By Elizabeth Hammer, MD
Faculty Peer Reviewed
This week we saw some winners and some losers. The 2013 Academy Award Nominations were announced. Nobody was elected to the Baseball Hall of Fame. A flu outbreak in Boston led the city’s mayor to declare a public health emergency, while Pertussis is working on a comeback. And the NIH released an extensive report on health in the US that found that not only do Americans have poorer health and lower life expectancies, but they also are less likely to live past age 50 as compared with their counterparts in other developed countries. In light of this news, we’ll start off with new research into diseases of those who do make it to the golden years.
This week the NEJM, two studies focused on developments in the search for genetic risk factors for Alzheimer’s disease. Jonsson et al sequenced the genomes of 2,261 Icelanders. They found that a rare missense mutation (rs75932628) in TREM2 – a gene encoding the myeloid 2 cell receptor that triggers immune responses in phagocytic cells – conferred a significantly increased risk of Alzheimer’s (odds ratio, 2.92; 95% confidence interval, 2.09-4.09; p=3.42×10-10). They then replicated this finding in case-control series from the United States, Norway, the Netherlands, and Germany (combined odds ratio, 2.83; 95% confidence interval 1.45-5.4; p=0.002). Interestingly, the researchers also found that 80-100 year old carriers of the rs75932628 allele without Alzheimer’s had poorer cognitive function than non-carriers (p=0.003).
Along a similar line of inquiry, Guerreiro et al used genetic sequencing techniques to determine that there were significantly more variants in the TREM2 gene of 1,902 individuals with Alzheimer’s disease as compared with controls (p=0.02). The most common variant allele, rs75932628, was significantly associated with Alzheimer’s disease (P<0.001). This association was then confirmed by a meta-analysis that pooled three genome-wide association studies of Alzheimer’s disease (p=0.002) and by direct genotyping of an additional 1,887 patients with disease and 4,061 healthy controls (p<0.001). Furthermore, the researchers demonstrated that TREM2 is differentially expressed in a mouse model of Alzheimer’s disease and in control mice.
Taken together, these two studies provide convincing evidence that TREM2 variants, although rare, increase the risk of late-onset Alzheimer’s to an extent similar to that of the ApoeE e4 allele, the major known genetic risk factor for this disease. The exact pathway, though, has yet to be elucidated. Given the role of TREM2 in microglial phagocytic activity and activation of inflammatory cytokines, researchers postulate that the identified TREM2 variant causes damage by impairing the brain’s ability to clear toxic products like beta amyloid and to resolve inflammation-associated damage. It is also interesting to note that, while heterozygotes are susceptible to late-onset Alzheimer’s disease, homozygous carriers of the TREM2 mutation is associated with Nasu-Hakola, an early-onset brain and bone disorder. The implications of this connection remain to be seen is likely will guide further research into Alzheimer’s pathogenesis. Stay tuned.
On a different note, the vitamin wars continued this week in JAMA as McAlindon et al set out to determine whether vitamin D supplementation reduces symptomatic and structural progression of knee osteoarthritis (OA). In a randomized, double-blind, placebo-controlled trial, 146 participants were assigned to receive placebo or oral cholecafecerol, with dosage escalations to elevate serum levels to at least 36 ng/ml, the lower limit of effectiveness in prior epidemiologic studies. After two years there was no difference between the two groups in WOMAC scale ratings of knee pain or MRI determined cartilage. Although it is possible that the two-year duration was insufficient, as the original epidemiologic studies of vitamin D supplementation followed participants over eight years, for now vitamin D is no magic bullet for OA.
Skipping across the pond to The Lancet, Huxley et al outlined the effects of smoking in a prospective study of 1.2 million women in the United Kingdom. Smoking prevalence in young women did not peak until the 1960s so prior studies may have underestimated its impact. The researchers found that smokers had three times the 12-year mortality rate (adjusted mortality ratio of 2.76, 95% confidence interval 2.71-2.81) and about 10 fewer years of life expectancy as compared with women who had never smoked. 23 of the 30 most common causes of death – particularly lung cancer, heart disease, and strokes – were significantly increased in smokers. Encouragingly, though, women who quit smoking by age 40 avoided 90 percent of the excess mortality caused by smoking and women who quit by age 30 avoided 97 percent. This suggests that, as with men, smoking is harmful, but kicking the habit can reverse much of that harm.
Here are a few other interesting reads from this week:
1. Kaner E, et al. Effectiveness of screening and brief alcohol intervention in primary care (SIPS trial): pragmatic cluster randomised controlled trial. BMJ 2013; 346;e8501. http://www.bmj.com/content/346/bmj.e8501
This study found that there was no significant difference after six and twelve months on Alcohol Use Disorders Identification Test (AUDIT) scores whether individuals who had initially screened positive were provided with a written leaflet only, five minutes of structured advice, or 20 minutes of lifestyle counseling. Perhaps less is more.
2. Buse JB, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. The Lancet 2013; 381(9861):117-124. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61267-7/fulltext
This open-label, randomized parallel group study comparing two glucagon-like peptide receptor (GLP-1) agonists found that although both improved glycemic control, once weekly exenatide was inferior to once daily liraglutide in terms of lowering HbA1c, though exenatide was associated with fever adverse events.
3. Rong Y, et al. Egg consumption and risk of coronary heart disease and stroke: dose-response meta-analysis of prospective cohort studies. BMJ 2013; 342: e8539. http://dx.doi.org/10.1136/bmj.e8539
Up to one egg per day was not associated with an increased risk of coronary heart disease or stroke in this dose-response meta-analysis.
Dr. Elizabeth Hammer is a 2nd-year resident at NYU Langone Medical Center
Peer reviewed by Todd Cutler, Associate Editor, Clinical Correlations
References:
Jonsson T, et al. Variant of TREM2 associated with risk of Alzheimer’s disease. N Engl J Med 2013; 368(2):107-116. http://www.nejm.org/doi/full/10.1056/NEJMoa1211103
Guerreiro R, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2):117-127. http://www.nejm.org/doi/full/10.1056/NEJMoa1211851
McAlindon T, et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. JAMA 2013; 302(2):155-162. http://jama.jamanetwork.com/article.aspx?articleid=1556148
Huxley R, et al. Full hazards of smoking and benefits of stopping for women. The Lancet 2013; 381(9861):96-98. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61720-6/fulltext