Identification of Atrial Fibrillation Risk Variant RS2200733 In Indian Young Adult Population

Atrial fibrillation (AF) is a common cardiac arrhythmia that affects millions of people. a substantial genetic contribution to AF has been identified by number of studies over the years. The SNP that is often linked with genetic predisposition to AF is rs2200733 located in the intergenic region close to PITX2 gene which is implicated in cardiac structure and function. rs2200733 is commonly observed in major global populations. Our study aimed to establish the prevalence of this important SNP among young healthy adults in order to assess the risk of genetic susceptibility which could culminate into AF later in life. The study identified a substantial frequency of rs2200733 in Indian population at 21%.

Atrial fibrillation and left atrial size and function: a Mendelian randomization study

Atrial fibrillation (AF) patients have enlarged left atria (LA), but prior studies suggested enlarged atria as both cause and consequence of AF. The aim of this study is to investigate the causal association between AF and LA size and function. In the UK Biobank, all individuals with contoured cardiovascular magnetic resonance data were selected. LA maximal volume (LA max), LA minimal volume (LA min), LA stroke volume and LA ejection fraction were measured and indexed to body surface area (BSA). Two-sample Mendelian randomization analyses were performed using 84 of the known genetic variants associated with AF to assess the association with all LA size and function in individuals without prevalent AF. A total of 4274 individuals (mean age 62.0 ± 7.5 years, 53.2% women) were included. Mendelian randomization analyses estimated a causal effect between genetically determined AF and BSA-indexed LA max, LA min, and LA ejection fraction, but not between AF and LA stroke volume. Leave-one-out analyses showed that the causal associations were attenuated after exclusion of rs67249485, located near PITX2 gene. Our results suggest that AF causally increases LA size and decreases LA ejection fraction. The AF risk allele of rs67249485, located near the PITX2 gene, contributes strongly to these associations.

Chronological Expression of PITX2 and SIX1 Genes and the Association between Their Polymorphisms and Chicken Meat Quality Traits

Meat quality is closely related to the development of skeletal muscle, in which PITX2 and SIX1 genes play important regulatory roles. The present study firstly provided the data of chronological expression files of PITX2 and SIX1 genes in the post-hatching pectoral muscle and analyzed the association of their polymorphisms with the meat quality traits of Wuliang Mountain Black-bone (WLMB) chickens. The results showed that both PITX2 and SIX1 genes were weakly expressed in the second and third weeks, and then increased significantly from the third week to the fourth week. Furthermore, there was a significant positive correlation between the expression levels of the two genes. Twelve and one SNPs were detected in the chicken PITX2 and SIX1 genes, respectively, of which four SNPs (g.9830C > T, g.10073C > T, g.13335G > A, g.13726A > G) of the PITX2 gene and one SNP (g.564G > A) of the SIX1 gene were significantly associated with chicken meat quality traits. For the PITX2 gene, chickens with the CT genotype of g.9830C > T showed the highest meat color L*, shear force (SF), pH, and the lowest electrical conductivity (EC), and drip loss (DL) (p < 0.05 or p < 0.01); chickens with the CC genotype of g.10073C > T had the lowest L*, pH, and the highest DL (p < 0.01). For the SIX1 gene, chickens with the GG genotype of g.564G > A had the highest (p < 0.05) SF and pH. Furthermore, pH had a significant correlation with all the other meat quality traits. The current study could contribute to the research of regulatory mechanisms of meat quality and lay the foundation for improving meat quality based on marker-assisted selection in chickens.

Expression Analysis of the PITX2 Gene and Associations between Its Polymorphisms and Body Size and Carcass Traits in Chickens

PITX2 is expressed in and plays an important role in myocytes of mice, and it has effects on late myogenic differentiation in chickens. However, the expression profile and polymorphisms of PITX2 remain unclear in chickens. Therefore, the aim of the present study was to detect its expression and investigate single nucleotide polymorphisms (SNPs) within its exons and then to evaluate whether these polymorphisms affect body size as well as carcass traits in chickens. The expression analysis showed that the expression level of chicken PITX2 mRNA in the leg muscle and hypophysis was significantly higher (p < 0.01) than those in other tissues. The results of polymorphisms analysis identified two SNPs (i.e., g.9830C > T and g.10073C > T) in exon 1 and 10 SNPs (i.e., g.12713C > T, g.12755C > T, g.12938G > A, g. 3164C > T, g.13019G > A, g.13079G > A, g.13285G > A, g.13335G > A, g.13726A > G and g.13856C > T) in exon 3, including four novel SNPs (i.e., g.9830C > T, g.12713C > T, g.12938G > A and g.13856C > T). In the loci of g.10073C > T and g.12713C > T, chickens with the CT genotype had the highest (p < 0.05 or p < 0.01) breast depth and breast angle, respectively. For the locus of g.13335G > A, chickens with the GG genotype had the highest (p < 0.05 or p < 0.01) breast angle and shank circumference. For the locus of g.13726A > G, chickens with the GG genotype had the highest breast width, fossil keel bone length and shank circumference. The locus of g.12713A > G had significant effects on the PITX2 mRNA expression level in leg muscle. The H1H7 diplotype showed the highest shank circumference, and the H2H8 diplotype showed the highest breast muscle rate. The present research suggested that polymorphisms of the exons of the PITX2 gene were significantly associated with the body size and carcass traits of Wuliang Mountain Black-bone chickens and the PITX2 gene could be a potential candidate gene for molecular marker-aided selection in Wuliang Mountain Black-bone chickens and other chicken breeds.

Novel PITX2 Mutations including a Mutation Causing an Unusual Ophthalmic Phenotype of Axenfeld-Rieger Syndrome

Purpose. The aims of this study were to examine novel mutations in PITX2 and FOXC1 in Chinese patients with anterior segment dysgenesis (ASD) and to compare the clinical presentations of these mutations with previously reported associated phenotypes. Methods. Twenty-six unrelated patients with different forms of ASD were enrolled from our paediatric and genetic eye clinic. The ocular manifestations of both eyes of each patient were recorded. Genomic DNA was prepared from venous leukocytes. All coding exons of PITX2 and FOXC1 were amplified by polymerase chain reaction (PCR) from genomic DNA and subjected to direct DNA sequencing. Analysis of mutations in control subjects was performed by heteroduplex single-strand conformation polymorphism (SSCP) analysis. Results. Sequence analysis of the PITX2 gene revealed four mutations, including c.475_476delCT (P.L159VfsX39), c.64C > T (P.Q22X), c.296delG (P.R99PfsX56), and c.206G > A (P.R69H). The first three mutations were found to be novel. The c.475_476delCT (P.L159VfsX39) mutation, located at the 3′ end of the PITX2-coding region, was identified in a Chinese Axenfeld-Rieger syndrome (ARS) patient who presented with an unusual severe phenotype of bilateral aniridia. The clinical characteristics, including the severity and manifestations of the patient’s phenotype, were compared with reported PITX2-associated aniridia phenotypes of ARS in the literature. Conclusions. These results expand the mutation spectrum of the PITX2 gene in patients with ARS. The PITX2 gene may be responsible for a significant portion of ARS with additional systemic defects in the Chinese population. This is the first reported case of a mutation at the 3′ end of the PITX2-coding region extending the phenotypic consequences to bilateral aniridia. The traits of ARS could display tremendous variability in severity and manifestations due to the dominant-negative effect of PITX2. Our results further emphasize the importance of careful clinical and genetic analysis in determining mutation-disease associations and may lead to a better understanding of the role of PITX2 in ocular development.