Identification of shared genetic risks underlying metabolic syndrome and its related traits in the Korean population.

Introduction: Observational studies have demonstrated strong correlations between metabolic syndrome (MetS) and its related traits. To gain insight into the genetic architecture and molecular mechanism of MetS, we investigated the shared genetic basis of MetS and its related traits and further tested their causal relationships. Methods: Using summary statistics from genome-wide association analyses of about 72,000 subjects from the Korean Genome and Epidemiological Study (KoGES), we conducted genome-wide multi-trait analyses to quantify the overall genetic correlation and Mendelian randomization analyses to infer the causal relationships between traits of interest. Results: Genetic correlation analyses revealed a significant correlation of MetS with its related traits, such as obesity traits (body mass index and waist circumference), lipid traits (triglyceride and high-density lipoprotein cholesterol), glycemic traits (fasting plasma glucose and hemoglobin A1C), and blood pressure (systolic and diastolic). Mendelian randomization analyses further demonstrated that the MetS-related traits showing significant overall genetic correlation with MetS could be genetically determined risk factors for MetS. Discussion: Our study suggests a shared genetic basis of MetS and its related traits and provides novel insights into the biological mechanisms underlying these complex traits. Our findings further inform public health interventions by supporting the important role of the management of metabolic risk factors such as obesity, unhealthy lipid profiles, diabetes, and high blood pressure in the prevention of MetS.

Development of a Polygenic Risk Score for BMI to Assess the Genetic Susceptibility to Obesity and Related Diseases in the Korean Population.

Hundreds of genetic variants for body mass index (BMI) have been identified from numerous genome-wide association studies (GWAS) in different ethnicities. In this study, we aimed to develop a polygenic risk score (PRS) for BMI for predicting susceptibility to obesity and related traits in the Korean population. For this purpose, we obtained base data resulting from a GWAS on BMI using 57,110 HEXA study subjects from the Korean Genome and Epidemiology Study (KoGES). Subsequently, we calculated PRSs in 13,504 target subjects from the KARE and CAVAS studies of KoGES using the PRSice-2 software. The best-fit PRS for BMI (PRSBMI) comprising 53,341 SNPs was selected at a p-value threshold of 0.064, at which the model fit had the greatest R2 score. The PRSBMI was tested for its association with obesity-related quantitative traits and diseases in the target dataset. Linear regression analyses demonstrated significant associations of PRSBMI with BMI, blood pressure, and lipid traits. Logistic regression analyses revealed significant associations of PRSBMI with obesity, hypertension, and hypo-HDL cholesterolemia. We observed about 2-fold, 1.1-fold, and 1.2-fold risk for obesity, hypertension, and hypo-HDL cholesterolemia, respectively, in the highest-risk group in comparison to the lowest-risk group of PRSBMI in the test population. We further detected approximately 26.0%, 2.8%, and 3.9% differences in prevalence between the highest and lowest risk groups for obesity, hypertension, and hypo-HDL cholesterolemia, respectively. To predict the incidence of obesity and related diseases, we applied PRSBMI to the 16-year follow-up data of the KARE study. Kaplan-Meier survival analysis showed that the higher the PRSBMI, the higher the incidence of dyslipidemia and hypo-HDL cholesterolemia. Taken together, this study demonstrated that a PRS developed for BMI may be a valuable indicator to assess the risk of obesity and related diseases in the Korean population.

Genetic association study identifies genetic variants for non-alcoholic fatty liver without comorbidities in the Korean population.

BACKGROUND: Non-alcoholic fatty liver (NAFL) refers to a disease in which fat builds up in the liver, similar to what occurs for those who drink a lot of alcohol, even in cases of not drinking alcohol at all or only in a small amount. Along with non-alcoholic steatohepatitis (NASH), NAFL is a type of non-alcoholic fatty liver disease (NAFLD). Currently, the prevalence of NAFLD is increasing worldwide. A wide range of comorbidities that can increase the risk of NAFLD includes obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. OBJECTIVE: This study aimed to discover genetic variants for NAFL in the Korean population. METHODS: Differing from previous studies, we conducted a genome-wide association study for NAFL in the selected subjects without comorbidities to rule out bias due to the inclusion of confounding effects of comorbidities. We grouped 424 NAFL cases and 5,402 controls from the Korean Genome and Epidemiology Study (KoGES) subjects without comorbidities such as dyslipidemia, type 2 diabetes, and metabolic syndrome. All subjects including cases and controls did not consume alcohol at all, or consumed less than 20 g/day for men and less than 10 g/day for women. RESULTS: The logistic association analysis adjusting for sex, age, BMI, and waist circumference identified one novel genome-wide significant variant (rs7996045, P = 2.3 × 10-8) for NAFL. This variant was located in the intron of CLDN10 and was not detected using previous conventional approaches in which confounding effects resulting from comorbidities were not considered in the study design stage. In addition, we detected several genetic variants showing suggestive association for NAFL (P < 10-5). CONCLUSION: The unique strategy in our association analysis of excluding major confounding factors provides, for the first time, an insight into the genuine genetic basis influencing NAFL.

The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians.

Metabolic traits are heritable phenotypes widely-used in assessing the risk of various diseases. We conduct a genome-wide association analysis (GWAS) of nine metabolic traits (including glycemic, lipid, liver enzyme levels) in 125,872 Korean subjects genotyped with the Korea Biobank Array. Following meta-analysis with GWAS from Biobank Japan identify 144 novel signals (MAF ≥ 1%), of which 57.0% are replicated in UK Biobank. Additionally, we discover 66 rare (MAF < 1%) variants, 94.4% of them co-incident to common loci, adding to allelic series. Although rare variants have limited contribution to overall trait variance, these lead, in carriers, substantial loss of predictive accuracy from polygenic predictions of disease risk from common variant alone. We capture groups with up to 16-fold variation in type 2 diabetes (T2D) prevalence by integration of genetic risk scores of fasting plasma glucose and T2D and the I349F rare protective variant. This study highlights the need to consider the joint contribution of both common and rare variants on inherited risk of metabolic traits and related diseases.

Genetic association-based functional analysis detects HOGA1 as a potential gene involved in fat accumulation.

Although there are a number of discoveries from genome-wide association studies (GWAS) for obesity, it has not been successful in linking GWAS results to biology. We sought to discover causal genes for obesity by conducting functional studies on genes detected from genetic association analysis. Gene-based association analysis of 917 individual exome sequences showed that HOGA1 attains exome-wide significance (p-value < 2.7 × 10-6) for body mass index (BMI). The mRNA expression of HOGA1 is significantly increased in human adipose tissues from obese individuals in the Genotype-Tissue Expression (GTEx) dataset, which supports the genetic association of HOGA1 with BMI. Functional analyses employing cell- and animal model-based approaches were performed to gain insights into the functional relevance of Hoga1 in obesity. Adipogenesis was retarded when Hoga1 was knocked down by siRNA treatment in a mouse 3T3-L1 cell line and a similar inhibitory effect was confirmed in mice with down-regulated Hoga1. Hoga1 antisense oligonucleotide (ASO) treatment reduced body weight, blood lipid level, blood glucose, and adipocyte size in high-fat diet-induced mice. In addition, several lipogenic genes including Srebf1, Scd1, Lp1, and Acaca were down-regulated, while lipolytic genes Cpt1l, Ppara, and Ucp1 were up-regulated. Taken together, HOGA1 is a potential causal gene for obesity as it plays a role in excess body fat development.

Identification and functional validation of HLA-C as a potential gene involved in colorectal cancer in the Korean population.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide and is influenced by environmental and genetic factors. Although numerous genetic loci for CRC have been identified, the overall understanding of the genetic factors is yet to be elucidated. We sought to discover new genes involved in CRC applying genetic association analysis and functional study. RESULTS: We conducted exome array analysis on 194 CRC and 600 control subjects for discovering new candidate CRC genes. Fisher's exact test detected one exome-wide significant functional locus for CRC on SMCO1 (P < 10-6) and two suggestive functional loci on HLA-C and NUTM1 (10-6 ≤ P < 10-4). To evaluate the biological role of three candidate CRC genes, the differential expression of these genes between CRC and non-cancer colorectal cells was analyzed using qRT-PCR and publicly available gene expression data. Of three genes, HLA-C consistently revealed the significant down-regulation in CRC cells. In addition, we detected a reduction in cell viability in the HLA-C overexpression CRC cell line, implying the functional relevance of HLA-C in CRC. To understand the underlying mechanism exerted by HLA-C in CRC development, we conducted RNA sequencing analyses of HLA-C overexpression CRC cells and non-cancer colorectal cells. Pathway analysis detected that significantly down-regulated genes in HLA-C overexpression CRC cells were highly enriched in cancer-related signaling pathways such as JAK/STAT, ErbB, and Hedgehog signaling pathways. CONCLUSIONS: Exome array CRC case-control analysis followed by functional validation demonstrated that HLA-C likely exerts its influence on CRC development via cancer-related signaling pathways.

Identification of genetic variants for blood insulin level in sex-stratified Korean population and evaluation of the causal relationship between blood insulin level and polycystic ovary syndrome.

BACKGROUND: Blood insulin level is an important risk factor for numerous disorders. Individual blood insulin level is known to be substantially influenced by genetic factors. Several genetic association studies identified a number of genetic variants for blood insulin level, but none of them was from a sex-stratified population. OBJECTIVE: This study aimed to identify male- and female-specific genetic variants related to blood insulin level and to evaluate the causal relationship between blood insulin level and polycystic ovary syndrome (PCOS) that is likely caused by high insulin in Korean women. METHODS: A genome-wide association study was conducted to identify genetic variants influencing blood insulin level in males (N = 4183) and females (N = 4659) in the Korean population. Two-sample Mendelian randomization (MR) analysis was used to investigate the causal effects of the insulin variants identified from GWAS on PCOS in Korean women. Genetic association data for PCOS were obtained from a PCOS study cohort (946 cases, 976 controls) in Ewha Womans University Hospital. RESULTS: GWAS linear regression analysis identified 13 female-specific SNPs and 13 male-specific SNPs showing suggestive associations (P < 10-5) with blood insulin level. The results from two-sample MR analysis using the GWAS variants for PCOS indicated that genetically determined insulin level was not associated with the risk of PCOS in Korean women. CONCLUSION: This study identified sex-specific genetic variants showing associations with insulin for the first time in East Asian populations. In addition, MR analysis using variants discovered from Korean women revealed that genetically determined high level of insulin is not the cause of PCOS.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Cancer-preventive effect of phenethyl isothiocyanate through tumor microenvironment regulation in a colorectal cancer stem cell xenograft model.

BACKGROUND: Phenethyl isothiocyanate (PEITC) is a glucosinolate derived from cruciferous vegetables and is a cancer-chemopreventive reagent. Cancer stem cells (CSCs) have roles in cancer chemoresistance, invasion, metastasis, and recurrence. Here, we investigated whether PEITC can suppress the properties of CSCs using NCCIT cells and HCT116-derived cancer stem-like cells. Furthermore, we established a CSC xenograft prevention model using nude mice. PURPOSE: The purpose of this study was to examine the actual cancer-preventive effects of PEITC in vitro and in a xenograft prevention model. STUDY DESIGN: We assessed the cancer-preventive effects of PEITC on CSCs using a novel xenograft prevention model. METHODS: NCCIT cells were treated with PEITC, and the expression of pluripotent markers was confirmed by reporter assays, western blotting, and qRT-PCR. In addition, to evaluate the effects of PEITC on CSC properties, sphere cells, which exhibit CSC properties, were established from the HCT116 cells. Furthermore, to examine the inhibitory effects and the underlying mechanism following daily intake of PEITC on CSCs, we performed an animal study in a mouse xenograft model and RNA-sequencing analysis. RESULTS: PEITC significantly reduced the CSC properties, including clonogenicity and the expression of pluripotent factors. Prior to CSC inoculation in vivo, the PEITC pre-treatment group showed a more effective reduction in the tumor growth rate and expression of CSC markers compared to the post-treatment groups. Furthermore, RNA-sequencing results showed that PEITC pre-treatment remarkably suppressed genes related to inflammatory and immune responses and chemokine-related signaling. CONCLUSION: PEITC might contribute to the prevention or delay of colorectal cancer growth by inhibiting CSCs via the regulation of inflammatory chemokines, which can affect the tumor microenvironment. Thus, our study suggests that the daily intake of phytochemicals derived from vegetables or dietary supplements could have cancer-preventive effects through regulation of the host-tumor microenvironment.

The burden of rare damaging variants in hereditary atypical parkinsonism genes is increased in patients with Parkinson's disease.

Increased burdens of rare coding variants in genes related to lysosomal storage disease or mitochondrial pathways were reported to be associated with idiopathic Parkinson's disease. Under a hypothesis that the burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed the burdens of rare coding variants with a case-control design. Two cohorts of whole-exome sequencing data and a cohort of genome-wide genotyping data of clinically validated idiopathic Parkinson's disease cases and controls, which were open to the public, were used. The sequence kernel association test-optimal was used to analyze the burden of rare variants in the hereditary parkinsonism gene set, which was constructed from the Online Mendelian Inheritance in Man database through manual curation. The hereditary parkinsonism gene set consisted of 17 genes with a locus symbol prefix for familial Parkinson's disease and 75 hereditary atypical parkinsonism genes. We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. Meta-analyses of the rare variant burden test in a subgroup of gene sets revealed an association between burdens of rare damaging variants with PD in a hereditary atypical parkinsonism gene set, but not in a subgroup gene set with a locus symbol prefix for familial Parkinson's disease. Our results highlight the roles of rare damaging variants in causative genes for hereditary atypical parkinsonian disorders. We propose that Mendelian genes associated with hereditary disorders accompanying parkinsonism are involved in Parkinson's disease-related genetic networks.

A Crosstalk on Codon Usage in Genes Associated with Leukemia.

Leukemia is the outcome of aggregation of damaged white blood cells. Several genes were reported to be associated with the pathogenesis of leukemia. These genes were computationally analyzed to decipher their codon usage bias (CUB) and to identify the prime factors influencing the codon usage profile as no work was reported yet. The mean values of synonymous codon usage order (SCUO) parameter indicated low CUB of the genes. Significant positive association of SCUO with overall GC and positional GCs might signal the presence of mutational pressure. However, neutrality plot suggested the dominant role of natural selection across the genes. Along with natural selection, the role of mutation pressure was also prominent and that might be responsible for lower CUB (SCUO = 0.19) of genes. Low translational speed might permit accuracy in the process. A strong inverse relationship of translational rate was observed with CUB of genes and folding energy.

Identification of Genetic Variants for Female Obesity and Evaluation of the Causal Role of Genetically Defined Obesity in Polycystic Ovarian Syndrome.

PURPOSE: Observational studies have demonstrated an increased risk of polycystic ovarian syndrome (PCOS) in obese women. This study aimed to identify genetic variants influencing obesity in females and to evaluate the causal association between genetically defined obesity and PCOS in Korean women. METHODS: Two-stage GWAS was conducted to identify genetic variants influencing obesity traits (such as body mass index [BMI], waist-hip ratio [WHR], and waist circumference [WC]) in Korean women. Two-sample Mendelian randomization (MR) analysis was employed to evaluate the causal effect of variants as genetic instruments for female obesity on PCOS. RESULTS: Meta-analysis of 9953 females combining discovery (N = 4658) and replication (N = 5295) stages detected four (rs11162584, rs6760543, rs828104, rs56137030), six (rs139702234, rs2341967, rs73059848, rs5020945, rs550532151, rs61971548), and two genetic variants (rs7722169, rs7206790) suggesting a highly significant association (P < 1×10-6) with BMI, WHR, and WC, respectively. Of these, an intron variant rs56137030 in FTO achieved genome-wide significant association (P = 3.39×10-8) with BMI in females. Using variants for female obesity, their effect on PCOS in 946 cases and 976 controls was evaluated by MR analysis. MR results indicated no significant association between genetically defined obesity and PCOS in Korean women. CONCLUSION: This study, for the first time, revealed genetic variants for female obesity in the Korean population and reported no causal association between genetically defined obesity and PCOS in Korean women.

Synonymous codon usage and context analysis of genes associated with pancreatic cancer.

Pancreatic cancer is a fatal disorder which originates in pancreas. Its mortality rate is increasing with time. Some studies also reported that pancreatic cancer would be ranked 2nd by the year 2030. Codon usage bias (CUB) arises when synonymous codons for each amino acid are not used randomly in the coding sequences of genes. We used bioinformatic methods to analyze the compositional properties, codon context and codon usage trend of the genes associated with pancreatic cancer as no work was reported yet. From the base composition analysis, the pancreatic cancer genes were found to be GC-rich and at the 3rd codon position the G/C ending codons were more preferred to A/T ending ones. The CUB was low in genes associated with pancreatic cancer. Correspondence analysis proposed that other than base constraints, CUB might also be affected by some other factors such as natural selection. Moreover, results of correlation analysis indicated that CUB and various GC contents i.e. GC, GC1, GC2, GC3 played important role in the release of free energy by transcripts of the genes associated with pancreatic cancer. The low compAI values of coding sequences suggested a low translation rate of the genes.

Codon usage trend in genes associated with obesity.

Obesity is not only a social menace but also an economic burden as it reduces productivity and increases health care cost. We used bioinformatic tools to analyze the CUB of obesity associated genes and compared with housekeeping genes (control) to explore the similarities and differences between two data sets as no work was reported yet. The mean effective number of codons (ENC) in genes associated with obesity and housekeeping gene was 50.45 and 52.03 respectively, indicating low CUB. The relative synonymous codon usage (RSCU) suggested that codons namely CTG and GTG were over-represented in both obesity and housekeeping genes while under-represented codons were TCG, TTA, CTA, CCG, CAA, CGT, ATA, ACG, GTA and GCG in obesity genes and TCG, TTA, CCG, ATA, ACG, GTA, and GCG in housekeeping genes. t test analysis suggested that 11 codons namely TTA (Leu), TTG (Leu), CCG (Pro), CAC (His), CAA (Gln), CAG (Gln), CGT (Arg), AGA (Arg), ATA (Ile), ATT (Ile) and GCG (Ala) were significantly differed (p < 0.05 or p < 0.01) between obesity and housekeeping genes. Highly significant correlation was observed between GC12 and GC3 in obesity and housekeeping genes i.e. r = 0.580** and r = 0.498** (p < 0.01) respectively indicating the effect of directional mutation pressure present in all codon positions.

Identification of female-specific genetic variants for metabolic syndrome and its component traits to improve the prediction of metabolic syndrome in females.

BACKGROUND: Metabolic syndrome (MetS), defined as a cluster of metabolic risk factors including dyslipidemia, insulin-resistance, and elevated blood pressure, has been known as partly heritable. MetS effects the lives of many people worldwide, yet females have been reported to be more vulnerable to this cluster of risks. METHODS: To elucidate genetic variants underlying MetS specifically in females, we performed a genome-wide association study (GWAS) for MetS as well as its component traits in a total of 9932 Korean female subjects (including 2276 MetS cases and 1692 controls). To facilitate the prediction of MetS in females, we calculated a genetic risk score (GRS) combining 14 SNPs detected in our GWA analyses specific for MetS. RESULTS: GWA analyses identified 14 moderate signals (Pmeta < 5X10- 5) specific to females for MetS. In addition, two genome-wide significant female-specific associations (Pmeta < 5X10- 8) were detected for rs455489 in DSCAM for fasting plasma glucose (FPG) and for rs7115583 in SIK3 for high-density lipoprotein cholesterol (HDLC). Logistic regression analyses (adjusted for area and age) between the GRS and MetS in females indicated that the GRS was associated with increased prevalence of MetS in females (P = 5.28 × 10- 14), but not in males (P = 3.27 × 10- 1). Furthermore, in the MetS prediction models using GRS, the area under the curve (AUC) of the receiver operating characteristics (ROC) curve was higher in females (AUC = 0.85) than in males (AUC = 0.57). CONCLUSION: This study highlights new female-specific genetic variants associated with MetS and its component traits and suggests that the GRS of MetS variants is a likely useful predictor of MetS in females.

Genetic risk score combining six genetic variants associated with the cellular NRF2 expression levels correlates with Type 2 diabetes in the human population.

BACKGROUND: Type 2 diabetes (T2D) is known as an inflammatory disease. NRF2 (Nuclear Factor Erythroid 2 Like2) encodes a transcription factor that binds to antioxidant response elements (AREs) and regulates the expression of genes involved in many antioxidant responses. OBJECTIVE: This study aimed to gain insight into individual anti-inflammatory activity to prevent T2D development in humans. METHODS: We performed a genome-wide association study (GWAS) to identify genetic variants influencing NRF2 expression in LCLs (lymphoblastoid cell lines) generated from 74 different individuals. Association analyses between T2D or its related traits and genetic risk score (GRS) calculated by combining genetic variants detected from GWAS for cellular NRF2 expression were performed using data from 8715 subjects. The T2D prediction model using GRS was evaluated by measuring the area under the curve (AUC) of the receiver operating characteristics (ROC) curve. RESULTS: Our GWAS identified six genetic variants (SNP) showing suggestive evidence of associations with cellular NRF2 expression (P < 10- 6). Logistic regression analysis demonstrated that GRS was associated with an increased risk of T2D (P value = 0.003, OR = 1.13). In addition, linear regression analyses showed positive associations between GRS and fasting glucose (P value = 0.028, ß = 0.62), 2-h glucose (P value = 0.0004, ß = 1.13) and HbA1C (P value = 0.033, ß = 0.03). In the T2D prediction model using GRS, the AUC of the ROC curve was 0.69. CONCLUSION: This study highlights genetic variants associated with cellular NRF2 expression and suggests that the GRS of NRF2 expression-associated variants is likely to be a useful indicator of T2D development in the human population.

Sulfuretin Prevents Obesity and Metabolic Diseases in Diet Induced Obese Mice.

The global obesity epidemic and associated metabolic diseases require alternative biological targets for new therapeutic strategies. In this study, we show that a phytochemical sulfuretin suppressed adipocyte differentiation of preadipocytes and administration of sulfuretin to high fat diet-fed obese mice prevented obesity and increased insulin sensitivity. These effects were associated with a suppressed expression of inflammatory markers, induced expression of adiponectin, and increased levels of phosphorylated ERK and AKT. To elucidate the molecular mechanism of sulfuretin in adipocytes, we performed microarray analysis and identified activating transcription factor 3 (Atf3) as a sulfuretin-responsive gene. Sulfuretin elevated Atf3 mRNA and protein levels in white adipose tissue and adipocytes. Consistently, deficiency of Atf3 promoted lipid accumulation and the expression of adipocyte markers. Sulfuretin's but not resveratrol's anti-adipogenic effects were diminished in Atf3 deficient cells, indicating that Atf3 is an essential factor in the effects of sulfuretin. These results highlight the usefulness of sulfuretin as a new anti-obesity intervention for the prevention of obesity and its associated metabolic diseases.

Hsa-miR-10a-5p downregulation in mutant UQCRB-expressing cells promotes the cholesterol biosynthesis pathway.

Ubiquinol cytochrome c reductase binding protein (UQCRB) is known to play crucial roles in the development of various types of diseases. However, the link between UQCRB and microRNAs remains unknown. In the present study, we performed microRNA sequencing of mutant UQCRB-expressing stable cell lines that exhibited pro-oncogenic activities caused by expression of the mutant UQCRB gene. Results showed that hsa-miR-10a-5p was significantly downregulated in the mutant UQCRB-expressing cell lines. Furthermore, mRNA sequencing and gene ontology analysis of differentially expressed genes (DEGs) revealed that the cholesterol biosynthesis pathway might be activation by mutant UQCRB expression. Moreover, inhibition of cholesterol synthesis in mutant UQCRB-expressing cells via treatment with the specific inhibitors suppressed the cell proliferation. Transfection with a hsa-miR-10a-5p mimic validated that lanosterol synthase (LSS) is a target of hsa-miR-10a-5p. In addition, hsa-miR-10a-5p was found to be downregulated in liver cancer cell lines overexpressing UQCRB. Taken together, our findings highlighted the potential use of hsa-miR-10a-5p as a biomarker for UQCRB related diseases.

Nonsynonymous Variants in PAX4 and GLP1R Are Associated With Type 2 Diabetes in an East Asian Population.

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 × 10-16 and OR 0.84, P = 3.55 × 10-8, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 × 10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 × 10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

Author Correction: Understanding the functional role of genistein in the bone differentiation in mouse osteoblastic cell line MC3T3-E1 by RNA-seq analysis.

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