Search

Cardiac arrhythmia is currently considered to be the direct cause of death in a majority of sudden unexplained death (SUD) cases, yet the genetic predisposition and corresponding endophenotypes contributing to SUD remain incompletely understood. In this study, we aimed to investigate the involvement of Coenzyme Q (CoQ) deficiency in SUD. First, we re-analyzed the exome sequencing data of 45 SUD and 151 sudden infant death syndrome (SIDS) cases from our previous studies, focusing on previously overlooked genetic variants in 44 human CoQ deficiency-related genes. A considerable proportion of the SUD (38%) and SIDS (37%) cases were found to harbor rare variants with likely functional effects. Subsequent burden testing, including all rare exonic and untranslated region variants identified in our case cohorts, further confirmed the existence of significant genetic burden. Based on the genetic findings, the influence of CoQ deficiency on electrophysiological and morphological properties was further examined in a mouse model. A significantly prolonged PR interval and an increased occurrence of atrioventricular block were observed in the 4-nitrobenzoate induced CoQ deficiency mouse group, suggesting that CoQ deficiency may predispose individuals to sudden death through an increased risk of cardiac arrhythmia. Overall, our findings suggest that CoQ deficiency-related genes should also be considered in the molecular autopsy of SUD. [ABSTRACT FROM AUTHOR]

Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screening strategies. Here, we investigated the genetic substrates of a young SUD cohort (18–40 years old) from China using whole-exome sequencing (WES), with the primary aim to identify novel SUD susceptibility genes. Within 255 previously acknowledged SUD-associated genes, 21 variants with likely functional effects (pathogenic/likely pathogenic) were identified in 51.9% of the SUD cases. More importantly, a set of 33 candidate genes associated with myopathy were identified to be novel susceptibility genes for SUD. Comparative analysis of the cumulative PHRED-scaled CADD score and polygenetic burden score showed that the amount and deleteriousness of variants in the 255 SUD-associated genes and the 33 candidate genes identified by this study were significantly higher compared with 289 randomly selected genes. A significantly higher genetic burden of rare variants (MAF < 0.1%) in the 33 candidate genes also highlighted putative roles of these genes in SUD. After incorporating these novel genes, the genetic testing yields of the current SUD cohort elevated from 51.9 to 66.7%. Our study expands understanding of the genetic variants underlying SUD and presents insights that improve the utility of genetic screenings. [ABSTRACT FROM AUTHOR]

Polymorphic variants of matrix metalloproteinase (MMP) genes were tested for association with breast cancer (BC) in women of the Central Black Earth Region (CBER) of Russia with consideration to whether a patient has or does not have a family history of BC. The study included 358 BC patients (of which 68 had a family history of BC) and 746 control women. Genotyping was performed at ten polymorphic MMP loci: rs1799750 of MMP1; rs243865 of MMP2; rs679620 of MMP3; rs1940475 of MMP8; and rs17576, rs17577, rs3918242, rs2250889, rs3787268, and rs3918249 of MMP9. Logistic regression was performed to assess the associations of the MMP variants with BC in the patient subgroups with or without a family history of BC (the control group was the same for the two subgroups). Low risk of BC in women with a family history of BC was associated with MMP2 rs243865 (OR 0.53–0.54, pperm ≤ 0.03) and MMP9 rs2250889 (OR 0.36–0.37, pperm ≤ 0.04). Higher risk of BC in women without a family history of BC was associated with MMP9 rs3787268 (OR = 2.16, pperm = 0.03) and the following haplotypes at the MMP9 polymorphisms (pperm ≤ 0.05): CA at rs3918249–rs17576 (OR = 2.15), ССА at rs3918242–rs3918249–rs17576 (OR = 1.69), ССAG at rs3918242–rs3918249–rs17576–rs3787268 (OR = 1.69), and CAGCG at rs3918249–rs17576–rs3787268–rs2250889–rs17577 (OR = 3.06). Three haplotypes were associated with a low risk of BC in women without a family history of BC: GG at rs17576–rs3787268 (OR = 0.60), GGC at rs17576–rs3787268–rs2250889 (OR = 0.63), and CGG at rs3918249–rs17576–rs3787268 (OR = 0.62). [ABSTRACT FROM AUTHOR]

There is increasing evidence for the role of rare copy-number variation (CNV) in the development of neuropsychiatric disorders. It is likely that such variants also have an effect on the variation of cognition in what is considered the 'normal' phenotypic range. The role of rare CNV (>20 KB in length; frequency <5 %) on general cognitive ability is investigated in a sample of 800 individuals (mean age = 16.5, SD = 1.2) using copy-number variants called from the Illumina 610K SNP genotyping array with the software QuantiSNP. We assessed three measures of CNV burden-total CNV length, number of CNV and average CNV length-for both deletions and duplications in combination and separately. No correlation was found between any of the measures of CNV burden and IQ, or when comparing the top and bottom 10 % of the sample for IQ, both on a genome-wide scale and at individual positions across the genome. [ABSTRACT FROM AUTHOR]

Demonstration of a direct relationship between plasma triglyceride (TG) concentration and atherosclerosis has proven difficult due to confounding variables that accompany elevated plasma TG, such as other dyslipidemias, obesity, and type 2 diabetes. However, human genetic studies have provided evidence suggesting a causal link between plasma TG and cardiovascular risk. Analyses in human patients with hypertriglyceridemia (HTG) also provides insight into the relationship between genetic variation, predisposition to elevated plasma TG, and risk of subsequent cardiovascular disease. Here, we review recent key studies that have contributed to our understanding of the genetic determinants of plasma TG concentration, including HTG susceptibility and phenotypic heterogeneity, and discuss our maturing model of the allelic and phenotypic spectrum of plasma TG. [ABSTRACT FROM AUTHOR]