In this section, we highlight the key high-impact studies, updates, and analyses published in medicine during the past week.
Loss-of-function Mutations in APOC3, Triglycerides, and Coronary Disease; Loss-of-function Mutations in APOC3 and Risk of Ischemic Vascular Disease
Apolipoprotein C3, a protein in remnant cholesterol particles, is associated with hypertriglyceridemia, which has been associated with increased risk for coronary heart disease. In two observational studies published this week, researchers examined the association between loss-of-function of the APOC3 gene and low TG levels and lower risk of ischemic vascular disease in population studies. In one, investigators identified mutations associated with low TG levels among 3734 participants whose genes were sequenced by the Exome Sequencing Project. Then, they determined the association between mutation carriers and non-carriers and risk of coronary heart disease in 110,970 participants across 15 studies. Loss-of-function mutations in the APOC3 gene(found in 1 in 150 people sequenced) were associated with lower plasma triglycerides than non-carriers (84.5 vs 137.5, p=6×10-9) as well as higher HDL cholesterol levels, and heterozygous carriers of an APOC3 mutation (n=498) had a 40% decreased risk of coronary heart disease compared to non-carriers (OR 0.6, 95%CI 0.47-0.75, p=4×10-6). In another study, researchers used data from prospective population studies in Denmark (n=75,725, median follow up of 34 years) to determine the association between plasma TG levels and risk of ischemic vascular/heart disease, and whether a loss-of-function mutation in APOC3 was also associated with a lower risk of ischemic vascular and heart disease in the same population. Decreasing plasma TG was proportionally associated with a lowered risk for ischemic vascular/heart disease, with participants in the lowest quintile of plasma TG level having approximately half the risk of developing ischemic vascular disease and ischemic heart disease (HR 0.55 and 0.49, respectively) compared to the highest quintile. APOC3 loss-of function mutation carriers (n=302) had on average 44% lower plasma TG levels (p<.001) and significantly lower risk of ischemic vascular and heart disease (HR 0.59, 95%CI 0.41-0.86, p=.007 and HR 0.64, 95%CI 0.41-0.89, p=.04, respectively). Both of these studies suggest that a functional loss of APOC3 may be protective against development of coronary artery and ischemic vascular disease, and thus this protein may be a target for future drug development.
Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection
The current standard for monitoring for rejection after heart transplantation, endomyocardial biopsy, is invasive and costly, and cell-free donor-derived DNA (cfdDNA, measurable in recipient blood and urine), may provide a noninvasive way to monitor the health of the donated organ. In this prospective cohort study, plasma from 65 heart transplant recipients (n=565 samples) was collected and analyzed longitudinally and compared to endomyocardial biopsy results (n=356) to determine the performance of using cfdDNA in measuring transplant rejection. Donor and recipient DNA were differentiated based on pre-transplant SNP genotyping. In 9 rejection-free patients, the proportion of cfdDNA dropped quickly after transplant to a low baseline level of 0.06+0.11% over a follow-up period of 1 year. In comparison, 3 patients who developed acute cellular rejection and/or antibody-mediated rejection had concurrent elevations in cfdDNA. A cfdDNA threshold of 0.25% was 58% sensitive and 93% specific in identifying acute cellular rejection, with an area under the curve (AUC) of 0.83 in receiver operating characteristic analysis. Notably, in 4 of 5 false-positive samples, those patients were subsequently diagnosed with mild rejection within 6 weeks of that sample, suggesting that elevations in cfdDNA may predict rejection before histological evidence of rejection, a potential time window for intervening to prevent more severe organ rejection.
Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults
Evidence for whether increased physical activity prevents or delays reduced mobility in older adults, an independent risk factor for morbidity and mortality, is limited. In this randomized, single-blinded trial (Lifestyle Interventions and Independence for Elders (LIFE)), 1635 sedentary volunteers aged 70-89 from a variety of community settings were assigned to a structured physical activity intervention or a health education program to determine the effect of increased moderate physical activity on losing the ability to walk 400m (major mobility disability) over a 2 year follow-up period. Participants in the physical activity group experienced less major mobility disability (HR 0.82, 95%CI 0.69-0.98, p=.03) and less persistent mobility disability (HR 0.72, 95%CI 0.57-0.91, p=.006) than the control group. Those with lower baseline physical function benefited more from the intervention (HR 0.75 for major mobility disability). The physical activity group had a higher hospitalization rate (not statistically significant) than the control group, counter to expectations based on prior observational cohorts. Overall, the LIFE study demonstrated objective, though modest, benefit of structured physical activity in preventing mobility disability in older adults.
Tumor necrosis factor-a (TNF-a) antagonists are effective in treating inflammatory bowel disease (IBD) but may be associated with an increased cancer risk, though long-term follow-up in a large population is needed. In this nationwide prospective cohort study, researchers analyzed data from 56,146 patients with IBD who were followed for a median of 9 years to determine how overall and site-specific cancer rates differed between those who did and did not receive treatment with TNF-a antagonists. Of the 8.1% of IBD patients exposed to TNF-a antagonists, 1.8% developed cancer, compared to 6.7% of unexposed patients (adjusted rate ratio 1.25, 95%CI 1.00-1.58, which decreased to 1.07, 95%CI 0.85-1.36 after further adjusting for azathioprine exposure). Similarly, there was no association between TNF-aantagonist exposure and development of site-specific cancers (including skin cancer, lymphoma, and colorectal cancer) after adjusting for azathioprine exposure, though the number of cases was small. Overall, among a large population of patients with IBD, treatment with TNF-a antagonists in patients with IBD was not observed to be associated with increased risk of malignancy.
Image: PD
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