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  • 1
    Online Resource
    Online Resource
    Fine-Mapping Array Design for Multi-Ethnic Studies of Multiple Sclerosis
    MDPI AG ; 2019
    In:  Genes Vol. 10, No. 11 ( 2019-11-07), p. 903-
    Details
    In: Genes, MDPI AG, Vol. 10, No. 11 ( 2019-11-07), p. 903-
    Abstract: While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge gained from replication efforts in Hispanic and African American populations can be utilized to more efficiently fine-map these risk loci. To this end, we have customized a genotyping array by adding ~20,000 bead types (~17,000 variants) to the base content of the Ilumina Infinium expanded multi-ethnic genotyping array and the Infinium ImmunoArray-24 v2 BeadChip. These custom bead types were chosen to allow for the detection of causal variation (1) in the presence of allelic and locus heterogeneity, by incorporating regulatory and coding variation within 1-Mb of previously identified risk variants and (2) in the absence of allelic and locus heterogeneity by incorporation of variants using linkage disequilibrium criteria, which are based on knowledge of replication status in Hispanic and African American study samples. This array has been designed to maximize fine-mapping potential for currently identified MS susceptibility loci, particularly in multi-ethnic populations. The strategies described here could be additionally informative for fine-mapping of other disease phenotypes.
    Type of Medium: Online Resource
    ISSN: 2073-4425
    URL: Article
    DOI: 10.3390/genes10110903
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527218-4
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  • 2
    Online Resource
    Online Resource
    Identification of Host Factors Associated with the Development of Equine Herpesvirus Myeloencephalopathy by Transcriptomic Analysis of Peripheral Blood Mononuclear Cells from Horses
    MDPI AG ; 2021
    In:  Viruses Vol. 13, No. 3 ( 2021-02-24), p. 356-
    Details
    In: Viruses, MDPI AG, Vol. 13, No. 3 ( 2021-02-24), p. 356-
    Abstract: Equine herpesvirus-1 is the cause of respiratory disease, abortion, and equine herpesvirus myeloencephalopathy (EHM) in horses worldwide. EHM affects as many as 14% of infected horses and a cell-associated viremia is thought to be central for EHM pathogenesis. While EHM is infrequent in younger horses, up to 70% of aged horses develop EHM. The aging immune system likely contributes to EHM pathogenesis; however, little is known about the host factors associated with clinical EHM. Here, we used the “old mare model” to induce EHM following EHV-1 infection. Peripheral blood mononuclear cells (PBMCs) of horses prior to infection and during viremia were collected and RNA sequencing with differential gene expression was used to compare the transcriptome of horses that did (EHM group) and did not (non-EHM group) develop clinical EHM. Interestingly, horses exhibiting EHM did not show respiratory disease, while non-EHM horses showed significant respiratory disease starting on day 2 post infection. Multiple immune pathways differed in EHM horses in response to EHV-1. These included an upregulation of IL-6 gene expression, a dysregulation of T-cell activation through AP-1 and responses skewed towards a T-helper 2 phenotype. Further, a dysregulation of coagulation and an upregulation of elements in the progesterone response were observed in EHM horses.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v13030356
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2516098-9
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  • 3
    Online Resource
    Online Resource
    Plasma Protein Levels Analysis in Multiple Sclerosis Sardinian Families Identified C9 and CYP24A1 as Candidate Biomarkers
    MDPI AG ; 2022
    In:  Life Vol. 12, No. 2 ( 2022-01-20), p. 151-
    Details
    In: Life, MDPI AG, Vol. 12, No. 2 ( 2022-01-20), p. 151-
    Abstract: Here we investigate protein levels in 69 multiple sclerosis (MS) cases and 143 healthy controls (HC) from twenty Sardinian families to search for promising biomarkers in plasma. Using antibody suspension bead array technology, the plasma levels of 56 MS-related proteins were obtained. Differences between MS cases and HC were estimated using Linear Mixed Models or Linear Quantile Mixed Models. The proportion of proteins level variability, explained by a set of 119 MS-risk SNPs as to the literature, was also quantified. Higher plasma C9 and CYP24A1 levels were found in MS cases compared to HC (p 〈 0.05 after Holm multiple testing correction), with protein level differences estimated as, respectively, 0.53 (95% CI: 0.25, 0.81) and 0.42 (95% CI: 0.19, 0.65) times plasma level standard deviation measured in HC. Furthermore, C9 resulted in both statistically significantly higher relapsing-remitting MS (RRMS) and secondary-progressive MS (SPMS) compared to HC, with SPMS showing the highest differences. Instead, CYP24A1 was statistically significantly higher only in RRMS as compared to HC. Respectively, 26% (95% CI: 10%, 44%) and 16% (95% CI: 9%, 39%) of CYP24A1 and C9 plasma level variability was explained by known MS-risk SNPs. Our results highlight C9 and CYP24A1 as potential biomarkers in plasma for MS and allow us to gain insight into molecular disease mechanisms.
    Type of Medium: Online Resource
    ISSN: 2075-1729
    URL: Article
    DOI: 10.3390/life12020151
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662250-6
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  • 4
    Online Resource
    Online Resource
    Homozygosity Haplotype and Whole-Exome Sequencing Analysis to Identify Potentially Functional Rare Variants Involved in Multiple Sclerosis among Sardinian Families
    MDPI AG ; 2021
    In:  Current Issues in Molecular Biology Vol. 43, No. 3 ( 2021-10-27), p. 1778-1793
    Details
    In: Current Issues in Molecular Biology, MDPI AG, Vol. 43, No. 3 ( 2021-10-27), p. 1778-1793
    Abstract: Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex- and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a non-parametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T 〉 G) in the splicing region on exon 27 of CUL9; (ii) a variant (50245517 A 〉 C) in the splicing region on exon 16 of ATP9A; (iii) a non-synonymous variant (43223539 A 〉 C), on exon 9 of TTBK1; (iv) a non-synonymous variant (42976917 A 〉 C) on exon 9 of PPP2R5D; and v) a variant (109859349-109859354) in 3′UTR of MYO16.
    Type of Medium: Online Resource
    ISSN: 1467-3045
    URL: Article
    DOI: 10.3390/cimb43030125
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2090836-2
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Heritability Estimation of Multiple Sclerosis Related Plasma Protein Levels in Sardinian Families with Immunochip Genotyping Data
    MDPI AG ; 2022
    In:  Life Vol. 12, No. 7 ( 2022-07-21), p. 1101-
    Details
    In: Life, MDPI AG, Vol. 12, No. 7 ( 2022-07-21), p. 1101-
    Abstract: This work aimed at estimating narrow-sense heritability, defined as the proportion of the phenotypic variance explained by the sum of additive genetic effects, via Haseman–Elston regression for a subset of 56 plasma protein levels related to Multiple Sclerosis (MS). These were measured in 212 related individuals (with 69 MS cases and 143 healthy controls) obtained from 20 Sardinian families with MS history. Using pedigree information, we found seven statistically significant heritable plasma protein levels (after multiple testing correction), i.e., Gc (h2 = 0.77; 95%CI: 0.36, 1.00), Plat (h2 = 0.70; 95%CI: 0.27, 0.95), Anxa1 (h2 = 0.68; 95%CI: 0.27, 1.00), Sod1 (h2 = 0.58; 95%CI: 0.18, 0.96), Irf8 (h2 = 0.56; 95%CI: 0.19, 0.99), Ptger4 (h2 = 0.45; 95%CI: 0.10, 0.96), and Fadd (h2 = 0.41; 95%CI: 0.06, 0.84). A subsequent analysis was performed on these statistically significant heritable plasma protein levels employing Immunochip genotyping data obtained in 155 healthy controls (92 related and 63 unrelated); we found a meaningful proportion of heritable plasma protein levels’ variability explained by a small set of SNPs. Overall, the results obtained, for these seven MS-related proteins, emphasized a high additive genetic variance component explaining plasma levels’ variability.
    Type of Medium: Online Resource
    ISSN: 2075-1729
    URL: Article
    DOI: 10.3390/life12071101
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662250-6
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