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 Mendelian randomization study of genetic predisposition to autoimmune diseases and COVID-19.

Autoimmune diseases and coronavirus disease 2019 (COVID-19) share many similarities. Concerns have arisen that autoimmune diseases may increase the susceptibility and severity of COVID-19. We used Mendelian randomization to investigate whether liability to autoimmune diseases is related to COVID-19 susceptibility and severity. Genetic instruments for 8 autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis and juvenile idiopathic arthritis, were obtained from published genome-wide association studies. Two-sample Mendelian randomization analyses of the associations of liability to each autoimmune disease with COVID-19 infection, hospitalized COVID-19, and very severe COVID-19 were performed using the latest publicly available genome-wide association study for COVID-19. Genetic liability to each of the autoimmune diseases was largely not associated with COVID-19 infection, hospitalized COVID-19, or very severe COVID-19 after accounting for multiple comparison. Sensitivity analysis excluding genetic variants in the human leukocyte antigen gene, which has an important role in the immune response, showed similar results. The autoimmune diseases examined were largely not genetically associated with the susceptibility or severity of COVID-19. Further investigations are warranted.

Investigating the effects of statins on ischemic heart disease allowing for effects on body mass index: a Mendelian randomization study.

Despite effective lipid reduction and corresponding benefits for cardiovascular disease prevention and treatment, statins have pleiotropic effects potentially increasing the risk of ischemic heart disease (IHD), particularly by increasing body mass index (BMI). We assessed whether the effects of genetically mimicked statins on IHD were strengthened by adjusting for BMI in men and women. We also assessed if increasing BMI was specific to statins in comparison to other major lipid-lowering treatments in current use, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe. Using univariable and multivariable Mendelian randomization (MR) we found genetically mimicked effects of statins increased BMI (0.33, 95% confidence interval (CI) 0.28 to 0.38), but genetically mimicked PCSK9 inhibitors and ezetimibe did not. Genetically mimicked effects of statins on IHD reduction in both sexes (odds ratio (OR) 0.55 per unit decrease in effect size of low-density lipoprotein cholesterol (LDL-c), 95% confidence interval (CI) 0.40 to 0.76), was largely similar after adjusting for BMI, in both men (OR 0.48, 95% CI 0.38 to 0.61) and women (OR 0.66, 95% CI 0.53 to 0.82). Compared with variations in PCSK9 and NPC1L1, only variation in HMGCR was associated with higher BMI. The effects on IHD of mimicking statins were similar after adjusting for BMI in both men and women. The BMI increase due to statins does not seem to be a concern as regards the protective effects of statins on IHD, however other factors driving BMI and the protective effects of statins could be.

Genetic validation of neurokinin 3 receptor antagonists for ischemic heart disease prevention in men - A one-sample Mendelian randomization study.

BACKGROUND: Ischemic heart disease (IHD) is a leading cause of mortality, particularly for men. Few interventions have focused on protecting specifically men. Emerging evidence may implicate testosterone. Neurokinin 3 receptor (NK3R) antagonists, an existing class of drugs being considered as treatments for reproductive conditions in women, affect testosterone; this study addresses genetic validation of their use to prevent IHD in men. METHODS: A one-sample Mendelian randomization (MR) study using the UK Biobank cohort study, based on independent (r2 < 0.005) genetic variants predicting testosterone in men (n = 157738) at genome wide significance in the target gene for NK3R antagonists (TACR3), was used to assess associations with IHD (cases=15056, non-cases=151964) and positive control outcomes (relative age voice broke, children fathered, hypertension) in men and a negative control outcome (IHD) in women using summary statistics. A two-sample MR study using the PRACTICAL consortium was used for the positive control outcome of prostate cancer. FINDINGS: Two relevant TACR3 genetic variants (rs116646027 and rs1351623) were identified in men. Genetically mimicked NK3R antagonists were inversely associated with IHD (odds ratio 0.54 per standard deviation lower testosterone, 95% confidence interval 0.31, 0.94) and with control outcomes (older relative age voice broke, fewer children and lower risk of hypertension and prostate cancer) as expected in men and in women (unrelated to IHD). INTERPRETATION: Genetic validation of a role of NK3R antagonists in IHD suggests their consideration as a new means of preventing IHD in men. Whether they protect against prostate cancer might bear further consideration. FUNDING: This study had no funding.

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.

Impact of Liability to Periodontitis on Glycemic Control and Type II Diabetes Risk: A Mendelian Randomization Study.

While the association of periodontitis with Type II diabetes (T2DM) is well-established, the causal relationship remains uncertain. We examined the causal association of periodontitis with glycemic traits (HbA1c, fasting glucose, and fasting insulin) and T2DM using Mendelian randomization (MR) taking advantage of large genome-wide association studies of European and East Asian adults, i.e., the UK Biobank (n ≈ 350,000) (HbA1c), trans-ancestral MAGIC (HbA1c, fasting glucose, and insulin), and DIAMANTE (74,124 cases/824,006 controls), and AGEN for T2DM in Europeans and East Asians, respectively. Periodontitis was instrumented using single-nucleotide polymorphisms (SNPs), strongly and independently predicting liability to periodontitis in each ancestry group. SNP-specific Wald estimates were combined using inverse variance weighting. Sensitivity analyses were performed using the weighted median and MR-Egger with meta-analysis of MR estimates for Europeans and East Asians. Genetically instrumented liability to periodontitis was not associated with glycemic traits or T2DM in either ancestry or when ancestry specific estimates were meta-analyzed. Our findings do not support a causal association of liability to periodontitis with glycemic traits or T2DM. However, further research is required confirming these findings among other racial/ethnic groups, especially groups who carry a heavy burden of both periodontitis and T2DM.

Investigating the association of testosterone with survival in men and women using a Mendelian randomization study in the UK Biobank.

Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. Testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI - 0.09 to 0.11). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

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.

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.

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation.

We examined whether specifically statins, of the major lipid modifiers (statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) have pleiotropic effects on ischemic heart disease (IHD) via testosterone in men or women. As a validation, we similarly assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. Using previously published genetic instruments we conducted a sex-specific univariable and multivariable Mendelian randomization study in the UK Biobank, including 179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases. Of these three lipid modifiers, only genetically mimicking the effects of statins in men affected testosterone, which partly mediated effects on IHD. Correspondingly, genetically mimicking effects of anakinra on testosterone and IHD presented a reverse pattern to that for statins. These insights may facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific explanations, investigations, prevention and treatment.

Use of Multivariable Mendelian Randomization to Address Biases Due to Competing Risk Before Recruitment.

Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist. Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk. Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80-2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68-0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy. Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.

Reproduction and longevity: A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease.

BACKGROUND: According to well-established evolutionary biology theory there is a trade-off between reproduction and longevity, implying that upregulating the reproductive axis might drive major diseases. We assessed whether the central driver of reproduction gonadotropin-releasing hormone 1 (GnRH1) had a causal effect on the leading cause of global morbidity and mortality, i.e. ischemic heart disease (IHD). As a contrast we similarly examined the role of GnRH2 because it is more a driver of female sexual behavior. METHODS: We applied strong (p-value <5 × 10-6) and independent genetic predictors of GnRH1 and GnRH2 to an extensively genotyped IHD case (n = 76,014) - control (n = 264,785) study and combined the genetic variant specific Wald estimates using inverse variance weighting (IVW) with multiplicative random effects, and as a sensitivity analysis used weighted median, MR-Egger and MR-PRESSO estimates, and repeated the analysis only using genome wide significant genetic predictors. FINDINGS: GnRH1, predicted by 11 genetic variants, was positively associated with IHD (IVW odds ratio (OR) 1.04 per effect size, 95% confidence interval (CI) 1.01 to 1.08), but GnRH2, predicted by 15 genetic variants, was not (IVW OR 0.98, 95% CI 0.95 to 1.02). Estimates from sensitivity analysis were similar. INTERPRETATION: GnRH1 is a potential IHD genetic target. Apart from demonstrating a central tenet of evolutionary biology in humans, our study suggests that existing treatments and environmental factors targeting GnRH1, its drivers or consequences could be re-purposed to prevent and treat IHD. Given, the importance of reproduction to the human species, many such exposures likely exist.

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.