Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes.

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.

Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels.

The purpose of this study was to test the hypothesis that glutamate cysteine ligase catalytic subunit (GCLC) promoter polymorphisms are susceptibility factors for type 1 diabetes (T1D), T1D age-at-onset and T1D autoantibodies. T1D patients and control subjects from the Swedish Childhood Diabetes Registry and the Swedish Diabetes Incidence Study registry were genotyped for two GCLC promoter polymorphisms; the GCLC -129 C to T single nucleotide polymorphism (GCLC -129 SNP) and the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR). Glutamate decarboxylase antibody (GAD65Ab) positive T1D patients with the GCLC -129 SNP C/T genotype have increased GAD65Ab levels (p-value, <0.05) compared to the GCLC -129 SNP C/C genotype. T1D patients with an age-at-onset of 14-35 years who possess the GCLC -129 SNP T/T genotype have a higher GAD65Ab index than T1D patients with the GCLC -129 SNP C/C genotype (p-value <0.05). In addition, T1D patients with an age-at-onset of 14-35 years possess the GCLC TNR 7/8 genotype at a lower frequency than the control subjects (OR, 0.33, 95% CI, 0.13-0.82). The GCLC -129 SNP and GCLC TNR appear to be in linkage disequilibrium (p-value<0.0001). These results suggest that GCLC promoter polymorphisms may influence GAD65Ab levels and may influence the age at which T1D is diagnosed.

Hospitalizations for back and neck problems: a comparison between the Province of Ontario and Washington State.

OBJECTIVE: To examine back and neck hospitalizations in the Province of Ontario and Washington State. Because of their different organization and financing, there has been considerable interest in comparing healthcare systems in Canada and the United States. Features of healthcare systems might be expected to result in greater variations in care for elective than urgent conditions. DATA SOURCE: Automated hospital discharge databases. STUDY DESIGN: Previously developed algorithms were used to identify surgical and nonsurgical hospitalizations for back and neck problems in the administrative databases. We compared overall rates of hospitalization and lengths of hospital stay in Ontario and Washington as well as small area variations within the province and state. PRINCIPAL FINDINGS: Surgical back and neck hospitalizations were three times as common in Washington, but medical hospitalizations were twice as common in Ontario. Provincial lengths of stay were longer for both surgical and nonsurgical hospitalizations. Admission rates varied substantially and significantly among small areas in both Washington and Ontario. Variations in hospital length of stay were greater in Ontario, particularly for nonsurgical back and neck hospitalizations. CONCLUSION: The two jurisdictions had very different patterns of hospital utilization for one of the most common health problems seen by physicians. Our results suggest that the global controls on hospital budgets and access to technology in Ontario were associated with lower rates of surgery, higher rates of hospital-based medical care, and longer lengths of stay. They also indicate that the utilization review process in Washington was associated with lower small area variation rates for medical back care.

5-year reoperation rates after different types of lumbar spine surgery.

STUDY DESIGN: Population-based cohort study of Washington State patients who underwent lumbar spine surgery for degenerative conditions in 1988. OBJECTIVES: To compare complications and reoperation rates during the 5-year period after surgery between patients who have undergone lumbar spine fusion surgery and those who have undergone laminectomy or discectomy alone. SUMMARY OF BACKGROUND DATA: Spinal fusion is associated with wider surgical exposure, more extensive dissection, and longer operative times than lumbar surgery without fusion, and previous studies have shown higher complication rates and hospital charges associated with these more complex procedures. In elderly patients, spinal fusion operations were associated with higher mortality rates than laminectomy or discectomy alone, and reoperation rates were not lower. In the current study, reoperations, mortality, and complications following lumbar spine surgery were examined for the general population. METHODS: A statewide hospital discharge database was used to identify all Washington patients who underwent spine surgery in 1988 and to determine the rate of reoperation during the subsequent 5 years. Administrative records also were used to identify complications, mortality, and hospital charges associated with the operations. Unadjusted complication and reoperation rates for the groups were compared using chi-square statistics. Adjusted rates were compared using logistic regression and proportional hazards (Cox) regression after controlling for age, gender, prior spine surgery, diagnosis, comorbidity, type of surgery, and coverage by Workers' Compensation. RESULTS: Of 6376 patients who underwent lumbar surgery for degenerative conditions in Washington in 1988, 1041 (16%) had operations involving spine fusion. Diagnoses of degenerative disc disease or possible instability were more frequent among patients undergoing fusion surgery, whereas herniated discs were more frequent among those undergoing discectomy or laminectomy alone. Complications were recorded in 18% of fusion patients and 7% of nonfusion patients (P < 0.01), but mortality rates did not differ. Unadjusted reoperation rates over the 5-year period were greater for patients who underwent fusion than for patients who underwent nonfusion surgery (18% vs. 15%, respectively), but after adjustment for baseline characteristics, fusion patients had only a slightly greater (and nonsignificant) risk of reoperation (relative risk 1.1, confidence interval .9-1.3). CONCLUSION: As in previous studies, complications in the current study occurred more frequently among patients who underwent lumbar spine fusion than among those who underwent laminectomy or discectomy alone. Reoperations were at least as frequent after fusion, but the authors could not assess treatment efficacy in terms of pain relief or improved function. Although the characteristics of patients undergoing fusion differed from those undergoing a laminectomy or discectomy alone, there appeared to be sufficient overlap in the clinical populations to warrant closer scrutiny of the safety, efficacy, and indications for spinal fusions, preferably in randomized trials.

Patient-oriented outcomes from low back surgery: a community-based study.

STUDY DESIGN: This study used a prospective cohort design. OBJECTIVE: To examine factors associated with favorable self-reported patient outcomes 1 year after elective surgery for degenerative back problems. SUMMARY OF BACKGROUND DATA: Many previous studies addressing the results of low back surgery have been conducted in academic institutions or by single surgeons. As part of a quality improvement effort, surgeons in private practice led a community-based outcomes management project in Washington State. METHODS: Patients ages 18 and older with the following diagnoses were eligible for the study: degenerative changes, herniated disc, instability, and spinal stenosis. Nine orthopedists and neurosurgeons enrolled a total of 281 patients. Participants were asked to complete baseline and 1-year follow-up surveys. Data concerning diagnoses, clinical signs, and operative procedures were provided by the surgeons. The researchers examined sociodemographic characteristics, self-reported symptoms before surgery, preoperative clinical signs, diagnoses, and operative procedures associated with three primary outcomes: better functioning, improved quality of life, and overall treatment satisfaction. RESULTS: Follow-up surveys were completed by 236 (84%) of the enrolled patients. Approximately two thirds of the study participants reported much better functioning (65%), a great quality of life improvement (64%), and a very positive perspective about their treatment outcome (68%). The following variables were associated with worse patient outcomes: older age, previous low back surgery, workers' compensation coverage, and consultation with an attorney before surgery. Patients undergoing a fusion procedure were more likely to report good outcomes. CONCLUSIONS: The authors' experience indicates that community-based outcomes data collection efforts are feasible and can be incorporated into usual clinical practice. The study results indicate that compensation payments and litigation are two important predictors of poor outcomes after low back surgery in community practice. Because of small numbers, varied diagnoses, and possible selection bias, the findings with respect to fusion should be interpreted cautiously.

IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk. METHODS: We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden. RESULTS: We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15-=0.017 (95% CI 0.005, 0.062), p<0.001]. CONCLUSIONS/INTERPRETATION: Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk.

Analysis of quantitative risk factors for a common oligogenic disease.

All three simulated loci influencing the quantitative variables Q1, Q2 and Q3 were successfully mapped by using a strategy of covariate adjustment and segregation analysis, coupled with association analyses and lod-score analyses.