IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort.

OBJECTIVE: Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time. DESIGN: 1153 Caucasian adults (age range: 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective. RESULTS: Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression [odds ratio (OR) 1.91 (95%CI 1.16-3.15); P = 0.012]. Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype. CONCLUSION: A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.

Haemostatic markers are associated with measures of vascular disease in adults with hypertension.

Haemostatic markers have been implicated in the development and progression of vascular disease. We investigated the associations of several haemostatic markers (fibrinogen, D-dimer, FV, FVII, FVIII, von Willebrand factor (vWF) and antithrombin III) with two quantitative measures of vascular disease in adults with hypertension. Participants included 1051 African Americans (65+/-9 years, 72% women) and 894 non-Hispanic whites (61+/-9 years, 55% women) belonging to hypertensive sibships. Phenotypes of vascular disease included the ankle-brachial index (ABI), a measure of peripheral arterial disease, and urinary albumin/creatinine ratio (UACR), a surrogate of glomerular endothelial function. Generalized estimating equations were used to assess whether plasma levels of haemostatic markers were associated with measures of arteriosclerosis, after adjustment for conventional risk factors and medication (statin, aspirin and oestrogen) use. Higher fibrinogen and D-dimer were significantly associated with lower ABI in African Americans (P<0.001 and 0.004 respectively) and in non-Hispanic whites (P<0.001 and 0.010 respectively). Higher fibrinogen (P<0.001), D-dimer (P=0.003), FVIII (P<0.001) and vWF (P<0.001) were significantly associated with higher UACR in African Americans, whereas, in non-Hispanic whites, higher fibrinogen (P=0.020) and FVII (P=0.006) were significantly associated with higher UACR. Our findings indicate that in adults with essential hypertension, several markers in the haemostatic pathway are independently associated with ABI and UACR, two measures of vascular disease..

Diaphragmatic responses to body position changes in obese patients with obstructive sleep apnea.

Patients with severe obesity and obstructive sleep apnea (OSA) have been shown to have abnormalities in respiratory muscle function and respiratory control. The present study was done to evaluate diaphragmatic function and the diaphragm fiber-length-compensating reflex in morbidly obese patients with OSA (1). Twelve normal subjects and 13 morbidly obese patients with OSA were studied in recumbent and upright positions. In the normal subjects, the diaphragm fiber-length-compensating reflex operated normally causing the diaphragm's inspiratory EMG to increase when the diaphragm's fibers shortened with assumption of the upright position. However, 8 of the 13 obese patients with OSA showed a decrease rather than an increase in the inspiratory diaphragmatic EMG on assuming the upright posture. Further data indicate greater diaphragmatic efficiency in the upright than in the supine position in a majority of the obese patients, a reversal of the normal response. Two possible explanations of these observations are: an abnormality of central respiratory control in obese patients with OSA and overstretching of the diaphragm in the recumbent obese patient. The observation of reduced maximal transdiaphragmatic pressures in the recumbent position in some of the obese patients with OSA supports the second explanation. Diaphragmatic overstretching may be an important mechanism in the development of hypoventilation in the morbidly obese.