Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19, 2022, Huffman et al.

Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19

Jennifer E. Huffman, Guillaume Butler-Laporte, Atlas Khan, Erola Pairo-Castineira, Theodore G. Drivas, Gina M. Peloso, Tomoko Nakanishi, COVID-19 Host Genetics Initiative, Andrea Ganna, Anurag Verma, J. Kenneth Baillie, Krzysztof Kiryluk, J. Brent Richards & Hugo Zeberg

Nature Genetics (2022)


Abstract

The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.

https://www.nature.com/articles/s41588-021-00996-8

Notably, this relates to the RNase-L/2-5A synthetase pathway, which was discussed in the ME/CFS literature around 10-20 years ago.

https://en.wikipedia.org/wiki/OAS1

 

Whoa!

 

Diagnostic evaluation of 2’, 5’-oligoadenylate synthetase activities and antibodies against Epstein–Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan

https://sci-hub.se/10.1016/j.micinf.2003.07.002

which uses Holmes 1988 definition. See: Chronic fatigue syndrome: a working case definition

https://pubmed.ncbi.nlm.nih.gov/2829679/

from which:

"We propose a new name for the chronic Epstein-Barr virus syndrome--the chronic fatigue syndrome--that more accurately describes this symptom complex as a syndrome of unknown cause characterized primarily by chronic fatigue."

Also using Holmes:

Serum concentrations of 2',5'-oligoadenylate synthetase, neopterin, and beta-glucan in patients with chronic fatigue syndrome and in patients with major depression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1073106/?page=1

Using Holmes > CDC 1994

Characterization of a 2′,5′-Oligoadenylate (2–5A)-dependent 37-kDa RNase L

https://www.jbc.org/article/S0021-9258(20)78367-5/fulltext#

author = Robert Suhadonik one time Peterson collaborator and incindentally a partner in Kenny De Meirlier's R.E.D labs

A review article

Impairments of the 2-5A Synthetase/RNase L Pathway in Chronic Fatigue Syndrome

https://iv.iiarjournals.org/content/invivo/19/6/1013.full.pdf

authors = Nijs & De Meilier


I think this is one of those typical dog chasing tail series or articles where poor case definition and lower powered research goes around in circles looking like something is happening.

 

How about this one? @CRG

Biochemical Evidence for a Novel Low Molecular Weight 2-5A-Dependent RNase L in Chronic Fatigue Syndrome

 

https://sci-hub.se/10.1089/jir.1997.17.377

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 17:377-385 (1997)

Suhadolnik et al

Just 10 patients/10 controls. Lots of chemistry, it was 25 years ago, probably seemed quite exciting at the time. This is probably the most revealing part of the text. My bold(s):

Several possible biochemical mechanisms can be proposed to account for the presence of the LMW (30 kDa) RNase L and absence of the 80-kDa and 42-kDa RNase L in CFS. First, the
LMW RNase L may be the result of proteolytic degradation of the 80 or 42 kDa 2-5A-dependent-RNase L by a cellular or virus-encoded protease. Numerous proteases have been demon¬
strated to have functional impact in normal and virus-infected cells. For example, PKR is hydrolyzed by a protease encoded by the poliovirus genome/17 uá references ß ' CFS PBMC ex¬
tracts prepared in the presence and absence of protease in hibitors show a 37-kDa immunoreactive 2-5A-dependent RNase L that does not arise from protease-mediated degrada¬
tion of the 80-kDa RNase L at the time of PBMC extract preparation and processing (Fig. 4, lanes 1 and 2). In addition, no protease-mediated degradation of the 37-kDa RNase L was ev¬
ident at the time of extract preparation and processing.

A second possible mechanism is that the LMW 2-5A- dependent RNase L in CFS is regulated by 2-5A in a manner distinct from the 80-kDa and 42-kDa forms of RNase L. The
upregulated RNase L activity observed in CFS PBMC extracts (as determined by ribosomal RNA cleavage assay) might be due solely to the LMW RNase L, particularly in view of the obser¬
vation that Jhe LMW RNase L is the only immunoreactive 2-5A binding protein detected in some PBMC extracts (Fig. 2, lanes 6-9, Fig. 3C, F). This laboratory has reported previously
that PBMC extracts from individuals with CFS have elevated levels of bioactive 2-5A/14·15' The 2-5A molecule may preferentially activate the LMW protein over the 80-kDa and 42-kDa
forms of RNase L. Steady-state kinetics and changes in Km with catalysis of the 2-5A-activated 80-kDa RNase L ligand have been quantitated by precise cleavage of oligoribonucleotide sub¬
strates containing known dyad sequences/34' Kinetic characterization and amino acid sequencing of the LMW RNase L observed in CFS PBMC extracts is under way in this laboratory.

A third possibility is that regulation of the LMW 2-5A-dependent RNase L enzyme activity may require protein-protein interactions with the 80-kDa or 42-kDa RNase L (or both).
In the absence of the 80-kDa and 42-kDa isoforms, the LMW RNase L may be unregulated. A loss of regulation of RNase L could result in a constitutively active LMW RNase L. The re¬
sulting continuous turnover of cellular RNA might contribute to the marked decrease in ATP pools that has been observed in CFS/35' It is also possible that the recently identified RNase L
inhibitor (RLI) may be involved in the regulation of RNase L in CFS/19·30·31' RLI is a negative regulator of RNase L that functions by inhibiting the binding of the allosteric activator,
2-5A, to RNase L. The role of RLI in regulation of the LMW RNase L in CFS remains to be established.

The biochemical and immunologie data presented here have identified a potential subgroup of individuals with CFS with an RNase L enzyme dysfunction that is more profound than pre¬
viously observed. CFS, as currently defined, may well represent a heterogeneous group of disorders. No unifying patho-physiology for CFS has been established. Analysis of the
clinical status of the individuals with CFS in this study failed to reveal any subgroup variables to account for the RNase L enzyme dysfunction, including circulating IFN level, type of
onset (acute vs. gradual), and length of illness. Expanded studies are underway to determine if the results presented in this study are representative of all patients with CFS and if these
findings can distinguish individuals with CFS from those with clinically similar illnesses. Longitudinal studies also are underway in this laboratory to establish if the RNase L enzyme
dysfunction observed in CFS is characteristic of a particular stage in the course of the illness or if the dysfunction fluctuates with time.