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At least 829 records · Page 46Linked to original sources
PubMed2003

Genetic mutation associated with meiotic metaphase-specific apoptosis in MRL/MpJ mice.

It has been reported that the MRL/MpJ mouse strain shows several unique phenotypes, including rapid wound healing, inherent collagen disease, heat shock-resistant spermatocytes, and metaphase-specific apoptosis (Msa) in the testis. In the present study, we found the genetic mutation associated with Msa by chromosomal mapping with 555 backcross progeny. The Sertoli cell index of abnormal metaphasic spermatocytes was clearly divided into two groups in the first 200 male backcross progeny, which were created by mating female F1 (female C57BL/6 x male MRL/MpJ) with male MRL/MpJ mice, indicating that Msa was caused by only one gene. The result of chromosomal mapping throughout the 555 backcross progeny by using microsatellite markers and single nucleotide polymorphism (SNP) revealed that Msa was mapped on the telomeric region of chromosome 1 and was significantly linked with exonuclease 1 (Exo1) and choroideremia-like (rab escort protein 2) (Chml/Rep2) genes. It was found that the Chml/Rep2 gene was not a candidate for Msa by means of the nucleotide sequences of several inbred strains. On the Exo1 gene in strain MRL/MpJ, but not in other strains, it was surprisingly noted that the truncated forms (tr1-Exo1 and tr2-Exo1) were expressed in all tissues examined as well as normal Exo1 by reverse transcriptase-polymerase chain reaction (RT-PCR). Additionally, the truncated forms of the Exo1 gene were suggested to be transcribed by alternative splicing of the 9th exon, possibly resulting from nucleotide substitution of the branch site existing in the 8th intron. These results suggested that the testicular meiotic Msa in MRL/MpJ mice was a unique phenotype caused by incomplete alternative splicing of the Exo1 gene.

Animals↗
PubMed2004

The dysbindin gene in major depression: an association study.

The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results.

Adult↗
PubMed2004

Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene.

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL ( Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.

Amino Acid Sequence↗
PubMed2004

Sodium nitroprusside and peroxynitrite effect on hepatic DNases: an in vitro and in vivo study.

BACKGROUND: It has been documented that nitric oxide (NO) donor sodium nitroprusside (SNP) and authentic peroxynitrite are capable of promoting apoptosis in a number of different cell types. Various endonucleases have been proposed as candidates responsible for the internucleosomal cleavage of the genomic DNA observed during apoptosis, but the main effect is attributed to the alkaline-DNases (Mg2+- and caspase-dependent) and acid-DNase. The aim of this study was to examine an in vivo and in vitro possibility for alkaline- and acid-DNases to be activated by SNP and peroxynitrite. RESULTS: The effect on liver tissue alkaline and acid DNase activity together with the markers of tissue and plasma oxidative and nitrosative stress (lipid peroxidation, SH group content, carbonyl groups and nitrotyrosine formation) was investigated in plasma and liver tissue. The activity of liver alkaline DNase increased and that of acid DNase decreased after in vivo treatment with either SNP or peroxynitrite. A difference observed between the in vivo and in vitro effect of oxide donor (i.e., SNP) or peroxynitrite upon alkaline DNase activity existed, and it may be due to the existence of the "inducible" endonuclease. After a spectrophotometric scan analysis of purified DNA, it was documented that both SNP and peroxynitrite induce various DNA modifications (nitroguanine formation being the most important one) whereas DNA fragmentation was not significantly increased. CONCLUSION: Alkaline DNase activation seems to be associated with the programmed destruction of the genome, leading to the fragmentation of damaged DNA sites. Thus, the elimination of damaged cells appears to be a likely factor in prevention against mutation and carcinogenesis.

Journal Article↗
PubMed2006

Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping.

We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genome-wide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a "validation" set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a "field" set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a "test" set of 57 probands from breast cancer kindreds (4 or more cases/kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the "validation" set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the "field" set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the "test" set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design.

Adult↗
PubMed2005

Leptin promoter mutations affect leptin levels and performance traits in dairy cows.

Leptin concentrations in body fluids and tissues undergo dynamic changes during the periparturient period. Polymorphisms in the leptin gene have been shown to be associated with differences in leptin concentration during late pregnancy but not during lactation. As the promoter of leptin regulates the expression of leptin, polymorphisms in this region could play an important role in the differences in leptin expression observed during the periparturient period. We sequenced the leptin promoter and discovered 20 SNP in a 1.6-kbp region of the bovine leptin promoter. Fourteen of these SNP were genotyped for all animals and these were found to be associated with leptin concentrations during late pregnancy but not during lactation. Three of these SNP are located in a 135-bp promoter region and together explained 14.3% of the variance in prepartum leptin concentrations which indicates that this region might be important for pregnancy-induced leptin synthesis. In the association study of the 14 SNP with dairy traits three were separately found to be associated with fertility, energy balance and protein yield. These might serve as markers for future breeding programmes for better fertility and energy balance without significantly influencing milk yield in dairy cattle.

Animals↗
PubMed2006

Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study.

OBJECTIVE: The FBXO11 gene is the human homologue of the gene mutated in the novel deaf mouse mutant jeff (Jf), a single gene model of otitis media. We have evaluated single nucleotide polymorphisms (SNPs) in the FBXO11 gene for association with chronic otitis media with effusion/recurrent otitis media (COME/ROM). DESIGN: A total of 13 SNPs were genotyped across the 98.7 kilobases of genomic DNA encompassing FBXO11. Data were analyzed for single SNP association using generalized estimating equations, and haplotypes were evaluated using Pedigree Disequilibrium Test methods. PATIENTS: The Minnesota COME/ROM Family Study, a group of 142 families (619 subjects) with multiple affected individuals with COME/ROM. MAIN OUTCOME MEASURES: Genetic association of COME/ROM with polymorphisms in FBXO11. RESULTS: The FBXO11 SNPs are contained in a single linkage disequilibrium haplotype block. Ten of the 13 SNPs were sufficiently polymorphic in the sample to permit analysis. In univariate genetic analysis, 1 reference SNP (hereinafter rs) (rs2134056) showed nominal evidence of association to COME/ROM (P = .02), and 2 SNPs approached significance (rs2020911, P = .06; rs3136367, P = .09). In multivariable analyses, including known risk factors for COME/ROM (sex, exposure to smoking, attending day care centers, no prior breastfeeding, and having allergies), the evidence of independent association was reduced for each SNP (eg, rs2134056, from P = .02 to P = .08). In subsequent analyses using the Pedigree Disequilibrium Test, the association of FBXO11 SNP rs2134056 (P = .06) with COME/ROM was confirmed. Incorporating multiple SNPs in 2- and 3-locus SNP haplotypes, those haplotypes containing rs2134056 also exhibited evidence of association of FBXO11 and COME/ROM (P values ranging from .03 to .10). CONCLUSION: We have observed evidence consistent with an association between polymorphisms in FBXO11, the human homologue of the Jeff mouse model gene, and COME/ROM.

Animals↗
PubMed2005

Association between equine temperament and polymorphisms in dopamine D4 receptor gene.

The variable number of tandem repeats (VNTR) polymorphism of the dopamine D4 receptor (DRD4) gene has been reported to be associated with the personality trait of novelty-seeking in humans. In the genus Equus, this region includes an 18-bp repeat unit and there are inter- and intraspecies differences in the number of repetitions. Because horses are unique among livestock species in that their temperament is considered important, we investigated the possible role of this region on equine temperament in thoroughbred horses. We simultaneously determined the sequences of this polymorphic region and administered a questionnaire survey to horse caretakers with questions about 20 different traits of their horses' temperament. Although there was no difference in the number of repeats among the 136 thoroughbred horses studied, two single nucleotide polymorphisms (SNPs), one of which might cause an amino acid change (A-G substitution), existed. By analyzing the association between these SNPs and temperament scores, a significant association was revealed between two temperament traits (Curiosity and Vigilance) and the A-G substitution. Horses without the A allele had significantly higher Curiosity and lower Vigilance scores than those with the A allele at the A-G substitution. In addition, similar associations between both temperament scores and each genotype of the A-G substitution were observed in two subgroups divided according to the time of their introduction to the farm. These results suggested that the SNP in the VNTR region of the equine DRD4 gene might be related to individual differences in equine temperament.

Animals↗
PubMed2005

Dominantly inherited cutaneous small-vessel lymphocytic vasculitis maps to chromosome 6q26-q27.

Outside the context of hereditary deficiencies of complement and IgA, Mendelian inherited predisposition to small vessel lymphocytic vasculitis (SVLV) has rarely been documented. Here we report a large, multigenerational family segregating symmetrical cutaneous SVLV affecting the cheeks, thighs and hands. In all affected family members the disease presented in early infancy and there was no evidence for an association with systemic disease. Skin biopsy of lesions showed a lymphocytic vasculitis with red blood cell extravasation. Complementary studies, with extensive investigation focused on dysfunction of the immunological system were negative. The pattern of inheritance of SVLV in the family was compatible with an autosomal dominantly acting disease gene with incomplete penetrance. To localize the disease causing gene in the family a genome-wide linkage search was conducted using a high-density SNP array. Haplotype construction and analysis of recombination events permitted the minimal interval defining the disease locus to be refined to a 4.7 Mb region on chromosome 6q26-q27. The genes CCR6 and GPR31, which map to the linked region represent plausible candidates for the disease on the basis of their biological function. Extensive screening of both genes by mutational analysis failed to identify a deleterious mutation in the family.

Chromosome Mapping↗
PubMed2005

IL-12 and IL-10 polymorphisms and their effects on cytokine production.

Interleukin (IL)-12 is an inducer of differentiation of T helper (Th) cells towards Th1, whereas IL-10 is mainly an anti-inflammatory cytokine inhibiting Th1 functions. Single nucleotide polymorphisms (SNPs) in the regulatory sequences of genes are presumed to be associated with the differential production of cytokines. One IL12B 3'untranslated region (UTR) and five of IL10 gene promoter region SNPs were screened in 152 individuals by genotyping. IL-10 and IL-12 secretion of lipopolysaccharide (LPS), purified protein derivative (PPD) and Staphylococcus aureus Cowan strain I (SAC) stimulated peripheral blood mononuclear cells (PBMCs) was determined. The frequencies of the less frequent IL12B +16974 C, IL10 -2763 A -3575 A, -1082 G, -819 T and -592 A alleles were 27.4, 32.2, 25.9, 14.8, 9.3 and 8.6%, respectively. Individuals CC homozygous at IL12B 3'UTR had significantly higher IL-12 secretion levels from LPS and PPD stimulated PBMCs than AC heterozygotes (P = 0.03 and P = 0.02) or AA homozygotes (P = 0.02 and P = 0.05, respectively). IL10 -2763 and -3575 SNPs did not show any effect on in vitro secretion levels, whereas the association of proximal promoter -1082 SNP with IL-10 production is confirmed. IL10 proximal and distal promoter SNP distribution with estimated haplotype variations has implicated considerable similarities with the Caucasian populations in Turkey.

3' Untranslated Regions↗
PubMed2006

Variable SNP density in aspartyl-protease genes of the malaria parasite Plasmodium falciparum.

An analysis of the diversity of the aspartyl proteases of Plasmodium falciparum, known as plasmepsins (PMs), was completed in view of their possible role as drug targets. DNA sequence polymorphisms were identified in nine pm genes including their non-coding (introns and 5' flanking) sequences. All genes contained at least one single nucleotide polymorphism (SNP). Extensive microsatellite diversity was observed predominantly in non-coding sequences. All but one non-synonymous polymorphism (a conservative substitution) were mapped to the surface of the predicted protein, contradicting a possible role in enzymatic activity. The distribution of SNPs was found to be non-random among pm genes, with pm6 and pm10 having significantly higher SNP densities, suggesting they were under selection. For pm6 the majority of the SNPs were in introns and some of these may contribute to splice site variation. SNPs were found at a high density in both the coding and non-coding sequences of pm10. Recombination was important in generating additional diversity at this locus. Although direct selection for pm10 mutations could not be ruled out, the presence of balancing selection and a high density of SNPs in non-coding sequence led us to propose that another gene under selection may be influencing the diversity in the region. By sequencing short DNA tags in a 200 kb region flanking pm10 we show that a cluster of antigen genes, known to be under diversifying selection, may contribute to the observed diversity. We discuss the importance of diversity and local selection effects when choosing drug targets for intervention strategies.

Animals↗
PubMed2005

Single nucleotide polymorphisms in the apoptosis receptor gene TNFRSF6.

The homotrimeric Fas receptor, an inducer of lymphocyte apoptosis, plays a critical role in cellular pathways of immune homeostasis and immunologic tolerance. Inherited and acquired defects in the Fas gene, TNFRSF6 (tumor necrosis factor receptor superfamily member 6) have been associated with human autoimmune lymphoproliferative syndrome (ALPS) and a spectrum of other complex autoimmune diseases and malignancies. In addition to over 60 deleterious mutations associated with dominant inhibitory defects or null mutations of TNFRSF6, several sequence variants have been noted. To facilitate interpretation of genotypes of this important locus, we sequenced DNA from unrelated, healthy Caucasians and African Americans. Two new and 12 previously recorded SNPs were confirmed, and their allele frequencies were determined. We also investigated haplotype frequencies and linkage disequilibrium (LD) coefficients for these SNPs in Caucasians. Four TNFRSF6 SNP pairs were found to be in strong LD. The TNRFSF6 SNPs are useful for linkage and loss of heterozygosity studies probing the role of Fas-mediated apoptosis in autoimmune diseases and malignancies.

Black or African American↗
PubMed2005

Screening for recently selected alleles by analysis of human haplotype similarity.

There is growing interest in the use of haplotype-based methods for detecting recent selection. Here, we describe a method that uses a sliding window to estimate similarity among the haplotypes associated with any given single-nucleotide polymorphism (SNP) allele. We used simulations of natural selection to provide estimates of the empirical power of the method to detect recently selected alleles and found it to be comparable in power to the popular long-range haplotype test and more powerful than methods based on nucleotide diversity. We then applied the method to a recently selected allele--the sickle mutation at the HBB locus--and found it to have a signal of selection that was significantly stronger than that of simulated models both with and without strong selection. Using this method, we also evaluated >4,000 SNPs on chromosome 20, indicating the applicability of the method to regional data sets.

Alleles↗
PubMed2003

Identification of three single nucleotide polymorphisms in the chicken insulin-like growth factor 1 and 2 genes and their associations with growth and feeding traits.

The chicken insulin-like growth factor (IGF)1 and IGF2 genes have been partially sequenced in six individuals of each of two chicken strains of the Black Penedesenca breed (PN and MN). These two strains are genetically diverse for growth traits. Sequence alignment revealed the existence of three single nucleotide polymorphisms (SNP) (IGF1-SNP1, IGF2-SNP2, and IGF2-SNP3). These three SNP and a fourth IGF1 polymorphism (IGF1-SNP4) were typed in 60 individuals from each strain by using PCR-RFLP or primer extension analysis. No significant associations among these four SNP, growth traits, and plasma IGF1 concentration were identified. In contrast, suggestive associations (P < or = 0.05) were found between IGF1-SNP1 and average daily gain at 107 d and feed efficiency at 44, 73, and 107 d. However, these associations were not simultaneously found in both strains suggesting that they might have been produced by linkage disequilibrium with another mutation located in the IGF1 locus or another linked gene. Since the PN and MN strains differ very markedly on their feed intake, the chicken leptin gene was included in the sequence analysis. Unfortunately, attempts to amplify several regions of this gene were unsuccessful. Even when primers complementary to highly conserved regions were used, the PCR consistently failed. Other authors have reported similar problems when trying to amplify avian leptin sequences.

Animals↗
PubMed2004

Common polymorphisms in the glyoxalase-1 gene and their association with pro-thrombotic factors.

Advanced glycation endproducts (AGEs) form at an accelerated rate in diabetes and contribute to the development of macrovascular disease. Their precursors are detoxified by the glyoxalase system. Perturbations of the glyoxalase-1 gene may alter AGEs' interactions and affect pro-thrombotic factors. We screened the glyoxalase-1 gene for mutations and measured pro-thrombotic markers in 537 subjects from 89 healthy probands. Common single nucleotide polymorphisms (SNPs) were identified at positions -7 (C to T) and 20203 (C to A) from the translation start site. These SNPs were in Hardy-Weinberg equilibrium (CC=105, CA=266, AA=148; p>0.05; CC=126, CT=279, TT=114; p>0.05, respectively) and in linkage disequilibrium (D=27%, p<0.01), with mutant allele frequencies of 48% and 52% respectively. A significant association was found between SNPs at position 20203 and PAI-1 antigen concentrations and -7 and factor XIII A2B2 complex (p=0.001 and p=0.042). After Bonferroni correction a significant association remained between the SNP at 20203 and PAI-1 concentrations (p=0.005), and after adjustment for pedigree the association accounted for 1.3% of its heritability (p=0.04). No significant associations were found for SNP -7 T to C and factor VII activity, tPa concentrations, fibrinogen concentrations or factor XIII concentrations and SNP 20203 C to A and factor VII concentrations, PAI-1 concentrations, tPa concentrations or fibrinogen concentrations. Common variants in the glyoxalase-1 gene are associated with some pro-thrombotic factors, account for part of their heritability in healthy pedigrees and may alter susceptibility to macrovascular complications.

Adult↗
PubMed2004

Mutation screen of the glutamate decarboxylase-67 gene and haplotype association to unipolar depression.

Abnormally low concentrations of brain gamma-aminobutyric acid (GABA) have been reported in unipolar depression. Almost all of the brain GABA is synthesized by glutamate decarboxylase (GAD) enzymes (GAD67 and GAD65). These enzymes, therefore, play a central role in brain GABA homeostasis. We screened all the 17 exons of the GAD67 gene for mutations using single strand conformation polymorphism (SSCP) or denaturing high pressure liquid chromatography (dHPLC) in a sample of 43 individuals diagnosed with major unipolar depression or other disorders with putative GABAergic dysfunction. We identified eight novel variants (five synonymous base substitutions, two insertion/deletions and one tandem repeat). Three relatively common (minor allele frequency >20%) single nucleotide polymorphisms (SNPs), located in the 5' non-coding region (exon 0), intron 8, and the 3' non-coding region (exon 16) of the gene, were genotyped in 103 European-American (EA) subjects with depression and 125 EA psychiatrically screened controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated using the 3LOCUS program. Significant LD was observed between the intron 8 SNP and the exon 16 SNP and between the exon 0 SNP and the exon 16 SNP. Three common GAD67 haplotypes were observed in this population, which accounted for >90% of the possible GAD67 three-locus haplotypes. Comparison of SNP and haplotype frequencies between individuals with depression and controls revealed no differences. These results demonstrate a significant within-gene LD for GAD67 in the EA population and begin to establish a haplotype map for this gene. Furthermore, these results suggest that common genetic variation within the GAD67 gene does not play a major role in the predisposition to unipolar depression.

DNA↗
PubMed2006

High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.

BACKGROUND: Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10. This screen included 44 multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7. METHODS: To investigate this family more thoroughly, a high-density single nucleotide polymorphism (SNP) screen was performed. Two-point and multipoint linkage analyses were performed using both parametric and nonparametric methods. RESULTS: For both the microsatellite and SNP markers, linkage analysis suggested the involvement of a locus or loci proximal to the telomeric regions of chromosomes 2q and 7p, with both regions generating a LOD* score of 3.0 using a nonparametric identity by descent relative sharing method. CONCLUSIONS: The regions with the strongest evidence for linkage map proximal to the telomeres on these two chromosomes. In addition to mutations and/or variants in a major gene, these loci may harbor a microdeletion and/or translocation; potentially, polygenic factors may also be involved. This single family may be promising for narrowing the search for NTD susceptibility genes.

Chromosomes, Human, Pair 2↗
PubMed2002

A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease.

Graves' disease (GD) is caused by an interplay of genetic factors and environmental triggers. The major antigen in GD is the thyrotropin receptor (TSHR) on the surface of the thyroid epithelial cell. Population-based case-control studies have largely shown no association of GD with the D36H (Asp to His) and P52T (Pro to Thr) single nucleotide polymorphisms (SNPs) in the N-terminal region of the extracellular domain of the TSHR gene in Caucasian populations. Recently, a D727E (Asp to Glu) SNP in the intracellular C-terminal domain of the TSHR was reported to be associated with GD in a Russian population. In the present study we assessed whether the codon 727 SNP is associated with GD in a Caucasian population. We found no significant differences in codon 727 SNP frequencies between GD patients and controls. In addition, our results did not show an effect of the SNP on the GD phenotype and on disease severity. Further analysis showed no evidence that the TSHR 727 SNP modulated the risk for GD conferred by HLA (DR3) and/or CTLA-4 (SNP 49 G allele) genes. A meta-analysis combining our data and those of 2 previous studies showed a very weak association between the D727E SNP and GD (p = 0.03, relative risk = 1.6). Therefore, we concluded that the TSHR gene is not a major gene for GD in our population.

Gene Expression↗