Association Study Of Single Nucleotide Polymorphisms Research Articles

Structural variants contribute to phenotypic variation in maize.

Comprehensively identifying the loci shaping trait variation has been challenging, in part because standard approaches often miss many types of genetic variants. Structural variants, especially transposable elements are likely to affect phenotypic variation but we need better methods in maize for detecting polymorphic structural variants and TEs using short-read sequencing data. Here, we used a whole genome alignment between two maize genotypes to identify polymorphic structural variants and then genotyped a large maize diversity panel for these variants using short-read sequencing data. We characterized variation of SVs within the panel and identified SV polymorphisms that are associated with life history traits and genotype-by-environment interactions. While most of the SVs associated with traits contained TEs, only one of the SV's boundaries clearly matched TE breakpoints indicative of a TE insertion, whereas the other polymorphisms were likely caused by deletions. All of the SVs associated with traits were in linkage disequilibrium with nearby single nucleotide polymorphisms (SNPs), suggesting that this method did not identify variants that would have been missed in a SNP association study.

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture.

Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.

The impact of the cytoplasmic ubiquitin ligase TNFAIP3 gene variation on transcription factor NF-κB activation in acute kidney injury

Nuclear factor κB (NF-κB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI) and manifests in transplanted kidneys as delayed graft function. The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- κB signaling pathway. Common population-specific TNFAIP3 coding variants that reduce A20's enzyme function and increase NF- κB activation have been linked to heightened protective immunity and autoimmune disease, but have not been investigated in AKI. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies single nucleotide polymorphisms of F127C; namely F127C;R22Q, F127C;G281E, F127C;W448C and F127C;N449K that reduce A20's anti-inflammatory function in an NF- κB reporter assay. To investigate the impact of TNFAIP3 hypomorphic coding variants in AKI we tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The mouse Tnfaip3 coding variant I325N increases NF- κB activation without overt inflammatory disease, providing an immune boost as I325N mice exhibit enhanced innate immunity to a bacterial challenge. Surprisingly, despite exhibiting increased intra-kidney NF- κB activation with inflammation in IRI, the kidney of I325N mice was protected. The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- κB-dependent anti-apoptotic factors BCL-2, BCL-XL, c-FLIP and A20, altering the active redox state of the kidney with a reduction of superoxide levels and the enzyme super oxide dismutase-1, and enhancing cellular protective mechanisms including increased Foxp3+ T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.

In Silico Analysis of Gene Expression Location and Single Nucleotide Polymorphisms (SNPs) of The Glucagon Like Peptide 1 Receptor (GLP-1R)

Association studies of SNPs have become very important in determining how genetic variants are linked to complex diseases, quantitative traits, and physiological responses. Genetic polymorphisms in the GLP-1R gene have potentially decreased protein stability and are associated with many diseases, especially diabetes and obesity. This study aimed to screen the expression and investigate the genetic polymorphism of the GLP-1R by using several beneficial bioinformatics tools. We observed database Ensembl, GTEx portal, and KEGG to identify the structure, expression, and molecular pathway of GLP-1R. In silico computational methods (SIFT, PolyPhen v2, PROVEAN, and PhD-SNP) were used to identify nsSNPs of the GLP-1R that potentially influence protein structure and function. I-Mutant was used to investigate possibly damaging nsSNPs, while GeneMANIA was used to investigate GLP-1R gene-gene interactions. GLP-1R is localized on chromosome 6p21, contains 13 exons, and has the regulation variant (CTCF, promotor, enhancer, and promotor flank region). GLP-1R is highly expressed in the pancreas to stimulate glucose-dependent insulin secretion and suppress glucagon secretion. Seven nsSNPs of the GLP-1R gene were found to be potentially deleterious: rs10305421, rs201672448, rs10305492, rs2295006, rs6923761, rs1042044, rs140642887, and rs10305510. I-Mutant server showed that nsSNPs rs140642887 was unstable, decreased GLP-1R protein stability, and impaired other genes' interaction and function (SP1, SP3, GNAS, and GCG). This study is the first in silico analysis of the polymorphic GLP-1R gene, and will serve as a great resource for developing precision medications to treat diseases associated with these polymorphisms.

Ancestry-specific high-risk gene variant profiling unmasks diabetes-associated genes.

How ancestry-associated genetic variance affects disparities in the risk of polygenic diseases and influences the identification of disease-associated genes warrants a deeper understanding. We hypothesized that the discovery of genes associated with polygenic diseases may be limited by the overreliance on single-nucleotide polymorphism (SNP)-based genomic investigation, as most significant variants identified in genome-wide SNP association studies map to introns and intergenic regions of the genome. To overcome such potential limitations, we developed a gene-constrained, function-based analytical method centered on high-risk variants (hrV) that encode frameshifts, stopgains or splice site disruption. We analyzed the total number of hrV per gene in populations of different ancestry, representing a total of 185 934 subjects. Using this analysis, we developed a quantitative index of hrV (hrVI) across 20 428 genes within each population. We then applied hrVI analysis to the discovery of genes associated with type 2 diabetes mellitus (T2DM), a polygenic disease with ancestry-related disparity. HrVI profiling and gene-to-gene comparisons of ancestry-specific hrV between the case (20 781 subjects) and control (24 440 subjects) populations in the T2DM national repository identified 57 genes associated with T2DM, 40 of which were discoverable only by ancestry-specific analysis. These results illustrate how a function-based, ancestry-specific analysis of genetic variations can accelerate the identification of genes associated with polygenic diseases. Besides T2DM, such analysis may facilitate our understanding of the genetic basis for other polygenic diseases that are also greatly influenced by environmental and behavioral factors, such as obesity, hypertension and Alzheimer's disease.

Genome-wide association study of SNP- and gene-based approaches to identify susceptibility candidates for lupus nephritis in the Han Chinese population.

BackgroundLupus nephritis (LN) is one of the most common and serious complications of systemic lupus erythaematosus (SLE). Genetic factors play important roles in the pathogenesis of LN and could be used to predict who might develop LN. The purpose of this study was to screen for susceptible candidates of LN across the whole genome in the Han Chinese population.Methods592 LN patients and 453 SLE patients without renal damage were genotyped at 492,970 single nucleotide polymorphisms (SNPs) in the genome-wide association study (GWAS). Fifty-six SNPs were selected for replication in an independent cohort of 188 LN and 171 SLE without LN patients. Further quantitative real-time (qRT) PCR was carried out in 6 LN patients and 6 healthy controls. Gene-based analysis was conducted using the versatile gene-based test for GWAS. Subsequently, enrichment and pathway analyses were performed in the DAVID database.ResultsThe GWAS analysis and the following replication research identified 9 SNPs showing suggestive correlation with LN (P<10-4). The most significant SNP was rs12606116 (18p11.32), at P=8.72×10−6. The qRT-PCR results verified the mRNA levels of LINC00470 and ADCYAP1, the closest genes to rs12606116, were significantly lower in LN patients. From the gene-based analysis, 690 genes had suggestive evidence of association (P<0.05), including LINC00470. The enrichment analysis identified the involvement of transforming growth factor beta (TGF-β) signalings in the development of LN. Lower plasma level of TGF-β1 (P<0.05) in LN patients and lower expression of transforming growth factor beta receptor 2 in lupus mice kidney (P<0.05) futher indicate the involvement of TGF-β in LN.ConclusionsOur analyses identified several promising susceptibility candidates involved in LN, and further verification of these candidates was necessary.

Influence of CLOCK Gene Variants on Weight Response after Bariatric Surgery.

The Circadian Locomotor Output Cycles Kaput (CLOCK) gene has been linked to metabolic dysfunction and obesity. The purpose of this study was to analyze the association between single nucleotide polymorphisms (SNPs) of CLOCK gene with obesity and with long-term weight response after different bariatric surgery (BS) techniques. The cohort includes 375 patients with morbid obesity (MO) and 230 controls. In the association study of SNPs with weight response we combined several variables as phenotype at 6 years after surgery. The study protocol was registered in ISRCTN (ID80961259). The analysis of the selected SNPs was performed by allelic discrimination using Taqman® probes. The genotype association study was performed using the SNPStats program, with comparisons adjusted for sex, age, initial Body Mass Index, type 2 diabetes and hypertension diagnosis, and type of surgery. In the case-control study two of three SNPs were significantly associated with MO. The variant rs1801260 had a protective effect for MO whereas the TT genotype of rs3749474 variant had the strongest association with MO (OR = 2.25 (1.39–3.66); p = 0.0006). In the linear regression analysis both variants showed significant association with long-term weight loss and weight regain after BS, independently of the pre-surgery patient profile.

Genome-Wide 3'-UTR Single Nucleotide Polymorphism Association Study Identifies Significant Prostate Cancer Risk-Associated Functional Loci at 8p21.2 in Chinese Population.

MicroRNAs (miRNAs) are involved in the regulation of gene expression via incomplete base pairing to sequence motifs at the three prime untranslated regions (3′‐UTRs) of mRNAs and play critical roles in the etiology of cancers. Single nucleotide polymorphisms (SNPs) in the 3′‐UTR miRNA‐binding regions may influence the miRNA affinity. However, this biological mechanism in prostate cancer (PCa) remains unclear. Here, a three‐stage genome‐wide association study of 3′‐UTR SNPs (n=33 117) is performed in 5515 Chinese men. Three genome‐wide significant variants are discovered at 8p21.2 (rs1567669, rs4872176, and rs4872177), which are all located in a linkage disequilibrium region of the NKX3‐1 gene. Phenome‐wide association analysis using the FinnGen data reveals a specific association of rs1567669 with PCa over 2,264 disease endpoints. Expression quantitative trait locus analyses based on both Chinese PCa cohort and the GTEx database show that risk alleles of these SNPs are significantly associated with low expression of NKX3‐1. Based on the MirSNP database, dual‐luciferase reporter assays show that risk alleles of these SNPs downregulate the expression of NKX3‐1 via increased miRNA binding. These results indicate that the SNPs at the 3′‐UTR of NKX3‐1 significantly downregulate NKX3‐1 expression by influencing the affinity of miRNA and increase the PCa risk.

Exploring Association Between Serotonin and Neurogenesis Related Genes in Obsessive-Compulsive Disorder in Chinese Han People: Promising Association Between DMRT2, miR-30a-5p, and Early-Onset Patients.

Obsessive-compulsive disorder (OCD) is a deliberating disorder with complex genetic and environmental etiologies. Hypotheses about OCD mainly include dysregulated neurotransmitters, especially serotonin, and disturbed neurodevelopment. Single nucleotide polymorphism (SNP) association studies regarding OCD are often met with inconsistent results. However, stratification by age of onset may sometimes help to limit the heterogenicity of OCD patients. Therefore, we conducted a stratified SNP association study enrolling 636 patients and 612 healthy controls. Patients were stratified by age of onset as early-onset (EO-OCD) and late-onset (LO-OCD). Blood extracted from the patients was used to genotype 18 loci, including serotonin system genes, Slitrk1, Slitrk5, and DMRT2 and related miRNA genes. Logistic regression was used to compare allele and genotype frequencies of variants. A general linear model was used to evaluate the association between variants and trait anxiety. In our study, rs3824419 in DMRT2 was associated with EO-OCD, G allele was the risk allele. Rs2222722 in miR-30a-5p was associated with EO-OCD, with the C allele being the risk allele. Rs1000952 in HTR3D was found associated with trait anxiety in OCD patients. The significance disappeared after FDR correction. Our results supported neurodevelopment-related genes, DMRT2 and miR-30a-5p, to be related to EO-OCD. However, we cannot prove serotonin genes to be directly associated with EO-OCD. While an association between HTR3D and trait anxiety was discovered, comparisons based on biological or clinical traits may be helpful in future studies. As our detective powers were limited, more large-scale studies will be needed to confirm our conclusion.

A Targeted Association Study of Blood-Brain Barrier Gene SNPs and Brain Atrophy

Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens. Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP). Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change. Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOEɛ4 allele and were significant post correction for multiple comparisons. Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation.

Revision Surgery After TJR: A Family Affair?: Commentary on an article by Anders Brüggemann, MD, PhD, et al.: "Risk of Revision After Arthroplasty Associated with Specific Gene Loci. A Genomewide Association Study of Single-Nucleotide Polymorphisms in 1,130 Twins Treated with Arthroplasty".

Revision Surgery After TJR: A Family Affair?: Commentary on an article by Anders Brüggemann, MD, PhD, et al.: "Risk of Revision After Arthroplasty Associated with Specific Gene Loci. A Genomewide Association Study of Single-Nucleotide Polymorphisms in 1,130 Twins Treated with Arthroplasty".

Association study of SNPs in LncRNA CDKN2B-AS1 with breast cancer susceptibility in Chinese Han population.

The study aimed to analysis the genetic variation of the lncRNA CDKN2B-AS1 SNPs, and explored the regulation of SNPs on the invasion and metastasis of Breast cancer (BC). The SNPs (Single Nucleotide Polymorphisms) was screened for genotyping among 504 Chinese Han patients and 505 controls, which were frequency-matched for age (±2 years). Logistic analysis was to explore the relationship between SNPs and the BC risk. Interactions between SNPs and reproductive factors was explored using the multifactor dimensionality reduction (MDR) method. qRT-PCR was conducted to detect the CDKN2B-AS1 expression in plasma of different rs10965215 and rs2518723 genotypes. The effect of rs10965215 A>G mutation on the binding ability of CDKN2B-AS1 and miR-4440 was verified by dual luciferase experiment. CCK-8, scratch and Transwell experiment were performed to explore the effect of miR-4440 over-expression on BC cell proliferation, migration and invasion. A total of 13 SNP was screened. The individuals with SNPs rs2518723C>T, rs10965215 A>G, rs77792598C>G, rs4977753 T>C, rs75917766C>T and rs78545330C>G mutations might increase the BC risk. MDR results revealed that individuals with rs10965215 G genotype who age at menarche≥13 and regardless of the number of abortion<2 or ≥2 had a higher risk of BC. The relative expression of CDKN2B-AS1 in rs10965215 homozygous wild AA genotype (8.88±3.43) was lower than heterozygous GA (11.08±2.90) and homozygous mutant GG genotype (11.31±2.90). When rs10965215 wild A genotype was carried, there was an interaction between CDKN2B-AS1 and miR-4440. The CCK-8, Transwell, and scratch experiment were all found that miR-4440 over-expression might enhance the proliferation, invasion and migration of BC cells. CDKN2B-AS1 gene polymorphism might be related to the susceptibility of BC, CDKN2B-AS1 rs10965215 A/G genotype probably affect the proliferation, invasion and migration of BC cells by modulating the interactions with of miR-4440.

Genetic Variation and Impact on Outcome in Traumatic Brain Injury: an Overview of Recent Discoveries.

Traumatic brain injury (TBI) has a significant burden of disease worldwide and outcomes vary widely. Current prognostic tools fail to fully account for this variability despite incorporating clinical, radiographic, and biochemical data. This variance could possibly be explained by genotypic differences in the patient population. In this review, we explore single nucleotide polymorphism (SNP) TBI outcome association studies. In recent years, SNP association studies in TBI have focused on global, neurocognitive/neuropsychiatric, and physiologic outcomes. While the APOE gene has been the most extensively studied, other genes associated with neural repair, cell death, the blood-brain barrier, cerebral edema, neurotransmitters, mitochondria, and inflammatory cytokines have all been examined for their association with various outcomes following TBI. The results have been mixed across studies and even within genes. SNP association studies provide insight into mechanisms by which outcomes may vary following TBI. Their individual clinical utility, however, is often limited by small sample sizes and poor reproducibility. In the future, they may serve as hypothesis generating for future therapeutic targets.

The first association study of single-nucleotide polymorphisms (SNPs) of the IFITM1 gene with influenza H1N1 2009 pandemic virus infection

BackgroundThe interferon-induced transmembrane (IFITM) protein family consists of interferon-stimulated genes (ISGs) that show potent antiviral capacity against a broad range of viruses. Many studies have been performed to investigate an association between IFITM3 polymorphisms and pandemic influenza A 2009 H1N1 virus infection. However, an association study of IFITM1 polymorphisms with susceptibility to this infection has not been reported thus far.ObjectiveTo identify an association between the susceptibility to pandemic influenza A 2009 H1N1 virus infection and IFITM1 polymorphisms, we compared genotype, allele and haplotype frequencies of the IFITM1 gene between healthy controls and pandemic influenza A 2009 H1N1-infected patients. In addition, we investigated linkage disequilibrium (LD) by Haploview 4.2 and the binding ability of transcription factors according to IFITM1 polymorphism alleles by PROMO. Furthermore, we measured the LD value between the IFITM1 gene and the IFITM3 gene.ResultsWe found 3 novel single-nucleotide polymorphisms (SNPs) and did not find an association between IFITM1 SNPs and susceptibility to pandemic influenza A 2009 H1N1 virus infection. We found strong LD among IFITM1 SNPs but did not find a difference in the transcription factor-binding ability according to regulatory IFITM1 SNP alleles. In addition, we found strong LD between IFITM1 SNPs and IFITM3 SNPs.ConclusionTo the best of our knowledge, this report is the first association study of the susceptibility to pandemic influenza A 2009 H1N1 virus infection and IFITM1 polymorphisms.

A comprehensive evaluation of association between homocysteine levels and single nucleotide polymorphisms with hypertension risk: A protocol of systematic review and network meta-analysis.

According to the relevant reports that single nucleotide polymorphisms (SNPs) may contribute to change of homocysteine (HCY) levels and increase the risk of hypertension (HTN). During the inconsistent results, this meta-analysis purpose is systematically review and synthesized relevant data on HCY levels and SNPs in HTN. The systematic search database, from the following database to find out the association studies of SNPs and HTN publications up until March 2020 from the databases of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), the Chinese Science and Technology Periodical Database (VIP) and Wan fang databases, and Chinese Biomedical Literature Database (CBM). Network meta-analysis and Thakkinstian's algorithm were used to select the most appropriate genetic model, along with false positive report probability (FPRP) for noteworthy associations. All statistical analyses were calculated with STATA software (version 14.0; StataCorp, College Station, TX). This meta-analysis will provide high-quality evidence to the effects of SNP on HTN and levels of HCY, and find between SNPs and HTN susceptibility on in all the genetic models, and choose the best one. This meta-analysis will research which SNP is the most correlated with HTN risk. INPLASY202050002.

A comprehensive evaluation of single nucleotide polymorphisms associated with osteosarcoma risk: A protocol for systematic review and network meta-analysis.

Single nucleotide polymorphisms (SNPs) have been inconsistently associated with osteosarcoma (OS) risk. This meta-analysis aimed to synthesize relevant data on SNPs associated with OS. Databases were searched to identify association studies of SNPs and OS published through January 2020 from the databases of PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, and Wan fang databases. Network meta-analysis and Thakkinstian algorithm were used to select the most appropriate genetic model, along with false positive report probability for noteworthy associations. The methodological quality of data was assessed based on the STrengthening the REporting of Genetic Association Studies statement Stata 14.0 will be used for systematic review and meta-analysis. This study will provide a high-quality evidence to find the SNP most associated with OS susceptibility and the best genetic model. This study will explore which SNP is most associated with OS susceptibility. INPLASY202040023.

A comprehensive evaluation of single nucleotide polymorphisms associated with gastric cancer risk: A protocol for systematic review and network meta-analysis.

Single nucleotide polymorphisms (SNPs) have been inconsistently associated with gastric cancer (GC) risk. This meta-analysis aimed to synthesize relevant data on SNPs associated with GC. Databases were searched to identify association studies of SNPs and GC published through January 2020 from the databases of PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, and Wan fang databases. Network meta-analysis and Thakkinstian algorithm were used to select the most appropriate genetic model, along with false positive report probability for noteworthy associations. The methodological quality of data was assessed based on the STrengthening the REporting of Genetic Association Studies statement Stata 14.0 will be used for systematic review and meta-analysis. This study will provide a high-quality evidence to find the SNP most associated with GC susceptibility and the best genetic model. This study will explore which SNP is most associated with GC susceptibility. INPLASY202040132.

A comprehensive assessment of single nucleotide polymorphisms associated with pancreatic cancer risk: A protocol for systematic review and network meta-analysis.

Single nucleotide polymorphisms (SNPs) have been inconsistently associated with pancreatic cancer (PC) risk. This meta-analysis aimed to synthesize relevant data on SNPs associated with PC. Databases were searched to identify association studies of SNPs and PC published through January 2020 from the databases of PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database (VIP) and Wanfang databases. Network meta-analysis and Thakkinstian algorithm were used to select the most appropriate genetic model, along with false positive report probability (FPRP) for noteworthy associations. The methodological quality of data was assessed based on the STREGA statement Stata 14.0 will be used for systematic review and meta-analysis. This study will provide a high-quality evidence to find the SNP most associated with pancreatic cancer susceptibility and the best genetic model. This study will explore which SNP is most associated with pancreatic cancer susceptibility.Registration: INPLASY202040023.

Nicholas Gordon Martin.

We performed a candidate single-nucleotide polymorphism association study of cleft lip and palate in 1992 which earned more citations than it had subjects (N = 230).

Quality Control Measures and Validation in Gene Association Studies: Lessons for Acute Illness.

Acute illness is a complex constellation of responses involving dysregulated inflammatory and immune responses, which are ultimately associated with multiple organ dysfunction. Gene association studies have associated single-nucleotide polymorphisms (SNPs) with clinical and pharmacological outcomes in a variety of disease states, including acute illness. With approximately 4 to 5 million SNPs in the human genome and recent studies suggesting that a large portion of SNP studies are not reproducible, we suggest that the ultimate clinical utility of SNPs in acute illness depends on validation and quality control measures. To investigate this issue, in December 2018 and January 2019 we searched the literature for peer-reviewed studies reporting data on associations between SNPs and clinical outcomes and between SNPs and pharmaceuticals (i.e., pharmacogenomics) published between January 2011 to February 2019. We review key methodologies and results from a variety of clinical and pharmacological gene association studies, including trauma and sepsis studies, as illustrative examples on current SNP association studies. In this review article, we have found three key points which strengthen the potential accuracy of SNP association studies in acute illness and other diseases: providing evidence of following a protocol quality control method such as the one in Nature Protocols or the OncoArray QC Guidelines; enrolling enough patients to have large cohort groups; and validating the SNPs using an independent technique such as a second study using the same SNPs with new patient cohorts. Our survey suggests the need to standardize validation methods and SNP quality control measures in medicine in general, and specifically in the context of complex disease states such as acute illness.