KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population.

OBJECTIVES: Crohn's disease (CD; MIM 266600) is one of the most common forms of inflammatory bowel disease (IBD), and represents a significant burden to health care in developed countries. Our aim was to determine whether a gene in the IBD linkage region on chromosome 19q13, with a role in Paneth cell secretion and T-cell activation, conferred genetic susceptibility to the development of CD. METHODS: In total, 792 CD cases and 1,244 controls of Australian origin (Caucasian) were genotyped for seven single-nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.2. CD cases were phenotyped using the Montreal classification. The replication set comprised an additional 326 CD cases and 951 population-based Caucasian controls. Analysis of the KCNN4 mRNA transcript was carried out using quantitative reverse transcriptase-PCR. RESULTS: KCNN4 SNP rs2306801 was associated with CD (primary P=0.0008, odds ratio (OR) (95% confidence interval (CI)): 0.76 (0.65-0.89); replication P=0.01, OR (95% CI): 0.77 (0.61-0.97). Stratification by disease location identified the association between SNP rs2306801 and ileal CD (P=0.01). Non-inflamed ileal mucosa from CD patients carrying any of the common disease-predisposing NOD2 variants (R702W, G908R, 1007fs) had significantly reduced levels of KCNN4 mRNA expression (P=0.001). KCNN4 protein expression was detected in Paneth cells, and in T cells in inflamed lamina propria. CONCLUSIONS: Our data implicate the role of KCNN4 in ileal CD. The dual roles of KCNN4 in Paneth cell secretion and T-cell activation and also its nature as a potassium channel make it an important and practical therapeutic target.

Validation of the GALS musculoskeletal screening exam for use in primary care: a pilot study.

BACKGROUND: As the proportion of the Canadian population > or =65 grows, so too does the prevalence of musculoskeletal (MSK) conditions. Approximately 20% of visits to family physicians occur as a result of MSK complaints. The GALS (Gait, Arms, Legs, and Spine) screening examination was developed to assist in the detection of MSK abnormalities. Although MSK exams are primarily performed by rheumatologists or other MSK specialists, expanding their use in primary health care may improve the detection of MSK conditions allowing for earlier treatment. The primary goal of this study was to evaluate the use of the GALS locomotor screen in primary care by comparing the results of assessments of family physicians with those of rheumatologists. The secondary goal was to examine the incidence of MSK disorders and assess the frequency with which new diagnoses not previously documented in patients' charts were identified. METHODS: Patients > or =65 years old recruited from an academic family health centre were examined by a rheumatologist and a family physician who recorded the appearance of each participant's gait and the appearance and movement of the arms, legs and spine by deeming them normal or abnormal. GALS scores were compared between physicians with the proportion of observed (Pobs), positive (Ppos) and negative (Pneg) agreement being the primary outcomes. Kappa statistics were also calculated. Descriptive statistics were used to describe the number of "new" diagnoses by comparing rheumatologists' findings with each patient's family practice chart. RESULTS: A total of 99 patients consented to participate (92 with previously diagnosed MSK conditions). Results showed reasonable agreement between family physicians and rheumatologists; Pobs = 0.698, Ppos = 0.614 and Pneg = 0.752. The coefficient of agreement (estimated Kappa) was 0.3675 for the composite GALS score. For individual components of the GALS exam, the highest agreement between family physicians and rheumatologists was in the assessment of gait and arm movement. CONCLUSION: Previously reported increases in undiagnosed signs and symptoms of musculoskeletal conditions have highlighted the need for a simple yet sensitive screening exam for the identification of musculoskeletal abnormalities. Results of this study suggest that family physicians can efficiently use the GALS examination in the assessment of populations with a high proportion of musculoskeletal issues.