The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase ( SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD.

Method

We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products.

Results

A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS).

Conclusion

We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect.

Related collections

Most cited references 18

Record: found
Abstract: found
Article: not found

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.

B Namjou, P H Kothari, J A Kelly … (2011)

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

0 comments Cited 83 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data.

Gregory M Cooper, Jay Shendure (2011)

Genome and exome sequencing yield extensive catalogues of human genetic variation. However, pinpointing the few phenotypically causal variants among the many variants present in human genomes remains a major challenge, particularly for rare and complex traits wherein genetic information alone is often insufficient. Here, we review approaches to estimate the deleteriousness of single nucleotide variants (SNVs), which can be used to prioritize disease-causal variants. We describe recent advances in comparative and functional genomics that enable systematic annotation of both coding and non-coding variants. Application and optimization of these methods will be essential to find the genetic answers that sequencing promises to hide in plain sight.

0 comments Cited 71 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Rare variants in the CYP27B1 gene are associated with multiple sclerosis.

Giulio Disanto, A Sadovnick, Alexandre Montpetit … (2011)

Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering. We performed whole exome sequencing to further understand the heightened prevalence of MS in these families. Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10(-5)). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3-9.4; p = 5 × 10(-7)). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10(-9)). A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated. Copyright © 2011 American Neurological Association.

0 comments Cited 69 times – based on 0 reviews      Review now

All references

Author and article information

Journal

Journal ID (nlm-ta): Eur J Endocrinol

Journal ID (iso-abbrev): Eur. J. Endocrinol

Journal ID (publisher-id): EJE

Title: European Journal of Endocrinology

Publisher: BioScientifica (Bristol )

ISSN (Print): 0804-4643

ISSN (Electronic): 1479-683X

Publication date (Print): December 2012

Publication date (Electronic preprint): 4 September 2012

Volume: 167

Issue: 6

Pages: 825-828

Affiliations

[1 ]Institute of Genetic Medicine International Centre for Life, Newcastle University Central Parkway, Newcastle upon Tyne, NE1 3BZUK

[2 ]Royal Victoria Infirmary Newcastle upon TyneUK

Author notes

(Correspondence should be addressed to E H Gan; Email: earn.gan@ 123456ncl.ac.uk )

Article

Publisher ID: EJE120579

DOI: 10.1530/EJE-12-0579

PMC ID: 3494867

PubMed ID: 23011869

SO-VID: 12a753af-6c7d-4813-9ab6-9c9aa67166d3

License:

This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 4 July 2012

Date accepted : 25 September 2012

Funding

Funded by: EU-Framework-7

Award ID: 201167

Comments

Comment on this article

Cited by 3

See all cited by

Most referenced authors 253

See all reference authors

The flagship journal of the Society for Endocrinology. Learn more