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

Lahooti H, Cultrone D, Edirimanne S, Walsh JP, Delbridge L, Cregan P, Champion B, Wall JR - Clin Ophthalmol (2015)

Bottom Line: The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients.Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008.Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

View Article: PubMed Central - PubMed

Affiliation: Thyroid Research Laboratory, Sydney Medical School - Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia ; Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia.

ABSTRACT

Background: The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703.

Methods: High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM.

Results: DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008.

Conclusion: Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

No MeSH data available.


Related in: MedlinePlus

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.
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f4-opth-9-1731: 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.

Mentions: The functional significance of rs2275703 was also studied by measuring CASQ1 protein concentration in thyroid tissues from 21 patients with GH and 9 with GO and in 22 control subjects with nodular goiter or cancer. All these patients and control had rs2275703 polymorphism. Results are summarized in Figure 4A showing mean concentration of CASQ1 protein was significantly reduced in patients with GH (Mann–Whitney test: **P=0.007) compared with the control subjects. Figure 4B showed mean serum CASQ1 antibodies’ titers were significantly reduced in patients with GO (*P=0.019) and in patients with GH (**P=0.003). Figure 5 shows 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 for wild-type homozygote genotypes. Figure 6 shows significant correlation 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.


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

Lahooti H, Cultrone D, Edirimanne S, Walsh JP, Delbridge L, Cregan P, Champion B, Wall JR - Clin Ophthalmol (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590686&req=5

f4-opth-9-1731: 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.
Mentions: The functional significance of rs2275703 was also studied by measuring CASQ1 protein concentration in thyroid tissues from 21 patients with GH and 9 with GO and in 22 control subjects with nodular goiter or cancer. All these patients and control had rs2275703 polymorphism. Results are summarized in Figure 4A showing mean concentration of CASQ1 protein was significantly reduced in patients with GH (Mann–Whitney test: **P=0.007) compared with the control subjects. Figure 4B showed mean serum CASQ1 antibodies’ titers were significantly reduced in patients with GO (*P=0.019) and in patients with GH (**P=0.003). Figure 5 shows 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 for wild-type homozygote genotypes. Figure 6 shows significant correlation 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.

Bottom Line: The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients.Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008.Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

View Article: PubMed Central - PubMed

Affiliation: Thyroid Research Laboratory, Sydney Medical School - Nepean Clinical School, The University of Sydney, Kingswood, NSW, Australia ; Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, Australia.

ABSTRACT

Background: The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703.

Methods: High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM.

Results: DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008.

Conclusion: Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

No MeSH data available.


Related in: MedlinePlus