Precision Medicine and Cardiovascular Health: Insights from Mendelian Randomization Analyses

Cardiovascular disease (CVD) is considered a primary driver of global mortality and is estimated to be responsible for approximately 17.9 million deaths annually. Consequently, a substantial body of research related to CVD has developed, with an emphasis on identifying strategies for the prevention and effective treatment of CVD. In this review, we critically examine the existing CVD literature, and specifically highlight the contribution of Mendelian randomization analyses in CVD research. Throughout this review, we assess the extent to which research findings agree across a range of studies of differing design within a triangulation framework. If differing study designs are subject to non-overlapping sources of bias, consistent findings limit the extent to which results are merely an artefact of study design. Consequently, broad agreement across differing studies can be viewed as providing more robust causal evidence in contrast to limiting the scope of the review to a single specific study design. Utilising the triangulation approach, we highlight emerging patterns in research findings, and explore the potential of identified risk factors as targets for precision medicine and novel interventions.ope

Changes in secondhand smoke exposure levels and risk of type 2 diabetes in middle age: the Korean Genome and Epidemiology Study (KoGES)

Objectives: Secondhand smoke (SHS) was known as one of the risk factors for type 2 diabetes. So far, some studies revealed the association of SHS exposure and type 2 diabetes, however, no studies to show the relationship of cumulative SHS exposure with type 2 diabetes exist. Therefore, the objectives of this study were to identify subgroups of participants who share similar trajectories in SHS exposure levels in middle age by using latent class growth modeling, and determine the independent association of these SHS exposure level trajectories with risk of incident type 2 diabetes. Methods: In Korean Genome and Epidemiology Study (2001-2014), 2079 participants aged 40 years and above who received biennially health check-up to follow-up and with available information of SHS exposure were selected. Four distinct trajectory groups (low-stable, moderate to low, moderate, and high to low) were identified for SHS exposure levels using trajectory modeling methods. Multivariable Cox proportional hazards model was used to examine the association of trajectories with risk of type 2 diabetes. Results: During 24 083.3 person-years of follow-up (mean follow-up duration, 11.6 years), 200 incident cases of type 2 diabetes and 640 incident cases of impaired fasting glucose (IFG) were identified. In multivariable Cox model, 'High to low' trajectory was significantly associated with risk of type 2 diabetes (OR 1.9; 95% CI 1.3 to 2.8) compared with 'Low-stable'. For IFG, all trajectories had significantly 30%-30% higher risk of type 2 diabetes compared with the 'Low-stable' trajectory. Conclusions: Changes in SHS exposure levels have been shown to associate with subsequent type 2 diabetes risk. Reversing high exposure level of SHS in middle-aged adulthood may still lead to worse progressions of type 2 diabetes than remaining stable exposure level.ope

Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study

OBJECTIVE: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.ope

The Influence on Cardiovascular Mortality of the Metabolic Syndrome in Korean Postmenopausal Women

Objectives: Metabolic syndrome components, insulin resistance and central obesity cause type 2 diabetes and hypertension. This will increase the risk of cardiovascular disease. Women after menopause are at increased risk of metabolic syndrome. Several researchers studied that in menopause, metabolic syndrome increased cardiovascular mortality. We studied the impact on cardiovascular mortality of postmenopausal women with metabolic syndrome in the Republic of Korea. Methods: Twenty four thousand nine hundred forty nine postmenopausal women aged 40 years or older were enrolled at health promotion centers of national university hospital located in 18 regions during 1994-2004. Age, weights, height, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), cholesterol, triglyceride (TG), high-density lipoprotein were evaluated and history taking about alcohol consumption, smoking, and exercise was performed. In addition, subjects who died of cardiac disease were analyzed from January 1995 to December 2009. Results: Metabolic syndrome was higher in postmenopausal women with increased in age, BMI, blood pressure (BP), FBG, cholesterol, TG. Thirty cardiac deaths occurred during the observation period. Factors affecting cardiac death were age, smoking, FBG and when age and smoking were controlled. FBG was an important factor affecting cardiovascular mortality in our study. When controlling age, smoking, and alcohol consumption, metabolic syndrome caused an increased relative risk of cardiovascular mortality. Survival rate was much lower in postmenopausal women with metabolic syndrome than those without metabolic syndrome. Conclusion: Metabolic syndrome in Korean postmenopausal women increased cardiovascular mortality.ope

혈청지질 농도와 우울증과의 관련성 연구

Objective : Low cholesterol is associated with depression among western countries. The objective of this study was to examine the relationship between cholesterol and depression in Korean population with low levels of serum cholesterol. Methods : The data of about 740,000 individuals, aged 30-64 years at entry in the Korean Cancer Prevention Study, were used. Total cholesterol levels were measured in 1992. Depression was measured using the modified DSM-IV (Diagnostic Criteria of Major Depressive Episode in Diagnostic and Statistical Manual of Mental Disorders-IV) scale. Total cholesterol was classified into four groups (quartile). Odds Ratios of low level of cholesterol were evaluated using multi-variable logistic models. Results : The prevalence of major depression was 7.7% in men and 10.4% in women. After adjustment for various confounding variables, an inverse association was detected between cholesterol levels and depression intensity among men and women. The odds ratio (95% confidence interval) of the lowest quartile of cholesterol was 1.16 (1.13-1.20) on major depression compared with the highest quartile of cholesterol in men. The corresponding odds ratio among women was 1.09 (1.04-1.15). The strongest association among 9 items of depression was found at "decreased appetite and lost weight" in both men (OR=1.68) and women (OR=1.43). Conclusions : Low cholesterol is associated with major depression in men and women. Further studies are necessary to evaluate the cross-validation, to explore the biological mechanism, and to identify the clinical implication.ope

Bilirubin and risk of ischemic heart disease in Korea: a two-sample Mendelian randomization study

OBJECTIVES: Bilirubin is an endogenous antioxidant that protects cells against oxidative stress. Increased plasma levels of bilirubin have been associated with a reduced risk of ischemic heart disease (IHD) in previous studies. Nonetheless, whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown. Therefore, we applied two-sample Mendelian randomization to evaluate the causal association between bilirubin levels and IHD risk in a Korean population. METHODS: A total of 5 genetic variants-TRPM8 (rs10490012), USP40 (rs12993249), ATG16L1 (rs2119503), SLCO1B1 (rs4149014), and SLCO1B3 (rs73233620)-were selected as genetic instruments for serum bilirubin levels using a communitybased cohort, the Korean Genome and Epidemiology Study, comprising 33,598 subjects. We then evaluated their impact on IHD using the Korean Cancer Prevention Study-II cohort. RESULTS: Among the 5 instrumental variables that showed significant associations with serum bilirubin levels, rs12993249 (USP40) showed the most significant association (p<2.36×10-105). However, we found no significant association between serum bilirubin levels and IHD. Sensitivity analyses demonstrated a consistent association, suggesting that our observations were robust. CONCLUSIONS: Using two-sample Mendelian randomization, we found no association between serum bilirubin levels and IHD. Further studies that confirm the observed interactions among other ethnicities are warranted.ope

The FGF and FGFR gene family and risk of cleft lip with or without cleft palate

Background : Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods : We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results : Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion : Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.ope

Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate

CONTEXT: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking. OBJECTIVE: To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics. DESIGN, SETTING, AND PARTICIPANTS: A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012. MAIN OUTCOME MEASURES: All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years). RESULTS: Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts. CONCLUSION: The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.ope

Effects of Obesity and Family History of Diabetes on the Association of CETP rs6499861 with HDL-C Level in Korean Populations

Objectives: The aim of this study was to examine the associations of cholesterol ester transfer protein (CETP) rs6499861 and rs12708980 with high-density lipoprotein cholesterol (HDL-C) considering obesity and family history of diabetes (FHD) in Korean men and women. Methods: We analyzed the association of CETP single nucleotide polymorphisms (SNPs) with HDL-C among individuals selected from a hospital (n=4 294) and the Bundang-gu area in Korea (n=2 304). Results: We found that the CETP SNP rs6499861 was associated with a lower HDL-C level (effect per allele: -2.044 mg/dL, p<0.0001). Individuals with a rs6499861 CG/GG genotype had a 1.45-fold higher risk of an abnormal level of HDL-C (<40 mg/dL) than those with a CC genotype. This genotype-HDL-C association was stronger in women (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.39-2.85) compared with men (OR, 1.33; 95% CI, 1.10-1.61) and in women with a FHD (OR, 4.82; 95% CI, 1.86-12.5; p=0.0012) compared with women without a family history. Relative to individuals with a CC genotype and body mass index (BMI) <25.69 kg/m2, individuals with a CG/GG genotype and BMI ≥25.69 kg/m2 had an OR (95% CI) of 2.61 (1.97-3.47). Conclusions: These findings indicate that CETP variants are linked to HDL-C level in Koreans and that this link is stronger in obese men and in women who have a FHD.ope

Projected mortality from lung cancer in South Korea, 1980-2004

BACKGROUND: In recent years, mortality from lung cancer has increased rapidly in Korea, a South East Asian country with a high prevalence of smoking. The objectives of this study are to examine how age, period, and birth cohort effects contributed to trends in lung cancer mortality in Korea 1980-1994, and to predict lung cancer mortality rates for 1995-2004. METHODS: Age- and sex-specific lung cancer mortality rates were obtained from annual reports of the National Office of Statistics in Korea. Poisson regression models were used to estimate age, period and cohort effects. RESULTS: Among men, age-adjusted annual mortality rates from lung cancer (per 100000) increased from 3.7 in 1980 to 17.8 in 1994; corresponding rates for women were 1.4 and 7.0. As age increased, mortality rates from lung cancer increased more rapidly in men than in women. Within the same age group, the mortality of younger cohorts was higher than older cohorts. The average annual number of lung cancer deaths projected for the years 2000-2004 among men and women will be 15441 and 3572 respectively, while the average annual age-adjusted mortality rates from lung cancer (per 100000) will be 65.4 for men and 15.1 for women. These rates correspond to 17.7- and 10.7-fold increases over the 1980 mortality rates in men and women, respectively. CONCLUSION: These results, in conjunction with trends in tobacco consumption, indicate that mortality from lung cancer in both men and women will increase substantially through the early part of the 21st century in Korea.ope