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Clinical Ophthalmology Volume 9, 2015 - Issue
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Original Research

Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves’ ophthalmopathy and Hashimoto’s thyroiditis

Hooshang Lahooti1 Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia;2 Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, AustraliaCorrespondence[email protected]
,
Daniele Cultrone1 Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia;2 Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia
,
Senarath Edirimanne1 Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia;2 Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia
,
John P Walsh3 Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia;4 School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, Australia
,
Leigh Delbridge5 Department of Surgery, Royal North Shore Hospital, The University of Sydney, St Leonards, NSW, Australia;6 Sydney Medical School – Northern Clinical School, The University of Sydney, St Leonards, NSW, Australia
,
Patrick Cregan1 Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia;2 Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia
,
Bernard Champion1 Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia;2 Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia
&
Jack R Wall1 Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia;2 Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia
 show all
Pages 1731-1740 | Published online: 18 Sep 2015

Figures & data

Table 1 Demographic and clinical details of patients with thyroid autoimmunity and control subjects without autoimmune disease

Table 2 Characteristics of four informative polymorphisms identified in CASQ1 gene

Table 3 Genotypes of CASQ1 SNPs: rs74123279, rs3747673, and rs2275703, in patients with autoimmune thyroid disease with and without ophthalmopathy and controls

Table 4 Minor and major alleles distribution of CASQ1 SNPs: rs74123279, rs3838216, rs3747673, and rs2275703, in patients with autoimmune thyroid disease with and without ophthalmopathy and controls

Table 5 Minor and major alleles distribution of CASQ1 SNPs rs74123279, rs3747673, rs2275703 in patients with and without ophthalmopathy

Figure 1 CASQ1 protein concentrations and CASQ1 antibody titer.

Notes: (A) Mean ± standard deviation, CASQ1 protein concentrations in thyroid tissues from patients having rs74123279 SNP with GH (61.56±18.32 pmol/mg), GO (81.44±43.98 pmol/mg) and as normal thyroid, from control patients with multinodular goiter or thyroid cancer (145.6±26.56 pmol/mg) determined from quantitative Western blotting. The difference between GH and controls and GO and controls was highly significant (Mann–Whitney test: *P=0.013 and *P=0.047, respectively). (B) Mean ± standard deviation, CASQ1 antibody titer in serum samples from patients having rs74123279 SNP that thyroid tissues were studied for measurement of CASQ1 protein concentrations with GH (305.1±45.65), GO (370.9±128.8), and as normal thyroid, from control patients with multinodular goiter or thyroid cancer (499.2±49.77) determined by enzyme-linked immunosorbent assay. The difference between GH and Controls was significant (Mann–Whitney test: *P=0.011), and GO and control failed to reach significance (Mann–Whitney test P=0.084).
Abbreviations: CASQ1, calsequestrin; SNP, single-nucleotide polymorphism; GH, Graves’ hyperthyroidism; GO, Graves’ ophthalmopathy; OD, optical density.
Figure 1 CASQ1 protein concentrations and CASQ1 antibody titer.

Figure 2 Correlation between mean (± SE) CASQ1 protein levels and SNP rs74123279 genotype of the CASQ1 gene in patients with GO, GH, which were significant (Mann–Whitney test: **P=0.0023 and *P=0.023) for wild-type homozygote genotypes, respectively, but not for the heterozygote genotypes (Mann–Whitney test: P=NS).

Abbreviations: SE, standard error; CASQ1, calsequestrin; SNP, single-nucleotide polymorphism; GO, Graves’ ophthalmopathy; GH, Graves’ hyperthyroidism; NS, not significant.
Figure 2 Correlation between mean (± SE) CASQ1 protein levels and SNP rs74123279 genotype of the CASQ1 gene in patients with GO, GH, which were significant (Mann–Whitney test: **P=0.0023 and *P=0.023) for wild-type homozygote genotypes, respectively, but not for the heterozygote genotypes (Mann–Whitney test: P=NS).

Figure 3 Correlation between mean (± SE) CASQ1 antibody titer and SNP rs74123279 genotype of the CASQ1 gene in patients with GO, GH, which were significant (Mann–Whitney test: *P=0.023 and *P=0.030) for the wild-type homozygote genotypes, respectively, but not for the heterozygote genotypes (Mann–Whitney test: P=NS).

Abbreviations: SE, standard error; CASQ1, calsequestrin; SNP, single-nucleotide polymorphism; GO, Graves’ ophthalmopathy; GH, Graves’ hyperthyroidism; NS, not significant; OD, optical density.
Figure 3 Correlation between mean (± SE) CASQ1 antibody titer and SNP rs74123279 genotype of the CASQ1 gene in patients with GO, GH, which were significant (Mann–Whitney test: *P=0.023 and *P=0.030) for the wild-type homozygote genotypes, respectively, but not for the heterozygote genotypes (Mann–Whitney test: P=NS).

Figure 4 Concentrations of the CASQ1 protein and serum levels of CASQ1 antibodies titers.

Notes: (A) Mean ± SE (control =166.3±31.8, GO =91.8±42.9, and GH =66.0±17.0 pmol/mg protein) concentrations of the CASQ1 protein in patients and control subject; rs2275703 polymorphism is present in both patients and controls. The mean concentration of CASQ1 was significantly reduced in patients with GH (Mann–Whitney test: **P=0.007) compared with the control subjects. (B) Comparing serum levels of CASQ1 antibodies titers in nine patients with GO and 21 patients with GH with 18 control subjects; rs2275703 polymorphism is present in both patients and controls. Mean ± SE (control =496.4±37.1, GO =346.5±116.2, and GH =297.6±44.3) antibody titers in patients and control subjects. The mean serum CASQ1 antibodies titers was significantly reduced in patients with GO (*P=0.019) and also significantly reduced in patients with GH (**P=0.003)
Abbreviations: SE, standard error; GO, Graves’ ophthalmopathy; GH, Graves’ hyperthyroidism; CASQ1, calsequestrin; OD, optical density.
Figure 4 Concentrations of the CASQ1 protein and serum levels of CASQ1 antibodies titers.

Figure 5 CASQ1 protein levels and heterozygote rs2275703 genotypes polymorphism of CASQ1.

Notes: Correlation between mean (± SE) CASQ1 protein levels and heterozygote rs2275703 genotypes polymorphism of the CASQ1 gene in patients with GO (Mann–Whitney test: *P=0.050), and in GH, this correlation was significant with homozygote genotypes (Mann–Whitney test, *P=0.031) but not significant with the wild-type homozygote genotypes (Mann–Whitney test, P=NS).
Abbreviations: SE, standard error; CASQ1, calsequestrin; GO, Graves’ ophthal-mopathy; GH, Graves’ hyperthyroidism; NS, not significant.
Figure 5 CASQ1 protein levels and heterozygote rs2275703 genotypes polymorphism of CASQ1.

Figure 6 CASQ1 antibody titer and wild-type rs2275703 homozygote genotypes.

Notes: Significant correlation was observed between mean (± SE) CASQ1 antibody titer and wild-type rs2275703 homozygote genotypes, in patients with GH, (Mann–Whitney test: *P=0.028) but not for the heterozygote or rare homozygote genotypes (Mann–Whitney test: P=NS).
Abbreviations: SE, standard error; CASQ1, calsequestrin; GH, Graves’ hyperthy roidism; NS, not significant; WT, wild type; GO, Graves’ ophthalmopathy; OD, optical density.
Figure 6 CASQ1 antibody titer and wild-type rs2275703 homozygote genotypes.

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