicked statins, ezetimibe, or angiotensin-converting enzyme inhibitors. CONCLUSIONS: PCSK9 inhibitors, ß-blockers, and calcium channel blockers may prolong lifespan in the general population, particularly men. Treatments targeting APOC3, LPL, or LDLR and metformin may be relevant to both sexes. Whether other null findings are attributable to lack of efficacy requires investigation. Further investigation of repurposing should be conducted.

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.

Selection bias as an explanation for the observed protective association of childhood adiposity with breast cancer.

OBJECTIVES: Recalled childhood adiposity is inversely associated with breast cancer observationally, including in Mendelian randomization (MR) studies. Breast cancer studies recruited in adulthood only include survivors of childhood adiposity and breast cancer or a competing risk. We assessed recalled childhood adiposity on participant reported sibling and maternal breast cancer to ensure ascertainment of nonsurvivors. STUDY DESIGN AND SETTING: We obtained independent strong genetic predictors of recalled childhood adiposity for women and their associations with participant reported own, sibling and maternal breast cancer from UK Biobank genome wide association studies. RESULTS: Recalled childhood adiposity in women was inversely associated with own breast cancer using Mendelian randomization inverse variance weighting (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.52-0.84) but less clearly related to participant reported sibling (OR 0.89, 95% CI 0.69-1.14) or maternal breast cancer (OR 0.84, 95% CI 0.67-1.05). CONCLUSION: Weaker inverse associations of recalled childhood adiposity with breast cancer with more comprehensive ascertainment of cases before recruitment suggests the inverse association of recalled childhood adiposity with breast cancer could be partly selection bias from preferential selection of survivors. Greater consideration of survival bias in public health relevant causal inferences would be helpful.

The relationship of fatty acids to ischaemic heart disease and lifespan in men and women using Mendelian randomization.

BACKGROUND: Observationally, polyunsaturated fatty acids (PUFAs) have health benefits compared with saturated fatty acids (SFAs); randomized controlled trials suggest fewer benefits. We used uni- and multi-variable Mendelian randomization to assess the association of major fatty acids and their sub-species with ischaemic heart disease (IHD) overall and sex-specifically and with lifespan sex-specifically, given differing lifespan by sex. METHODS: We obtained strong (P <5x10-8), independent (r2<0.001) genetic predictors of fatty acids from genome-wide association studies (GWAS) in a random subset of 114 999 UK Biobank participants. We applied these genetic predictors to the Cardiogram IHD GWAS (cases = 60 801, controls = 123 504) and to the Finngen consortium GWAS (cases = 31 640, controls = 187 152) for replication and to the UK Biobank for sex-specific IHD and for lifespan based on parental attained age (fathers = 415 311, mothers = 412 937). We used sensitivity analysis and assessed sex differences where applicable. RESULTS: PUFAs were associated with IHD [odds ratio 1.23, 95% confidence interval (CI) 1.05 to 1.44] and lifespan in men (-0.76 years, 95% CI -1.34 to -0.17) but not women (0.20, 95% CI -0.32 to 0.70). Findings were similar for omega-6 fatty acids and linoleic acid. Independent associations of SFAs, mono-unsaturated fatty acids or omega-3 fatty acids with IHD overall or lifespan in men and women were limited. CONCLUSIONS: PUFAs, via specific subspecies, may contribute to disparities in lifespan by sex. Sex-specific dietary advice might be a start towards personalized public health and addressing inequities.

Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study.

BACKGROUND: Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk. Here, we investigated genetically mimicked ASGR1 inhibitors on all-cause mortality and any possible adverse effects. METHODS: We conducted a drug-target Mendelian randomization study to assess genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and 25 a priori outcomes relevant to lipid traits, CAD, and possible adverse effects, i.e. liver function, cholelithiasis, adiposity and type 2 diabetes. We also performed a phenome-wide association study of 1951 health-related phenotypes to identify any novel effects. Associations found were compared with those for currently used lipid modifiers, assessed using colocalization, and replicated where possible. RESULTS: Genetically mimicked ASGR1 inhibitors were associated with a longer lifespan (3.31 years per standard deviation reduction in LDL-cholesterol, 95% confidence interval 1.01 to 5.62). Genetically mimicked ASGR1 inhibitors were inversely associated with apolipoprotein B (apoB), triglycerides (TG) and CAD risk. Genetically mimicked ASGR1 inhibitors were positively associated with alkaline phosphatase, gamma glutamyltransferase, erythrocyte traits, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), but were inversely associated with albumin and calcium. Genetically mimicked ASGR1 inhibitors were not associated with cholelithiasis, adiposity or type 2 diabetes. Associations with apoB and TG were stronger for ASGR1 inhibitors compared with currently used lipid modifiers, and most non-lipid effects were specific to ASGR1 inhibitors. The probabilities for colocalization were > 0.80 for most of these associations, but were 0.42 for lifespan and 0.30 for CAD. These associations were replicated using alternative genetic instruments and other publicly available genetic summary statistics. CONCLUSIONS: Genetically mimicked ASGR1 inhibitors reduced all-cause mortality. Beyond lipid-lowering, genetically mimicked ASGR1 inhibitors increased liver enzymes, erythrocyte traits, IGF-1 and CRP, but decreased albumin and calcium.

Association of iron homeostasis biomarkers in type 2 diabetes and glycaemic traits: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Mendelian randomization (MR) studies show iron positively associated with type 2 diabetes (T2D) but included potentially biasing hereditary haemochromatosis variants and did not assess reverse causality. METHODS: We assessed the relation of iron homeostasis with T2D and glycaemic traits bidirectionally, using genome-wide association studies (GWAS) of iron homeostasis biomarkers [ferritin, serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT) (n ≤ 246 139)], T2D (DIAMANTE n = 933 970 and FinnGen n = 300 483), and glycaemic traits [fasting glucose (FG), 2-h glucose, glycated haemoglobin (HbA1c) and fasting insulin (FI) (n ≤ 209 605)]. Inverse variance weighting (IVW) was the main analysis, supplemented with sensitivity analyses and assessment of mediation by hepcidin. RESULTS: Iron homeostasis biomarkers were largely unrelated to T2D, although serum iron was potentially associated with higher T2D [odds ratio: 1.07 per standard deviation; 95% confidence interval (CI): 0.99 to 1.16; P-value: 0.078) in DIAMANTE only. Higher ferritin, serum iron, TSAT and lower TIBC likely decreased HbA1c, but were not associated with other glycaemic traits. Liability to T2D likely increased TIBC (0.03 per log odds; 95% CI: 0.01 to 0.05; P-value: 0.005), FI likely increased ferritin (0.29 per log pmol/L; 95% CI: 0.12 to 0.47; P-value: 8.72 x 10-4). FG likely increased serum iron (0.06 per mmol/L; 95% CI: 0.001 to 0.12; P-value: 0.046). Hepcidin did not mediate these associations. CONCLUSION: It is unlikely that ferritin, TSAT and TIBC cause T2D although an association for serum iron could not be excluded. Glycaemic traits and liability to T2D may affect iron homeostasis, but mediation by hepcidin is unlikely. Corresponding mechanistic studies are warranted.

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.

Red meat consumption, cardiovascular diseases, and diabetes: a systematic review and meta-analysis.

AIMS: Observational studies show inconsistent associations of red meat consumption with cardiovascular disease (CVD) and diabetes. Moreover, red meat consumption varies by sex and setting, however, whether the associations vary by sex and setting remains unclear. METHODS AND RESULTS: This systematic review and meta-analysis was conducted to summarize the evidence concerning the associations of unprocessed and processed red meat consumption with CVD and its subtypes [coronary heart disease (CHD), stroke, and heart failure], type two diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM) and to assess differences by sex and setting (western vs. eastern, categorized based on dietary pattern and geographic region). Two researchers independently screened studies from PubMed, Web of Science, Embase, and the Cochrane Library for observational studies and randomized controlled trials (RCTs) published by 30 June 2022. Forty-three observational studies (N = 4 462 810, 61.7% women) for CVD and 27 observational studies (N = 1 760 774, 64.4% women) for diabetes were included. Red meat consumption was positively associated with CVD [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.05 to 1.16 for unprocessed red meat (per 100 g/day increment); 1.26, 95% CI 1.18 to 1.35 for processed red meat (per 50 g/day increment)], CVD subtypes, T2DM, and GDM. The associations with stroke and T2DM were higher in western settings, with no difference by sex. CONCLUSION: Unprocessed and processed red meat consumption are both associated with higher risk of CVD, CVD subtypes, and diabetes, with a stronger association in western settings but no sex difference. Better understanding of the mechanisms is needed to facilitate improving cardiometabolic and planetary health.

Effect of basal metabolic rate on lifespan: a sex-specific Mendelian randomization study.

Observationally, the association of basal metabolic rate (BMR) with mortality is mixed, although some ageing theories suggest that higher BMR should reduce lifespan. It remains unclear whether a causal association exists. In this one-sample Mendelian randomization study, we aimed to estimate the casual effect of BMR on parental attained age, a proxy for lifespan, using two-sample Mendelian randomization methods. We obtained genetic variants strongly (p-value < 5 × 10-8) and independently (r2 < 0.001) predicting BMR from the UK Biobank and applied them to a genome-wide association study of parental attained age based on the UK Biobank. We meta-analyzed genetic variant-specific Wald ratios using inverse-variance weighting with multiplicative random effects by sex, supplemented by sensitivity analysis. A total of 178 and 180 genetic variants predicting BMR in men and women were available for father's and mother's attained age, respectively. Genetically predicted BMR was inversely associated with father's and mother's attained age (years of life lost per unit increase in effect size of genetically predicted BMR, 0.46 and 1.36; 95% confidence interval 0.07-0.85 and 0.89-1.82), with a stronger association in women than men. In conclusion, higher BMR might reduce lifespan. The underlying pathways linking to major causes of death and relevant interventions warrant further investigation.

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.

Environment- and epigenome-wide association study of obesity in 'Children of 1997' birth cohort.

Background: Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city. Methods: We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kong's population-representative 'Children of 1997' birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity risk n ≤ 7119, WHR n = 5691) and ~17.6 years (n = 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n = 308) and CpG by CpG analysis (n = 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. Results: At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR. Conclusions: These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings. Funding: This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.

Genetic proxies for calcium channel blockers and cancer: a Mendelian randomization study.

Calcium channel blockers (CCBs) are commonly prescribed antihypertensives. However, concerns exist about potential off-target effects on cancer. This Mendelian randomization (MR) study examined the associations of genetic proxies for CCBs with the risk of cancer. We used published genetic proxies in the target genes of CCBs as instruments, and obtained MR estimates by applying them to large studies of 17 site-specific cancers (non-Hodgkin lymphoma, melanoma, leukemia, thyroid, rectal, pancreatic, oral cavity/pharyngeal, kidney, esophagus/stomach, colon, bladder, endometrial, cervical and breast, prostate, lung and ovarian cancer) from the Pan-Cancer study, with replication for breast cancer (133,384 cases, 113,789 controls from the Breast Cancer Association Consortium), prostate cancer (79,148 cases, 61,106 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium), lung cancer (11,348 cases, 15,861 controls from the International Lung Cancer Consortium), and ovarian cancer (25,509 cases, 40,941 controls from the Ovarian Cancer Association Consortium). We used inverse variance weighting for the main analysis and the weighted median, MR-Egger and Mendelian Randomization Pleiotropy Residual Sum and Outlier as sensitivity analyses. Genetic proxies for CCBs were not associated with any cancer after Bonferroni-correction (at the threshold of p < 0.003). Associations were robust to different MR methods. In conclusion, our study suggests no association of genetic proxies for CCBs with 17 different cancers. While the findings add some support to the safety profile of CCBs in long-term use, future replication is necessary to provide definitive evidence.

Investigating sex-specific associations of lipid traits with type 2 diabetes, glycemic traits and sex hormones using Mendelian randomization.

BACKGROUND: Low-density lipoprotein (LDL)-cholesterol is positively associated with cardiovascular disease (CVD) and inversely associated with type 2 diabetes, which could detract from lipid modification. Here, we examined whether lipid traits potentially relevant to CVD aetiology, i.e. apolipoprotein B (apoB), triglycerides (TG) and lipoprotein(a) [Lp(a)] exhibited the same associations. We investigated sex-specifically, including the role of sex hormones, because sex disparities exist in lipid profile and type 2 diabetes. We also replicated where possible. METHODS: We used Mendelian randomization (MR) to examine sex-specific associations of apoB, TG and Lp(a) with type 2 diabetes, HbA1c, fasting insulin, fasting glucose, testosterone and estradiol in the largest relevant sex-specific genome-wide association studies (GWAS) in people of European ancestry and replicated where possible. We also assessed sex-specific associations of liability to type 2 diabetes with apoB, TG and Lp(a). RESULTS: Genetically predicted apoB and Lp(a) had little association with type 2 diabetes or glycemic traits in women or men. Genetically predicted higher TG was associated with higher type 2 diabetes risk [odds ratio (OR) 1.44 per standard deviation (SD), 95% confidence interval (CI) 1.26 to 1.65], HbA1c and fasting insulin specifically in women. Higher TG was associated with lower testosterone in women and higher testosterone in men, but with lower estradiol in men and women. Genetic liability to type 2 diabetes was associated with higher TG in women, and possibly with lower apoB in men. CONCLUSIONS: Lipid traits potentially relevant to CVD aetiology do not exhibit contrasting associations with CVD and type 2 diabetes. However, higher TG is associated with higher type 2 diabetes risk and glycemic traits, which in turn further increases TG specifically in women, possibly driven by sex hormones.

Association of growth patterns during infancy and puberty with lung function, wheezing and asthma in adolescents aged 17.5 years: evidence from 'Children of 1997' Hong Kong Chinese Birth Cohort.

BACKGROUND: Rapid growth is related to adverse respiratory outcomes although possibly confounded or limited by growth modelling methods. We investigated the association of infant and pubertal growth with lung function, wheezing and asthma in a non-Western setting. METHODS: In Hong Kong's 'Children of 1997' Chinese birth cohort (n = 8327), weight during infancy and weight, height and body mass index (BMI) during puberty were modelled using a super-imposition by translation and rotation model to identify (larger or smaller) size, (earlier or later) tempo and (slower or faster) velocity. Sex-specific associations with forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC (Global Lung function Initiative z-score) and self-reported wheezing and asthma at ∼17.5 years were assessed. RESULTS: For each fraction higher than average weight growth velocity during infancy, FVC was higher in boys (0.90 SD, 95% CI 0.35; 1.44) and girls (0.77 SD, 95% CI 0.24; 1.30), FEV1/FVC was lower (-0.74 SD, 95% CI -1.38; -0.10) and wheezing was higher (odds ratio 6.92, 95% CI 1.60; 29.99) in boys and an inverse association with FVC was observed for tempo but not for size. Associations for weight growth velocity in puberty were similar but weaker. Greater size and higher velocity of BMI growth was associated with higher FVC, lower FEV1/FVC and higher asthma and wheezing risk. CONCLUSION: Accelerated infant and pubertal weight growth were associated with disproportionate lung size and airway growth, and higher risk of asthma; optimizing early-life growth patterns could be important.

Statins, Type 2 Diabetes, and Body Mass Index: A Univariable and Multivariable Mendelian Randomization Study.

CONTEXT: Statins and possibly other lipid modifiers increase type 2 diabetes risk and body mass index (BMI). However, to what extent BMI mediates the diabetogenic effects of lipid modifiers remains unclear. OBJECTIVE: We used Mendelian randomization (MR) to investigate the effects of commonly used lipid modifiers on type 2 diabetes risk and glycemic traits, and any mediation by BMI. METHODS: Using established genetic variants to mimic commonly used lipid modifiers (ie, statins, PCSK9 inhibitors, and ezetimibe), we assessed their associations with type 2 diabetes risk, glycated hemoglobin (HbA1c), fasting insulin, fasting glucose, and BMI in the largest relevant genome-wide association studies (GWAS) in people of European ancestry, and where possible, in East Asians. We used multivariable MR to examine the role of lipid modifiers independent of BMI. RESULTS: Genetically mimicked effects of statins and ezetimibe, but not PCSK9 inhibitors were associated with higher risk of type 2 diabetes (odds ratio [OR] 1.74 [95% CI, 1.49 to 2.03]; 1.92 [1.22 to 3.02]; 1.06 [0.87 to 1.29] per SD reduction in low-density lipoprotein (LDL)-cholesterol). Of these lipid modifiers, only genetic mimics of statins were associated with higher BMI (0.33 SD [0.29 to 0.38] per SD reduction in LDL-cholesterol), which explained 54% of the total effect of statins on type 2 diabetes risk. CONCLUSION: Higher BMI mediated more than half of the diabetogenic effects of statins, which did not extend to other commonly used lipid modifiers. Further investigations are needed to clarify drug-specific mechanisms underlying the effects of lipid modifiers on type 2 diabetes.