Uncommon Genetic Variants Research Articles

The pathogenesis of gout: molecular insights from genetic, epigenomic and transcriptomic studies.

The pathogenesis of gout involves a series of steps beginning with hyperuricaemia, followed by the deposition ofmonosodium urate crystal in articular structures and culminating in an innate immune response, mediated by the NLRP3 inflammasome, to the deposited crystals. Large genome-wide association studies (GWAS) of serum urate levels initially identified the genetic variants with thestrongest effects, mapping mainlyto genes that encode urate transporters in the kidney and gut. Other GWAS highlighted the importance of uncommon genetic variants. More recently, genetic and epigenetic genome-wide studies have revealed new pathways in the inflammatory process of gout, including genetic associations with epigenomic modifiers. Epigenome-wide association studies are also implicating epigenomic remodelling in gout, which perhaps regulates the responsiveness of the innate immune system to monosodium urate crystals. Notably, genes implicated in gout GWAS do not include those encodingcomponents of the NLRP3 inflammasome itself, but instead include genes encoding moleculesinvolved in its regulation. Knowledge of the molecular mechanisms underlying gout has advanced through the translation of genetic associations into specific molecular mechanisms. Notable examples include ABCG2, HNF4A, PDZK1, MAF and IL37. Current genetic studies are dominated by participants of European ancestry; however, studies focusing on other population groups are discovering informative population-specific variants associated with gout.

Prospective role of Donanemab and amyloid beta therapies in early Alzheimer’s disease: A systematic review

Amyloid-β (Aβ) peptide accumulation in the brain, leading to amyloid plaques, is considered to be the starting point of Alzheimer's disease. It is believed that these plaques impair cognitive and functional capacities and induce neurodegeneration. Research on uncommon genetic variants that either increase or decrease the quantity of Aβ deposited offers proof that amyloid plaques are involved in the disease's progression. Early-stage amyloid plaque buildup increases the likelihood that moderate cognitive impairment may progress to dementia.Donanemab, a humanized IgG1 antibody, targets an N-terminal pyroglutamate Aβ epitope that is unique to plaques that have already begun to develop. It is specific to this epitope and has no known clinical effect. Furthermore, it doesn't show any off-target binding to neurotransmitters, their receptors, or other Aβ species. In this systematic review, we first collect the necessary information after carefully reviewing four different study articles. After the data is collected, we evaluate it and create a graph to compare those study articles.

Atypical Presentation of MELAS in a 7-year-old Male: A Case Report (P5-8.009)

<h3>Objective:</h3> N/A <h3>Background:</h3> Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare, maternally inherited mitochondrial cytopathy that ensues respiratory chain deficiency affecting tissues with more demanding oxidative metabolism. As MELAS is a subtype of the overarching category of mitochondrial myopathies, patients rarely present predominantly with myopathy without typical symptoms of seizures and stroke-like episodes. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> <h3>Case Presentation:</h3> We present a 7-year-old male with no previous medical history who developed progressive proximal muscle weakness and elevated ESR over three years with no response to prednisone, IVIG, or methotrexate. Before the muscle biopsy, he was presumed to have juvenile dermatomyositis, given concurrent pink discoloration over his metacarpophalangeal joints and proximal muscle weakness. The eventual biopsy demonstrated increased SDH and ragged-red fibers, and genetic sequencing confirmed the patient’s m.3251 variant of the MT-TL1 gene. These findings established a highly unusual diagnosis of myopathy-predominant MELAS in a patient lacking seizure or stroke-like episodes, with an unremarkable brain MRI and possessing an uncommon genetic variant. <h3>Conclusions:</h3> <h3>Discussion:</h3> We compare our case to other reports of primary presentation of MELAS in the literature. Though rare for a patient to have the m.3251 variant of the MT-TL1 gene with only two prior reports of this variant cited, it is perhaps even more unique that this patient suffered principally proximal muscle weakness as his presenting symptom, associated only with elevated LDH, CK and liver transaminases while lacking seizures, or stroke symptoms that would be expected. This case demonstrates the utility of reexamining muscle weakness in pediatric patients who are unresponsive to steroids in a presumed myositis-like picture. Through this elusive case of MELAS, we highlight the relevance and application of muscle biopsy, electromyography, and genetic testing to accurately diagnose and treat muscular weakness. <b>Disclosure:</b> Ms. Schrodt has nothing to disclose. Dr. Afzal has nothing to disclose. Dr. Kafaie has nothing to disclose.

Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies.

Nonischemic dilated cardiomyopathy is a common form of heart muscle disease in which genetic factors play a critical etiological role. In this regard, both rare disease-causing mutations and common disease-susceptible variants, in the Bcl-2-associated athanogene 3 (BAG3) gene have been reported, highlighting the critical role of BAG3 in cardiomyocytes and in the development of dilated cardiomyopathy. The phenotypic effects of the BAG3 mutations help investigators understand the structure and function of the BAG3 gene. Indeed, we report herein that all of the known pathogenic/likely pathogenic variants affect at least 1 of 3 protein functional domains, ie, the WW domain, the second IPV (Ile-Pro-Val) domain, or the BAG domain, whereas none of the missense nontruncating pathogenic/likely pathogenic variants affect the proline-rich repeat (PXXP) domain. A common variant, p.Cys151Arg, associated with reduced susceptibility to dilated cardiomyopathy demonstrated a significant difference in allele frequencies among diverse human populations, suggesting evolutionary selective pressure. As BAG3-related therapies for heart failure move from the laboratory to the clinic, the ability to provide precision medicine will depend in large part on having a thorough understanding of the potential effects of both common and uncommon genetic variants on these target proteins. The current review article provides a roadmap that investigators can utilize to determine the potential interactions between a patient's genotype, their phenotype, and their response to therapeutic interventions with both gene delivery and small molecules.

Impact of Genetic Determinants of HbA1c on Type 2 Diabetes Risk and Diagnosis.

Glycated hemoglobin (A1c) is used to diagnose type 2 diabetes and monitor glycemic control. Specific genetic variants interfere with A1c and effects/frequencies of some variants vary by ancestry. In this review, we summarize findings from large trans-ethnic meta-analyses of genome-wide association studies (GWAS) of A1c and describe some variants influencing erythrocyte biology and interfering with A1c. Recent GWAS meta-analyses have revealed 60 loci associated with A1c in multi-ethnic populations. The main A1c genetic driver in African Americans is rs1050828 (G6PD). Some identified loci are located in/near genes known as monogenic causes of erythrocytic disorders (ANK1, SPTA1) or iron disorders (TMPRSS6, HFE). Uncommon genetic variants (not revealed by GWAS) that are known to cause hemoglobinopathies may also influence A1C levels, partly by interfering with laboratory assays. Specific genetic variants that have a large impact on A1c levels may influence clinical practice, especially in individuals of African descent. Efforts to reveal novel A1c loci should focus on increasing representation of GWAS in non-European ancestries, and on using better genome-wide coverage of uncommon variants that are specific to each population.

An update on the genetics of hyperuricaemia and gout.

A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation.

GSTO1 uncommon genetic variants are associated with recurrent miscarriage risk

To explore the role of the GSTO1 gene in the pathogenesis of recurrent miscarriage (RM). Genetic association study. Rome, Italy. 123 women with RM and 130 women without pregnancy complications. None. Genotyping of two single nucleotide polymorphisms (A140D and E208K) and a 3-bp deletion (E155del) of the GSTO1 gene. We found a statistically significant association between GSTO1*E208K variants and RM risk. Specifically, we identified this uncommon genetic variant only in women with RM. None of the women with physiologic pregnancies were carriers of K208 allele. GSTO1 has a role in detoxification metabolism, and we hypothesize that a functional variation of GSTO1 is a RM risk factor that interacts with environmental conditions.

A sequence of methodological changes due to sequencing

During the past 2 years, next-generation sequencing studies have revolutionized the field of genetic association studies. We review the concomitant evolution of statistical methods. As much of the genetic variability identified with sequencing is extremely rare, many new methods have been developed for rare variant association studies. Sequencing data available as a result of large public projects are also being integrated with genome-wide association study (GWAS) chip data to improve genotype imputation. A further trend in recent methodological development has been the use of the linear mixed effect model (LMM). LMMs are used for rare variant association to handle effect heterogeneity. They are also used more generally in GWAS to account for population structure. Many rare variant association tests have been developed to analyze the genetic variation discovered with large-scale DNA sequencing; however, no single approach outperforms others under all disease models and power tends to be low. Sequencing data are also contributing to improved imputation of uncommon genetic variants, although imputation of rare variants remains a challenge. The appropriate correction for population structure in rare variant analyses remains unclear; specialized adjustment techniques may be necessary.

Statistical tests for detecting associations with groups of genetic variants: generalization, evaluation, and implementation

With recent advances in sequencing, genotyping arrays, and imputation, GWAS now aim to identify associations with rare and uncommon genetic variants. Here, we describe and evaluate a class of statistics, generalized score statistics (GSS), that can test for an association between a group of genetic variants and a phenotype. GSS are a simple weighted sum of single-variant statistics and their cross-products. We show that the majority of statistics currently used to detect associations with rare variants are equivalent to choosing a specific set of weights within this framework. We then evaluate the power of various weighting schemes as a function of variant characteristics, such as MAF, the proportion associated with the phenotype, and the direction of effect. Ultimately, we find that two classical tests are robust and powerful, but details are provided as to when other GSS may perform favorably. The software package CRaVe is available at our website (http://dceg.cancer.gov/bb/tools/crave).

Abstract 1658: Post-GWAS genetic and functional studies for bladder cancer: An uncommon protective synonymous coding variant within the UGT1A6 gene explains the GWAS signal and affects cellular detoxification

Abstract Background: A recent genome-wide association study (GWAS) of bladder cancer identified a single nucleotide polymorphism (SNP), rs11892031, within the UGT1A gene cluster on chromosome 2q37.1, as a novel risk factor. UGT1A locus encodes nine UGT proteins that belong to phase II cellular detoxification system. UGTs are functionally important for detoxification of aromatic amines, which are known risk factors for bladder cancer found in industrial chemicals and tobacco smoke. UGTs are composed of shared exons 2-5 and individual alternative first exons that define enzymatic activity and substrate specificity. Materials and results: We sequenced all nine highly similar alternative first exons of UGT genes in more than 2,000 individuals and identified 27 non-synonymous and 19 synonymous known coding variants, but no novel variants. Imputation based on the GWAS dataset, a combined reference panel of HapMap 3 and 1000 Genomes Projects, and a subset of GWAS samples genotyped for all the identified coding variants, generated data for 1,170 SNPs within the whole UGT region. Of these markers, the strongest association was detected for an uncommon (MAF&amp;lt;0.03) protective genetic variant rs17863783 (OR=0.55, 95%CI=0.44-0.69, p=3.3x10-7 in 4,035 cases and 5, 284 controls; D’=0.96, r2=0.23 with rs11892031). No residual association in this region was detected after adjustment for rs17863783. Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Conclusions: Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease such as bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1658. doi:1538-7445.AM2012-1658

Lack of Association Between Essential Hypertension and GSTO1 Uncommon Genetic Variants in Italian Patients

Essential hypertension (EH) is a complex phenotype that is affected by multiple genetic and environmental factors. Some authors have explored the role of genetic variability of the glutathione S-transferase (GST) enzymes in EH risk with contrasting results. In particular, our previous study investigated two GSTO common polymorphisms, but we did not find a significant outcome. The aim of this research was to analyze two GSTO1 uncommon variants (E155del and E208K) in 193 EH patients and 210 healthy controls. The genetic association analysis did not find significant outcome between GSTO1 uncommon variants and EH: both single-locus and haplotype investigations did not reach the statistical significance levels. Nevertheless, the correspondence analysis seems to highlight a difference between sexes: female EH patients seem to be more related to E155/del155 and E208/K208 genotypes than male patients. Our studies confirm the lack of association between GSTO1 variants and EH risk, also for two uncommon genetic variants with large functional effects. However, our study highlighted some hypotheses (sex-specific marker, antioxidant function, arsenic metabolism, and modulation of inflammation processes) that might help to clarify the potential role of GSTO1 in EH pathophysiology.

GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: Association hypothesis for an uncommon genetic variant

Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimer's Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P=0.003; adjusted OR=3.70 (1.57–8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1-1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin-1β activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk.

A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients (47.10)

Abstract Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signaling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single-nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines, and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon and other proinflammatory mediators, and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I interferon production and absence of anti-RNA-binding protein antibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral interferon pathway in vivo in humans, and is associated with a novel sub-phenotype in SLE.

A loss‐of‐function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients

Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.

Quantitative studies of the interaction of cholecalciferol ((vitamin D3) and its metabolites with different genetic variants of the serum binding protein for these sterols.

Cholecalciferol (vitamin D3) and its 25-hydroxy metabolite are transported in plasma bound to a specific protein, the binding protein for cholecalciferol and its metabolites (DBP). DBP is identical with the group-specific component (Gc) proteins, which are known to display genetic polymorphism. Studies were conducted to explore whether or not major differences in the transport of cholecalciferol and its biological metabolites might exist among persons with different Gc phenotypes. Detailed quantitative studies were first carried out on the interaction of 25(OH)D3 with DBP in 21 different samples of serum, representing eight different Gc phenotypes. The studies used a filter disc assay method that provided highly reproducible quantitative results with cholecalciferol-related sterols. The Gc phenotypes studied included the three common types (Gc 1-1, 2-1, and 2-2) and several uncommon genetic variants (Gc Ab-Ab, Ab-1, Ab-2, Chip-1, and Chip-2). The binding affinities for 25(OH)D3 observed with these different sera were all fairly similar to each other. More extensive studies were then conducted to compare the binding of four cholecalciferol-related sterols to each of three genetic variants of DBP, by using sera from homozygous persons with the Gc 1-1, Gc 2-2 and Gc Ab-Ab phenotypes. The ligands tested included cholecalciferol, 25(OH)D3, 1,25(OH)2D3, and 24(R) 25(OH)2D3. The affinities of the three genetic types of DBP/Gc protein were found to be similar for each of the four cholecalciferol-related sterols. The apparent association constants for 25(OH)D3 and 24,25(OH)2D3 were similar (approx. 1--2 x 10(8) M-1); lesser affinities were observed for 1,25(OH)2D3 (kA approx. 1 x 10(7) M-1) and for cholecalciferol (kA approx. 3--4 x 10(5) M-1). Thus the common genetic variants of DBP/Gc protein, and the uncommon genetic variants studied here, all appear to have similar binding properties for cholecalciferol and its several metabolites.

Hemoglobin ionographic properties of Peromyscus and other mammals

1. 1. Ten species of Peromyscus collected at various sites from Arizona to Pennsylvania show multiple hemoglobins in eight species and single hemoglobins in two. 2. 2. Eighteen Peromyscus hemoglobins from nine different species show only three different electrophoretic mobilities, and molecular hydridization data suggest that these similarities of charge may extend to subunits of these specific hemoglobins. 3. 3. Ionographic patterns that are characteristic for one species may occur as uncommon genetic variants in another. 4. 4. Electrophoretic mobility and numbers of separable hemoglobins are quite variable among eight additional mammalian species collected while trapping Peromyscus. 5. 5. The five microtine species studied show single hemoglobins of similar mobilities.