Association of <i>TNF-α</i> rs1799964 and <i>IL-1β</i> rs16944 polymorphisms with multiple system atrophy in Chinese Han population

<p><b>Background</b>: Recent evidence suggested that several single nucleotide polymorphisms (SNPs) of inflammation-related genes (<i>TNF-α</i> rs1799964, <i>IL-1α</i> rs1800587, <i>IL-1β</i> rs16944, <i>IL-8</i> rs4073, <i>ICAM-1</i> rs5498) were associated with multiple system atrophy (MSA). Herein, we conducted this case-control study to evaluate the possible correlation between the five SNPs related to inflammation and MSA in Chinese Han population.</p> <p><b>Methods and Patients</b>: We recruited 154 sporadic patients with MSA and 223 health controls in this study. All subjects were genotyped for the five SNPs using polymerase chain reaction amplification and Sanger sequencing.</p> <p><b>Results</b>: <i>TNF-α</i> rs1799964, genotype distribution and minor allele frequency (MAF) showed significant differences between patients and controls, which might illustrate the minor allele C may increase the risk for MSA (genotype, <i>P</i> = 0.006, OR = 1.245, 95% CI = [1.066–1.455]; allele, <i>P</i> = 0.001, OR = 1.887, 95% CI = [1.303–2.733]). For rs16944, patients carrying AA genotype showed a nearly 5-year early age at onset (AAO) than GG genotype (50.52 ± 7.45 years vs. 54.90 ± 7.21 years, <i>P</i> = 0.037). No differences were found in genotype distribution and MAF of the five SNPs between patients with MSA with predominant cerebellar ataxia (MSA-C) and with predominant Parkinsonism (MSA-P).</p> <p><b>Conclusion</b>: Our study suggests that rs1799964 of <i>TNF-α</i> may act as a risk factor for MSA and the <i>IL-1β</i> rs16944 might be a genetic factor that modifies the AAO in MSA. Moreover, the exact mechanism of neuroinflammatory response in MSA deserves further exploration.</p

Targeted Next-Generation Sequencing Revealed Novel Mutations in Chinese Ataxia Telangiectasia Patients: A Precision Medicine Perspective

<div><p>Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency due to mutations in the <i>ATM</i> gene. We performed targeted next-generation sequencing (NGS) on three unrelated patients and identified five disease-causing variants in three probands, including two pairs of heterozygous variants (FAT–1:c.4396C>T/p.R1466X, c.1608-2A>G; FAT–2:c.4412_4413insT/p.L1472Ffs*19, c.8824C>T/p.Q2942X) and one pair of homozygous variants (FAT–3: c.8110T>G/p.C2704G, Hom). With regard to precision medicine for rare genetic diseases, targeted NGS currently enables the rapid and cost-effective identification of causative mutations and is an updated molecular diagnostic tool that merits further optimization. This high-throughput data-based strategy would propel the development of precision diagnostic methods and establish a foundation for precision medicine.</p></div

Pedigrees and putative pathogenic mutations.

<p>Segregation of mutations in FAT–1, FAT–2 and FAT–3 pedigrees was determined by Sanger sequencing (represented by arrows) (A-C). The splicing mutation of FAT–1 pedigree was verified via RT-PCR and Sanger sequencing (A). The conserved protein residues were targeted by the mutations identified in the patients (D).</p

Overview of NGS data production.

<p>Overview of NGS data production.</p

Distribution of the GGGGCC repeats size in SCA3/MJD patients and controls.

<p>There was no significant difference in the distribution of the GGGGCC repeats length between SCA3/MJD patients and controls.</p

Frequencies of C9orf72 genotypes.

<p>A presents the frequencies in SCA3/MJD patients. B presents the frequencies in controls.</p

Demographic information and average number of repeats between SCA3/MJD patients and controls.

<p>^a x ² test.</p><p>^b t-tests.</p><p>^c Mann-Whitney U test.</p><p>Demographic information and average number of repeats between SCA3/MJD patients and controls.</p

Analysis of the GGGGCC Repeat Expansions of the <i>C9orf72</i> Gene in SCA3/MJD Patients from China

<div><p>Neurodegenerative disorders are a heterogeneous group of chronic progressive diseases and have pathological mechanisms in common. A certain causative gene identified for a particular disease may be found to play roles in more than one neurodegenerative disorder. We analyzed the GGGGCC repeat expansions of <i>C9orf72</i> gene in patients with SCA3/MJD from mainland China to determine whether the <i>C9orf72</i> gene plays a role in the pathogenesis of SCA3/MJD. In our study, there were no pathogenic repeats (>30 repeats) detected in either the patients or controls. SCA3/MJD patients with intermediate/intermediate or short/intermediate genotype (short: <7 repeats; intermediate: 7-30 repeats) of the GGGGCC repeats had an earlier onset compared with those with short/short genotype. The presence of the intermediate allele of the GGGGCC repeats in the patients decreased the age at onset by nearly 3 years. Our study firstly demonstrate that the development of SCA3/MJD may involve some physiological functions of the <i>C9orf72</i> gene and provide new evidence to the hypothesis that a specific mutation identified in one of the neurodegenerative disorders may be a modulator in this class of diseases.</p></div

The association of expanded CAG repeats in the expanded <i>ATXN3</i> gene with age at onset (AO) in SCA3/MJD patients.

<p>The X-axis indicates the expanded CAG repeat lengths and the Y-axis denotes AO in years. AO of SCA3/MJD is inversely correlated with the length of CAG repeat (<i>r</i> = －0.694, <i>p</i> = 0.000).</p