We performed a candidate gene association study in 540 patients with primary Sj?gren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 ? 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 ? 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 ? 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.
Sj?gren's syndrome (SS) is a chronic autoimmune disease characterized by dryness of the eyes and mouth. Currently, the highly polymorphic major histocompatibility complex (MHC) genes are the best documented genetic risk factor for the development of autoimmune disease. We examined the MHC class II alleles DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 in a group of Norwegian pSS patients and compared with a group of healthy controls. Because a number of studies have shown that some of the MHC class II alleles are not associated with the disease as a whole, but rather to the development of autoantibodies, anti-Ro52 autoantibodies in serum were measured and compared to MHC class II allele status. A clear association with pSS was detected for the DRB1*0301 and DRB3*0101 alleles, but these alleles were more closely associated with the presence of anti-Ro52 autoantibodies than with pSS itself. Moreover, the DQA1*0501 and DQB1*0201 alleles were only associated with the presence of anti-Ro52 autoantibodies. This study shows that the production of anti-Ro52 autoantibodies in pSS is associated with the DRB1*0301, DRB3*0101, DQA1*0501 and DQB1*0201 alleles which are in strong linkage disequilibrium.
Within the framework of the gerontological and geriatric population studies in Göteborg, Sweden, 473 elderly persons were examined using pure-tone audiometry in two recent cohorts. The aim of this study was to present cross-sectionally acquired hearing data in these contemporary groups aged 70 and 75. Another objective was to compare hearing function at the same age over the last two decades (time-lag study) in three 70-year-old cohorts and three 75-year-old cohorts. The largest time-lags were 14 years (75-year-olds) and 21 years (70-year-olds). The most recently tested cohort of 70-year-olds, studied in 1992, demonstrated median pure-tone averages (PTA: 0.5, 1 and 2 kHz) of 20.2 dB HL in the left ear of men and 18.2 dB HL in women. The left median pure-tone thresholds at 4 kHz were 56.0 dB HL in men and 34.7 dB HL in women. Hearing acuity in 70-year-olds was not demonstrated to have changed in any consistent fashion over a 21-year time-lag. For the most recently evaluated 75-year-olds, the median PTA in the left ear was 27.3 dB HL in men and 21.6 dB in women. The left median 4 kHz threshold was 67.3 in the male group and 45.5 dB HL in the female group. Hearing in 75-year-olds over a time-lag of 14 years demonstrated somewhat better pure-tone thresholds predominantly in the men's better ear in the earliest cohort when compared to the cohort tested in 1990-91. However, there were no consistent differences of pure-tone thresholds between these age cohorts, except for the intermediate cohort 2, in which the men had generally worse hearing. Thus, there was no apparent evidence of changes of the auditory function in elderly of the same age over the last two decades. Gender-specific dissimilarities in annual pure-tone threshold deterioration between the ages of 70 and 75 were found and are discussed.
Patterns of bone loss in the axial skeleton have been studied in a sample of Swedish women participating in a longitudinal population study which was started in 1968. In 1976, the mineral content of the lumbar spine (predominantly trabecular bone) was measured in vivo in 130 women by dual photon absorptiometry. Premenopausal or recently postmenopausal women were compared with women of identical age who had been postmenopausal for a long time. The first group was found to have significantly higher values of bone mineral content. Five years later, in 1981, the same women were re-examined with identical techniques. A slight decrease in bone mineral content with age was found in postmenopausal women. The findings were mostly in agreement with those of the first cross-sectional study, with bigger differences in bone mineral content between women of different menstrual status than between women of different age. In addition, the lower values in women with early menopause compared to those with late menopause remained in spite of increasing age.
OBJECTIVE: To screen for polymorphisms in the apoptosis regulating Fas and Fas ligand (FasL) genes in patients with primary Sjögren's syndrome (SS), and to explore associations with susceptibility to the disease. METHODS: Polymorphisms in Fas and FasL of 70 patients with primary SS and 72 controls were determined by polymerase chain reaction combined with the restriction enzyme fingerprinting single strand conformation polymorphism technique, verified by automatic sequencing and natural or amplification created restriction site tests. RESULTS: Polymorphisms were found in both Fas and FasL, but only some of the Fas polymorphisms were found in statistically significant differences between patients and controls. Patients displayed a higher frequency of the G/G genotype at position -671 than the controls, and the -671 G allele frequency for primary SS was increased compared to controls. A higher frequency of the C allele at position IVS2nt176 and IVS5nt82 was also found. Of note, the nucleotide variants in intron 2 and intron 5 were associated. CONCLUSION: We describe the positions and frequencies of several polymorphisms in the genes encoding Fas and FasL in patients with primary SS. None caused any amino acid change. Three Fas alleles, of which one is located in the promoter area, showed significant although modest differences between patients and controls.
To examine the intrarater and interrater reliability and agreement of the Danish version of the Dynamic Gait Index (DGI) in hospitalized and community-dwelling older people with balance impairments.
University hospital and outpatient rehabilitation.
A convenience sample of older people (=65y); 24 subjects from a hospital and 24 from an outpatient rehabilitation center. All subjects had either 1 or more falls within the last year or balance impairments evaluated by a physical therapist.
All subjects carried out the DGI twice with a 1.5-hour interval. Each subject was rated by 3 physical therapists in the first attempt (1 for intrarater and 2 for interrater comparison) and by the intrarater in the second attempt, in both settings. The reliability was calculated using the intraclass correlation coefficient (ICC, 2.1), while agreement was calculated as the smallest real difference (SRD).
The ICC for intrarater and interrater reliability of the total DGI was .90 and .92 at the hospital, while the SRD was 2.72 and 2.58 points, respectively. Correspondingly, the ICC for intrarater and interrater reliability of the total DGI at the rehabilitation center was .89 and .82, while the SRD was 3.49 and 3.99 points, respectively.
The intrarater and interrater reliability of the total DGI ranged from good to excellent in hospitalized and community-dwelling older people. Improvements of 3 and 4 DGI points for hospitalized and community-dwelling older people, respectively, should be regarded as a real change (with a 95% certainty).
The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fc? receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fc? receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fc? receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fc? receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.
An analysis of progression of sialadenitis in patients with primary and secondary SS has been performed. For this purpose patients were prospectively followed and evaluated with respect to stimulated whole salivary secretion and morphology of labial salivary gland biopsies. Twenty-one patients with primary SS and 18 with secondary SS were followed for a mean of 39 +/- 20 months (range 11-112 months). During this observation period the lymphocytic infiltration in minor salivary glands, measured as focus score, increased in 14/21 (67%) patients with primary SS and in 14/18 (78%) patients with secondary SS. Altogether there was a statistically significant increase in focus score in both primary and secondary SS, but no reduction in salivary production. Consequently, no correlation between changes in focus score and stimulated salivary secretion was found in either primary or secondary SS.
We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.