LINC00673 rs11655237 Polymorphism Is Associated With Increased Risk of Cervical Cancer in a Chinese Population

Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer deaths in women worldwide. Few single-nucleotide polymorphisms associated with risk of cervical cancer have been identified, yet genetic predisposition contributes significantly to this malignancy. Long noncoding RNA LINC00673 has been widely explored for its role in the development and prognosis of many tumors, and 2 genome-wide association studies identified that LINC00673 rs11655237 was associated with susceptibility to pancreatic cancer. In the current study, using a case–control study design, we found rs11655237 significantly increased susceptibility of cervical cancer in a Chinese population (odds ratio = 1.27; 95% confidence interval = 1.08-1.50; P = .005). Expression of LINC00673 was significantly higher in adjacent normal tissues than in paired cancer tissues ( P < .01) and significantly lower in the cancer or paired adjacent normal tissues of patients with cervical cancer having rs11655237 allele A than in those having rs11655237 allele G ( P < .001). Our results indicate that LINC00673 rs11655237 is associated with increased risk of cervical cancer, possibly by downregulating LINC00673 expression in cervical tissues.

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Genetic risk factors associated with gestational diabetes in a multi-ethnic population

PLoS ONE ◽

10.1371/journal.pone.0261137 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261137

Author(s):

Paula Benny ◽

Hyeong Jun Ahn ◽

Janet Burlingame ◽

Men-Jean Lee ◽

Corrie Miller ◽

...

Keyword(s):

Gestational Diabetes ◽

Association Studies ◽

Pacific Islanders ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

Multiethnic Cohort ◽

Increased Risk

Aims Genome-wide association studies have shown an increased risk of type-2-diabetes (T2DM) in patients who carry single nucleotide polymorphisms in several genes. We investigated whether the same gene loci confer a risk for gestational diabetes mellitus (GDM) in women from Hawaii, and in particular, Pacific Islander and Filipino populations. Methods Blood was collected from 291 women with GDM and 734 matched non-diabetic controls (Pacific Islanders: 71 GDM, 197 non-diabetic controls; Filipinos: 162 GDM, 395 controls; Japanese: 58 GDM, 142 controls). Maternal DNA was used to genotype and show allele frequencies of 25 different SNPs mapped to 18 different loci. Results After adjusting for age, BMI, parity and gravidity by multivariable logistic regression, several SNPs showed significant associations with GDM and were ethnicity specific. In particular, SNPs rs1113132 (EXT2), rs1111875 (HHEX), rs2237892 (KCNQ1), rs2237895 (KCNQ1), rs10830963 (MTNR1B) and rs13266634 (SLC30A8) showed significant associations with GDM in Filipinos. For Japanese, SNPs rs4402960 (IGFBP2) and rs2237892 (KCNQ1) were significantly associated with GDM. For Pacific Islanders, SNPs rs10830963 (MTNR1B) and rs13266634 (SLC30A8) showed significant associations with GDM. Individually, none of the SNPs showed a consistent association with GDM across all three investigated ethnicities. Conclusion Several SNPs associated with T2DM are found to confer increased risk for GDM in a multiethnic cohort in Hawaii.

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Association between ADAMTS7 TagSNPs and the risk of myocardialinfarction

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2019-136459 ◽

2019 ◽

Vol 95 (1127) ◽

pp. 487-492

Author(s):

Li-li Liang ◽

Yu-lan Zhou ◽

Jie Cheng ◽

Yu-tong Xiao ◽

Zi-bin Tang ◽

...

Keyword(s):

Association Studies ◽

Multivariate Logistic Regression Analysis ◽

Underlying Mechanism ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

General Validity ◽

Genome Wide ◽

Increased Risk ◽

Stratified Analysis

Purpose of the studyGenome-wide association studies have revealed an association of ADAMTS7 polymorphisms with the risk of cardiovascular diseases. Nonetheless, the role of ADAMTS7 polymorphisms on myocardial infarction (MI) risk remains poorly understood. Here, we aim to evaluate the effect of ADAMTS7 tag single nucleotide polymorphisms (SNPs) on individual susceptibility to MI.Study designGenotyping of the four tagSNPs (rs1994016, rs3825807, rs4380028 and rs7173743) was performed in 232 MI cases and 661 control subjects using PCR-ligase detection reaction (LDR) method. The association of these four tagSNPs with MI risk was performed with SPSS software.ResultsMultivariate logistic regression analysis showed that ADAMTS7 tagSNP rs3825807 exhibited a significant effect on MI risk. Compared with the TT homozygotes, the CT genotype (OR1.93, 95% CI1.30to 2.85, Pc=0.004) and the combined CC/CT genotypes (OR1.70, 95% CI1.16 to 2.50, Pc=0.028) were statistically significantly associated with the increased risk for MI. Further stratified analysis revealed a more significant association with MI risk among older subjects, hypertensives, non-diabetics and patients with hyperlipidaemia. Consistently, the haplotype rs1994016T–rs3825807C containing rs3825807 C allele exhibited increased MI risk (OR1.52, 95% CI1.10 to 2.10, p=0.010). However, we did not detect any association of the other three tagSNPs with MI risk.ConclusionsOur finding suggest that ADAMTS7 tagSNP rs3825807 contributes to MI susceptibility in the Chinese Han population. Further studies are necessary to conﬁrm the general validity of our ﬁndings and to clarify the underlying mechanism for this association.

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Long non-coding RNA polymorphisms on 8q24 are associated with the prognosis of gastric cancer in a Chinese population

PeerJ ◽

10.7717/peerj.8600 ◽

2020 ◽

Vol 8 ◽

pp. e8600 ◽

Cited By ~ 2

Author(s):

Yangyu Zhang ◽

Yanhua Wu ◽

Zhifang Jia ◽

Donghui Cao ◽

Na Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Chinese Population ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Chinese Populations ◽

Risk Of Death ◽

Non Coding Rna ◽

Increased Risk ◽

Long Non Coding Rna

Background Gastric cancer (GC) remains the third leading cause of cancer death in China. Although genome-wide association studies have identified the association between several single nucleotide polymorphisms (SNPs) on 8q24 and the risk of GC, the role of these SNPs in the prognosis of GC in Chinese populations has not yet been fully evaluated. Therefore, this study was conducted to explore the association between long non-coding RNA (lncRNA) polymorphisms on 8q24 and the prognosis of GC. Methods We genotyped 726 surgically resected GC patients to explore the association between eight SNPs in the lncRNAs CCAT1 (rs10087719, rs7816475), PCAT1 (rs1026411), PRNCR1 (rs12682421, rs13252298), and CASC8 (rs1562430, rs4871789, rs6983267) transcribed from the 8q24 locus and the prognosis of GC in a Chinese population. Results We found that the patients carrying rs12682421 AA genotypes survived for a shorter time than those with the GG/GA genotype (HR = 1.39, 95% confidence interval (CI) [1.09–1.78]). Compared with the CC/CT genotype, the TT genotype of rs1562430 was associated with an increased risk of death (HR = 1.38, 95% CI [1.06–1.80]). Furthermore, the results also identified the rs1026411 SNP as an independent prognostic factor for poor survival in GC patients. Patients carrying AA/AG variant genotypes had a 36% increased risk of death compared to those carrying the GG genotype (HR = 1.36, 95% CI [1.06–1.74]). These findings suggested that the rs12682421, rs1026411 and rs1562430 SNPs may contribute to the survival of GC and be prognostic markers for GC.

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The Genetic Basis of Hypertriglyceridemia

Current Atherosclerosis Reports ◽

10.1007/s11883-021-00939-y ◽

2021 ◽

Vol 23 (8) ◽

Author(s):

Germán D. Carrasquilla ◽

Malene Revsbech Christiansen ◽

Tuomas O. Kilpeläinen

Keyword(s):

Genetic Basis ◽

Association Studies ◽

Cumulative Effect ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Risk Variants ◽

Genome Wide ◽

Severe Hypertriglyceridemia ◽

Increased Risk ◽

Polygenic Scores

Abstract Purpose of Review Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. Recent Findings More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. Summary The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

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Pharmacogenomics of Lithium Response in Bipolar Disorder

Pharmaceuticals ◽

10.3390/ph14040287 ◽

2021 ◽

Vol 14 (4) ◽

pp. 287

Author(s):

Courtney M. Vecera ◽

Gabriel R. Fries ◽

Lokesh R. Shahani ◽

Jair C. Soares ◽

Rodrigo Machado-Vieira

Keyword(s):

Bipolar Disorder ◽

Association Studies ◽

Mood Stabilizer ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Non Coding Rna ◽

Genome Wide ◽

Lithium Response ◽

Genetic Loading ◽

Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

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Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽

10.3390/genes12081175 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1175

Author(s):

Amarni L. Thomas ◽

Judith Marsman ◽

Jisha Antony ◽

William Schierding ◽

Justin M. O’Sullivan ◽

...

Keyword(s):

Association Studies ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Runx1 Gene ◽

Gene Regulatory Elements ◽

Important Regulator ◽

Aml1 Gene ◽

Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

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Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Human Molecular Genetics ◽

10.1093/hmg/ddab060 ◽

2021 ◽

Author(s):

Robin N Beaumont ◽

Isabelle K Mayne ◽

Rachel M Freathy ◽

Caroline F Wright

Keyword(s):

Birth Weight ◽

Statistical Power ◽

Developmental Disorders ◽

Association Studies ◽

Later Life ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Common Genetic Variants ◽

Causal Genes

Abstract Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.

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Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2016.0569 ◽

2016 ◽

Vol 283 (1835) ◽

pp. 20160569 ◽

Cited By ~ 52

Author(s):

M. E. Goddard ◽

K. E. Kemper ◽

I. M. MacLeod ◽

A. J. Chamberlain ◽

B. J. Hayes

Keyword(s):

Complex Traits ◽

Genetic Architecture ◽

Quantitative Traits ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Crop Breeding ◽

Single Nucleotide ◽

Genome Wide ◽

Phenotype Identification

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

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Are there monogenic hereditary forms of bladder cancer or only genetic susceptibilities?

Pharmacogenomics ◽

10.2217/pgs-2020-0165 ◽

2021 ◽

Author(s):

Tarek Souaid ◽

Joya-Rita Hindy ◽

Ernest Diab ◽

Hampig Raphael Kourie

Keyword(s):

Bladder Cancer ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Significance Level ◽

Dna Mismatch ◽

Common Cancer ◽

Genome Wide ◽

Dna Mismatch Repair Genes ◽

Mutyh Associated Polyposis

Bladder cancer (BC) is the most common cancer involving the urinary system and the ninth most common cancer worldwide. Tobacco smoking is the most important environmental risk factor of BC. Several single nucleotide polymorphisms have been validated by genome-wide association studies as genetic risk factors for BC. However, the identification of DNA mismatch-repair genes, including MSH2 in Lynch syndrome and MUTYH in MUTYH-associated polyposis, raises the possibility of monogenic hereditary forms of BC. Moreover, other genetic mutations may play a key role in familial and hereditary transmissions of BC. Therefore, the aim of this review is to focus on the major hereditary syndromes involved in the development of BC and to report BC genetic susceptibilities established with genome-wide significance level.

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Abstract 288: Novel Mechanisms of Non-coding Genomic Regulation Identified in Cardiac Disease-in-a-dish Models

Circulation Research ◽

10.1161/res.119.suppl_1.288 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Aditya Kumar ◽

Stephanie Thomas ◽

Kirsten Wong ◽

Kevin Tenerelli ◽

Valentina Lo Sardo ◽

...

Keyword(s):

Heart Attack ◽

Connexin 43 ◽

Disease Risk ◽

Association Studies ◽

Correlation Coefficients ◽

Induced Pluripotent Stem Cell ◽

Genome Wide Association Studies ◽

Isogenic Line ◽

Nucleotide Polymorphisms ◽

Increased Risk

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at gene loci that affect cardiovascular function, and while mechanisms in protein-coding loci are obvious, those in non-coding loci are difficult to determine. 9p21 is a recently identified locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction. Associations have implicated SNPs in altering smooth muscle and endothelial cell properties but have not identified adverse effects in cardiomyocytes (CMs) despite enhanced disease risk. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs and either CAD positive or negative, we assessed CM function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. “heart attack-in-a-dish” stiffening from 11 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype and disease beat synchronously on soft matrices, R/R CMs cultured on dynamically stiffened hydrogels exhibited asynchronous contractions and had significantly lower correlation coefficients versus N/N CMs in the same conditions. Dynamic stiffening reduced connexin 43 expression and gap junction assembly in R/R CMs but not N/N CMs. To eliminate patient-to-patient variability, we created an isogenic line by deleting the 9p21 gene locus from a R/R patient using TALEN-mediated gene editing, i.e. R/R KO. Deletion of the 9p21 locus restored synchronous contractility and organized connexin 43 junctions. As a non-coding locus, 9p21 appears to repress connexin transcription, leading to the phenotypes we observe, but only when the niche is stiffened as in disease. These data are the first to demonstrate that disease-specific niche remodeling, e.g. a “heart attack-in-a-dish” model, can differentially affect CM function depending on SNPs within a non-coding locus.

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