Risk factors for critical COVID-19 illness during Delta- and Omicron-predominant period in Korea; using K-COV-N cohort in the National health insurance service.

BACKGROUND: This study evaluated the clinical characteristics of patients with COVID-19 in Korea, and examined the relationship between severe COVID-19 cases and underlying health conditions during the Delta (September 20, 2021 to December 4, 2021) and the Omicron (February 20, 2022 to March 31, 2022) predominant period. METHODS: This study assessed the association between critical COVID-19 illness and various risk factors, including a variety of underlying health conditions, using multiple logistic regression models based on the K-COV-N cohort, a nationwide data of confirmed COVID-19 cases linked with COVID-19 vaccination status and the National Health Insurance claim information. RESULTS: We analyzed 137,532 and 8,294,249 cases of COVID-19 infection during the Delta and the Omicron variant dominant periods, respectively. During the Delta as well as the Omicron period, old age (≥80 years) showed the largest effect size among risk factors for critical COVID-19 illness (aOR = 18.08; 95% confidence interval [CI] = 14.71-22.23 for the Delta; aOR = 24.07; 95% CI = 19.03-30.44 for the Omicron period). We found that patients with solid organ transplant (SOT) recipients, unvaccinated, and interstitial lung disease had more than a two-fold increased risk of critical COVID-19 outcomes between the Delta and Omicron periods. However, risk factors such as urban residence, underweight, and underlying medical conditions, including chronic cardiac diseases, immunodeficiency, and mental disorders, had different effects on the development of critical COVID-19 illness between the Delta and Omicron periods. CONCLUSION: We found that the severity of COVID-19 infection was much higher for the Delta variant than for the Omicron. Although the Delta and the Omicron variant shared many risk factors for critical illness, several risk factors were found to have different effects on the development of critical COVID-19 illness between those two variants. Close monitoring of a wide range of risk factors for critical illness is warranted as new variants continue to emerge during the pandemic.

Risk of Severe COVID-19 and Protective Effectiveness of Vaccination Among Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at higher risk for severe infection. However, the risk for severe COVID-19 and vaccine effectiveness among SOTRs remain unclear. METHODS: This retrospective study used a nationwide health care claims database and COVID-19 registry from the Republic of Korea (2020 to 2022). Adult SOTRs diagnosed with COVID-19 were matched with up to 4 non-SOTR COVID-19 patients by propensity score. Severe COVID-19 was defined as treatment with high-flow nasal cannulae, mechanical ventilation, or extracorporeal membrane oxygenation. RESULTS: Among 6783 SOTRs with COVID-19, severe COVID-19 was reported with the highest rate in lung transplant recipients (13.16%), followed by the heart (6.30%), kidney (3.90%), and liver (2.40%). SOTRs had a higher risk of severe COVID-19 compared to non-SOTRs, and lung transplant recipients showed the highest risk (adjusted odds ratio, 18.14; 95% confidence interval [CI], 8.53-38.58). Vaccine effectiveness against severe disease among SOTRs was 47% (95% CI, 18%-65%), 64% (95% CI, 49%-75%), and 64% (95% CI, 29%-81%) for 2, 3, and 4 doses, respectively. CONCLUSIONS: SOTRs are at significantly higher risk for severe COVID-19 compared to non-SOTRs. Vaccination is effective in preventing the progression to severe COVID-19. Efforts should be made to improve vaccine uptake among SOTRs, while additional protective measures should be developed.

Severe coronavirus disease 2019 in pediatric solid organ transplant recipients: Big data convergence study in Korea (K-COV-N cohort).

OBJECTIVES: The risk of severe COVID-19 in children with a solid organ transplant (SOT) is not well established. We compare the relative risk of severe COVID-19 infection between pediatric SOT and non-SOT children. METHODS: The newly constructed K-COV-N cohort (Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service) was used. Children with COVID-19 (<18 years old) who underwent SOT between January 2008 to January 2022 were included. Non-SOT children with COVID-19 were selected in a ratio of 1:4 using propensity score matching. Three definitions of severe COVID-19 were established based on their requirement for respiratory support: severe I (requiring respiratory support above a high-flow nasal cannula or prolonged hospitalization ≥6 days), severe II (requiring any oxygen supplement), and severe III (requiring any oxygen supplement or prolonged hospitalization ≥6 days). RESULTS: Among 2,957,323 children with COVID-19, 206 pediatric SOT recipients (SOTRs) were identified and included in the analysis along with 803 matched non-SOT children. Most infections (96.6%) occurred during the Omicron period; no cases of mortality were reported. Pediatric SOTR had a 3.6-fold (95% confidence interval = 1.1-11.7, P = 0.03) higher risk of severe I, and a 4.9-fold (95% confidence interval = 1.6-15.0, P = 0.006) higher risk of severe III than non-SOT children. No cases of severe II occurred in the non-SOT children. Although not statistically significant, no severe COVID-19 cases were reported in the vaccinated SOT group (0.0% vs 5.7%, P = 0.09 in severe III). CONCLUSION: Pediatric SOTRs have a significantly higher risk of severe COVID-19 than non-SOT children. Our findings support the need for tailored strategies for these high-risk children.

Chronic heavy alcohol consumption influences the association between genetic variants of GCK or INSR and the development of diabetes in men: A 12-year follow-up study.

Chronic heavy alcohol consumption is a risk factor for diabetes, which is characterized by impaired ß-cell function and insulin resistance. We aimed to determine whether the longitudinal associations between genetic variants of glucokinase (GCK) and insulin receptor (INSR) and the risk of developing diabetes were influenced by chronic heavy alcohol consumption. Data were obtained from the Korean Genome and Epidemiology Study. To identify candidate variants, 1,520 subjects (726 non-drinkers and 794 heavy drinkers) were included in the baseline cross-sectional study. After excluding patients with diabetes at baseline and those with insufficient data on diabetes incidence, prospective analyses were conducted in 773 subjects (353 non-drinkers and 420 heavy drinkers). In the baseline cross-sectional study, one SNP (rs758989) in GCK and four SNPs (rs7245757, rs1035942, rs1035940, and rs2042901) in INSR were selected as candidate SNPs that interact with alcohol to affect prediabetes and diabetes. We identified that these GCK and INSR polymorphisms are affected by chronic heavy alcohol consumption and have an effect on the incidence of diabetes. The incidence of diabetes was increased in chronic heavy alcohol drinkers carrying the C allele of GCK compared with never-drinkers with the C allele (HR, 2.15; 95% CI 1.30-3.57), and was increased in chronic heavy alcohol drinkers who were not carrying the INSR haplotype (-/-) compared with never-drinkers carrying the AACT haplotype (HR, 1.98; 95% CI 1.24-3.18). Moreover, we observed that the aggravating effects on the late insulin secretion (I/G120 and I/G AUC 60-120) in individuals who were chronic heavy drinkers with C allele of GCK. In the INSR haplotype, chronic heavy drinkers not carrying AACT were associated with lower disposition index. These results potentially suggest that chronic heavy alcohol consumption induce ß-cell dysfunction partially mediated by decreased GCK expression or decline of insulin sensitivity via inhibition of INSR, thereby contributing to the development of diabetes.

Genome-wide methylation analysis identifies ELOVL5 as an epigenetic biomarker for the risk of type 2 diabetes mellitus.

Genome-wide DNA methylation has been implicated in complex human diseases. Here, we identified epigenetic biomarkers for type 2 diabetes (T2D) underlying obesogenic environments. In a blood-based DNA methylation analysis of 11 monozygotic twins (MZTW) discordant for T2D, we discovered genetically independent candidate methylation sites. In a follow-up replication study (17 MZTW pairs) for external validation, we replicated the T2D-association at a novel CpG signal in the ELOVL fatty acid elongase 5 (ELOVL5) gene specific to T2D-discordant MZTW. For concordant DNA methylation signatures in tissues, we further confirmed that a CpG site (cg18681426) was associated with adipogenic differentiation between human preadipocytes and adipocytes isolated from the same biopsy sample. In addition, the ELOVL5 gene was significantly differentially expressed in adipose tissues from unrelated T2D patients and in human pancreatic islets. Our results demonstrate that blood-derived DNA methylation is associated with T2D risk as a proxy for cumulative epigenetic status in human adipose and pancreatic tissues. Moreover, ELOVL5 expression was increased in cellular and mouse models of induced obesity-related diabetes. These findings may provide new insights into epigenetic architecture by uncovering methylation-based biomarkers.

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Risk prediction of pulmonary tuberculosis using genetic and conventional risk factors in adult Korean population.

A complex interplay among host, pathogen, and environmental factors is believed to contribute to the risk of developing pulmonary tuberculosis (PTB). The lack of replication of published genome-wide association study (GWAS) findings limits the clinical utility of reported single nucleotide polymorphisms (SNPs). We conducted a GWAS using 467 PTB cases and 1,313 healthy controls obtained from two community-based cohorts in Korea. We evaluated the performance of PTB risk models based on different combinations of genetic and nongenetic factors and validated the results in an independent Korean population comprised of 179 PTB cases and 500 healthy controls. We demonstrated the polygenic nature of PTB and nongenetic factors such as age, sex, and body mass index (BMI) were strongly associated with PTB risk. None of the SNPs achieved genome-wide significance; instead, we were able to replicate the associations between PTB and ten SNPs near or in the genes, CDCA7, GBE1, GADL1, SPATA16, C6orf118, KIAA1432, DMRT2, CTR9, CCDC67, and CDH13, which may play roles in the immune and inflammatory pathways. Among the replicated SNPs, an intergenic SNP, rs9365798, located downstream of the C6orf118 gene showed the most significant association under the dominant model (OR = 1.59, 95% CI 1.32-1.92, P = 2.1×10-6). The performance of a risk model combining the effects of ten replicated SNPs and six nongenetic factors (i.e., age, sex, BMI, cigarette smoking, systolic blood pressure, and hemoglobin) were validated in the replication set (AUC = 0.80, 95% CI 0.76-0.84). The strategy of combining genetic and nongenetic risk factors ultimately resulted in better risk prediction for PTB in the adult Korean population.

An integrative study identifies KCNC2 as a novel predisposing factor for childhood obesity and the risk of diabetes in the Korean population.

Obesity is a major risk factor for type 2 diabetes. To unravel the genetic determinants of obesity-associated diabetes, we performed a genome-wide study using the 1,000 Genomes-based imputation in a Korean childhood cohort (KoCAS-1, n = 484) and carried out de novo replication in an independent population (KoCAS-2, n = 1,548). A novel variant (rs10879834) with multiple diverse associations for obesity-related traits was also found to be replicated in an adult cohort (KARE, n = 8,842). Functional annotations using integrative epigenetic analyses identified biological significance and regulatory effects with an inverse methylation-expression correlation (cg27154343 in the 5'-UTR of the KCNC2 gene), tissue-specific enhancer mark (H3K4me1), and pathway enrichment (insulin signaling). Further functional studies in cellular and mouse models demonstrated that KCNC2 is associated with anti-obesogenic effects in the regulation of obesity-induced insulin resistance. KCNC2 shRNA transfection induced endoplasmic reticulum (ER) stress and hepatic gluconeogenesis. Overproduction of KCNC2 decreased ER stress, and treatment with metformin enhanced KCNC2 expression. Taken together, these data suggest that reduction of KCNC2 is associated with modified hepatic gluconeogenesis and increased ER stress on obesity-mediated diabetic risk. An integrative multi-omics analysis might reveal new functional and clinical implications related to the control of energy and metabolic homeostasis in humans.

Genetic-risk assessment of GWAS-derived susceptibility loci for type 2 diabetes in a 10 year follow-up of a population-based cohort study.

To date, genome-wide meta-analyses have identified genetic susceptibility to type 2 diabetes mellitus (T2D) predominantly in populations of European ancestry. However, comprehensive genetic-risk assessment based on previous GWAS loci has not been fully tested in non-European populations. To evaluate whether a genetic-risk score (GRS) could improve T2D-risk prediction in the Korean population, a GRS (GRS-55) was constructed by summing 55 risk alleles based on the 1000 Genomes imputation in the Korean Association Resource study (T2D cases=1042 and controls=2943 at baseline). We also constructed another GRS (GRS-19) based on nominal significance and consistent direction of effect. In mean difference tests, the mean value of the GRS-19 was significantly higher in T2D cases than in controls at baseline examination. In a model adjusted for area, age, sex and body mass index, weighted GRS-19 was found to be associated with enhanced effect sizes of T2D risk under consistent C-statistics. In addition, we confirmed cumulative risk effects on incidence rates of T2D, fasting plasma glucose and glycated hemoglobin (HbA1c) levels in a longitudinal 10 year of follow-up study. These findings highlight that a genotype score comprised of 19 common variants contributed to T2D-risk prediction in the Korean population. Further multi-locus epistatic interactions may provide the possibility to improve risk prediction in C-statistics for discrimination or reclassification.

The genetic architecture of type 2 diabetes.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference.

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Identification of a Copy Number Variation on Chromosome 20q13.12 Associated with Osteoporotic Fractures in the Korean Population.

Osteoporotic fractures (OFs) are critical hard outcomes of osteoporosis and are characterized by decreased bone strength induced by low bone density and microarchitectural deterioration in bone tissue. Most OFs cause acute pain, hospitalization, immobilization, and slow recovery in patients and are associated with increased mortality. A variety of genetic studies have suggested associations of genetic variants with the risk of OF. Genome-wide association studies have reported various single-nucleotide polymorphisms and copy number variations (CNVs) in European and Asian populations. To identify CNV regions associated with OF risk, we conducted a genome-wide CNV study in a Korean population. We performed logistic regression analyses in 1,537 Korean subjects (299 OF cases and 1,238 healthy controls) and identified a total of 8 CNV regions significantly associated with OF (p < 0.05). Then, one CNV region located on chromosome 20q13.12 was selected for experimental validation. The selected CNV region was experimentally validated by quantitative polymerase chain reaction. The CNV region of chromosome 20q13.12 is positioned upstream of a family of long non-coding RNAs, LINC01260. Our findings could provide new information on the genetic factors associated with the risk of OF.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.

Genome-wide association study identifies two novel Loci with sex-specific effects for type 2 diabetes mellitus and glycemic traits in a korean population.

BACKGROUND: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. METHODS: We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. RESULTS: A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of ß-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. CONCLUSION: Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.