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

Recapitulation of previously reported associations for type 2 diabetes and metabolic traits in the 126K East Asians

Over the last decade, genome-wide association studies (GWASs) have provided an unprecedented amount of genetic variations that are associated with various phenotypes. However, previous GWAS were mostly conducted in European populations, and these biased results for non-Europeans may result in a significant reduction in risk prediction for non-Europeans. An issue with the early GWAS was the winner’s curse problem, which led to misleading results when constructing the polygenic risk scores (PRS). Therefore, more non-European population-based studies are needed to validate reported variants and improve genetic risk assessment across diverse populations. In this study, we validated 422 variants independently associated with glycemic indexes, liver enzymes, and type 2 diabetes in 125,872 samples from a Korean population, and further validated the results by assessing publicly available summary statistics from European GWAS (n = 898,130). Among the 422 independently associated variants, 284, 320, and 361 variants were replicated in Koreans, Europeans, and either one of the two populations. In addition, the effect sizes for Koreans and Europeans were moderately correlated (r = 0.33–0.68). However, 61 variants were not replicated in both Koreans and Europeans. Our findings provide valuable information on effect sizes and statistical significance, which is essential to improve the assessment of disease risk using PRS analysis

Evaluation of pleiotropic effects among common genetic loci identified for cardio-metabolic traits in a Korean population

BACKGROUND: The genetic contribution to complex diseases or traits, including cardio-metabolic traits, has been elucidated recently by large-scale genome-wide association studies. These genome-wide association studies have indicated that most pleiotropic loci contain genes associated with lipids. Clinically, lipid related abnormalities are strongly associated with other diseases such as type 2 diabetes, coronary artery disease and hypertension. The aim of this study was to evaluate the shared genetic background of lipids and other cardio-metabolic traits. METHODS: We conducted meta-analyses of the association between 157 published lipid-associated loci and 10 cardio-metabolic traits in 14,028 Korean individuals genotyped using the Exome chip (Illumina HumanExome BeadChip). We also examined whether the pleiotropic effects of such loci constituted independent (i.e., biological) pleiotropy or mediated pleiotropy in these metabolic pathways. RESULTS: Eighteen lipid-associated loci were significantly associated with one of six cardio-metabolic traits after correction for multiple testing (P < 3.70 × 10(−4)). Region 12q24.12 had pleiotropic effects on fasting plasma glucose, blood pressure and obesity-related traits (body mass index and waist-hip ratio) independent of its effects on the lipid profile. Lipid risk scores, calculated according to whether or not subjects carried the risk allele for lipid traits, were significantly associated with fasting plasma glucose, blood pressure and obesity-related traits. CONCLUSIONS: The 12q24.12 region showed ethnic-specific genetic pleiotropy among cardio-metabolic traits in this study. Our findings may help to account for molecular mechanisms based on shared genetic background underlying not only dyslipidemia, but also cardiovascular disease and type 2 diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12933-016-0337-1) contains supplementary material, which is available to authorized users

Influence of the timing of administration of crystalloid on maternal hypotension during spinal anesthesia for cesarean delivery: preload versus coload

BACKGROUND: Prophylactic fluid preloading before spinal anesthesia has been a routine procedure to prevent maternal hypotension during cesarean delivery. Unlike colloid, timing of infusion of crystalloid may be important because of its short stay in intravascular space. We hypothesized that crystalloid loading just after intrathecal injection compared to preload would be more effective in preventing maternal hypotension. METHODS: In this prospective controlled study, sixty parturients were randomized to receive 15 ml/kg of crystalloid before (preload group) or after (coload group) intrathecal drug injection for spinal anesthesia. Hypotension was defined if systolic arterial pressure decreased below 80% of baseline and ephedrine was administered to treat hypotension. The incidence of hypotension and the total dose of ephedrine were checked. Blood pressure, heart rate and nausea before childbirth were assessed. Neonatal outcomes were evaluated with Apgar scores and umbilical blood gas analysis. RESULTS: The incidence of hypotension was lower in the coload group compared to the preload group (53% vs. 83%, P = 0.026). The blood pressure showed the bigger drop during spinal anesthesia in the preload group (34 ± 13 vs. 25 ± 10 mmHg, P = 0.002) and smaller dose of ephedrine was required in the coload group (7.5 [0–30] vs. 15 [0–40] mg, P = 0.015). The incidence of nausea was also lower in the coload group (27% vs. 60%, P = 0.019). Neonatal outcome measures were comparable between two groups. CONCLUSIONS: In case of using crystalloids for cesarean delivery, coload is more effective than preload for the prevention of maternal hypotension after spinal anesthesia. TRIAL REGISTRATION: Clinical Research Information Service KCT0000324 (Jan 12(th), 2012

HIGH CROSSOVER RATE1 encodes PROTEIN PHOSPHATASE X1 and restricts meiotic crossovers in Arabidopsis.

Meiotic crossovers are tightly restricted in most eukaryotes, despite an excess of initiating DNA double-strand breaks. The majority of plant crossovers are dependent on class I interfering repair, with a minority formed via the class II pathway. Class II repair is limited by anti-recombination pathways; however, similar pathways repressing class I crossovers have not been identified. Here, we performed a forward genetic screen in Arabidopsis using fluorescent crossover reporters to identify mutants with increased or decreased recombination frequency. We identified HIGH CROSSOVER RATE1 (HCR1) as repressing crossovers and encoding PROTEIN PHOSPHATASE X1. Genome-wide analysis showed that hcr1 crossovers are increased in the distal chromosome arms. MLH1 foci significantly increase in hcr1 and crossover interference decreases, demonstrating an effect on class I repair. Consistently, yeast two-hybrid and in planta assays show interaction between HCR1 and class I proteins, including HEI10, PTD, MSH5 and MLH1. We propose that HCR1 plays a major role in opposition to pro-recombination kinases to restrict crossovers in Arabidopsis.Marie Curie International Training Network COMREC European Research Council (ERC) National Research Foundation of Korea Suh Kyungbae Foundatio

Identification of a genetic variant at 2q12.1 associated with blood pressure in East-Asians by genome-wide scan including gene-environment interactions

BACKGROUND: Genome-wide association studies have identified many genetic loci associated with blood pressure (BP). Genetic effects on BP can be altered by environmental exposures via multiple biological pathways. Especially, obesity is one of important environmental risk factors that can have considerable effect on BP and it may interact with genetic factors. Given that, we aimed to test whether genetic factors and obesity may jointly influence BP. METHODS: We performed meta-analyses of genome-wide association data for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that included analyses of interaction between single nucleotide polymorphisms (SNPs) and the obesity-related anthropometric measures, body mass index (BMI), height, weight, and waist/hip ratio (WHR) in East-Asians (n = 12,030). RESULTS: We identified that rs13390641 on 2q12.1 demonstrated significant association with SBP when the interaction between SNPs and BMI was considered (P < 5 × 10 (-8)). The gene located nearest to rs13390641, TMEM182, encodes transmembrane protein 182. In stratified analyses, the effect of rs13390641 on BP was much stronger in obese individuals (BMI ≥ 30) than non-obese individuals and the effect of BMI on BP was strongest in individuals with the homozygous A allele of rs13390641. CONCLUSIONS: Our analyses that included interactions between SNPs and environmental factors identified a genetic variant associated with BP that was overlooked in standard analyses in which only genetic factors were included. This result also revealed a potential mechanism that integrates genetic factors and obesity related traits in the development of high BP

Healthcare utilization, medical expenditure, and mortality in Korean patients with pulmonary hypertension

Background Limited data exists regarding healthcare utilization, medical expenses, and prognosis of pulmonary hypertension (PH) according to the World Health Organization (WHO) classification. We aimed to investigate mortality risk, healthcare utilization and medical expenditure in patients with PH across the five diagnostic subgroups. Methods We identified 2185 patients with PH, defined as peak tricuspid regurgitation velocity > 3.4 m/sec, among the consecutive patients referred for echocardiography between 2009 and 2015. Using diagnostic codes, medical records, and echocardiographic findings, the enrolled patients were classified according to the five subgroups by WHO classification. Healthcare utilization, costs, and all-cause mortality were assessed. Results Diagnostic subgroups of PH demonstrated significantly different clinical features. During a median of 32.4 months (interquartile range, 16.2–57.8), 749 patients (34.3%) died. Mortality risk was the lowest in group II (left heart disease) and highest in group III (chronic lung disease). The etiologies of pulmonary arterial hypertension (PAH) had significant influence on the mortality risk in group I, showing the worst prognosis in PAH associated with connective tissue disease. Medical expenditure and healthcare utilization were different between the PH subgroups: groups II and V had more hospitalizations and medical expenses than other groups. Regardless of PH subgroups, the severity of PH was associated with higher mortality risk, more healthcare utilization and medical expenditure. Conclusions Significant differences in clinical features and prognostic profiles between PH subgroups reflect the differences in pathophysiology and clinical consequences. Our findings highlight the importance of comprehensive understanding of PH according to the etiology and its severity.This study was supported by Seoul National University Bundang Hospital (13–2016-018).This study was supported by Seoul National University Bundang Hospital (13–2016-018)