Channing Laboratory

Head of Westport, MA, United States

Channing Laboratory

Head of Westport, MA, United States

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Fung T.T.,Simmons College | Van Dam R.M.,National University of Singapore | Hankinson S.E.,Channing Laboratory | Stampfer M.,Harvard University | And 2 more authors.
Annals of Internal Medicine | Year: 2010

Background: Data on the long-term association between low-carbohydrate diets and mortality are sparse. Objective: To examine the association of low-carbohydrate diets with mortality during 26 years of follow-up in women and 20 years in men. Design: Prospective cohort study of women and men who were followed from 1980 (women) or 1986 (men) until 2006. Low-carbohydrate diets, either animal-based (emphasizing animal sources of fat and protein) or vegetable-based (emphasizing vegetable sources of fat and protein), were computed from several validated food-frequency questionnaires assessed during follow-up. Setting: Nurses' Health Study and Health Professionals' Follow-up Study. Participants: 85 168 women (aged 34 to 59 years at baseline) and 44 548 men (aged 40 to 75 years at baseline) without heart disease, cancer, or diabetes. Measurements: Investigators documented 12 555 deaths (2458 cardiovascular-related and 5780 cancer-related) in women and 8678 deaths (2746 cardiovascular-related and 2960 cancer-related) in men. Results: The overall low-carbohydrate score was associated with a modest increase in overall mortality in a pooled analysis (hazard ratio [HR] comparing extreme deciles, 1.12 [95% CI, 1.01 to 1.24]; P for trend = 0.136). The animal low-carbohydrate score was associated with higher all-cause mortality (pooled HR comparing extreme deciles, 1.23 [CI, 1.11 to 1.37]; P for trend = 0.051), cardiovascular mortality (corresponding HR, 1.14 [CI, 1.01 to 1.29]; P for trend = 0.029), and cancer mortality (corresponding HR, 1.28 [CI, 1.02 to 1.60]; P for trend = 0.089). In contrast, a higher vegetable low-carbohydrate score was associated with lower allcause mortality (HR, 0.80 [CI, 0.75 to 0.85]; P for trend ≤ 0.001) and cardiovascular mortality (HR, 0.77 [CI, 0.68 to 0.87]; P for trend < 0.001). Limitations: Diet and lifestyle characteristics were assessed with some degree of error. Sensitivity analyses indicated that results were probably not substantively affected by residual confounding or an unmeasured confounder. Participants were not a representative sample of the U.S. population. Conclusion: A low-carbohydrate diet based on animal sources was associated with higher all-cause mortality in both men and women, whereas a vegetable-based low-carbohydrate diet was associated with lower all-cause and cardiovascular disease mortality rates. Primary Funding Source: National Institutes of Health. © 2010 American College of Physicians.


Cassidy A.,University of East Anglia | Rimm E.B.,Harvard University | Rimm E.B.,Channing Laboratory | O'Reilly E.J.,Harvard University | And 4 more authors.
Stroke | Year: 2012

Background and Purpose-To date, few studies have examined associations between the wide range of flavonoid subclasses and risk of ischemic, hemorrhagic, and total stroke. Methods-We conducted a prospective study among 69 622 women from the Nurses' Health Study. Total flavonoid and subclass intakes were calculated from semiquantitative food frequency questionnaires collected every 4 years using an updated and extended US Department of Agriculture flavonoid database. Results-During 14 years of follow-up, 1803 incident strokes were confirmed. After adjusting for potential confounders, women in the highest compared with the lowest quintile of flavanone intake had a relative risk of ischemic stroke of 0.81 (95% CI, 0.66-0.99; P=0.04). Citrus fruits/juices, the main dietary source of flavanones, tended to be associated with a reduced risk for ischemic stroke (relative risk, 0.90; 95% CI, 0.77-1.05) comparing extreme quintiles. Conclusions-Total flavonoid intake was not inversely associated with risk of stroke; however, increased intake of the flavanone subclass was associated with a reduction in the risk of ischemic stroke. Citrus fruit consumption may be associated with a reduction in stroke risk, and experimental data support these epidemiological associations that the flavanone content of citrus fruits may potentially be cardioprotective. Further prospective studies are needed to confirm these associations. © 2012 2012 American Heart Association, Inc.


Chan A.T.,Harvard University | Chan A.T.,Channing Laboratory | Ogino S.,Harvard University | Ogino S.,Dana-Farber Cancer Institute | And 4 more authors.
Gastroenterology | Year: 2011

Background & Aims: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) lower the risk of colorectal cancer (CRC). We investigated whether plasma inflammatory markers were associated with risk of CRC and if use of anti-inflammatory drugs was differentially associated with risk of CRC according to levels of inflammatory markers. Methods: We measured levels of high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, and the soluble tumor necrosis factor receptor 2 (sTNFR-2) in blood samples from 32,826 women, collected from 1989 to 1990. Through 2004, we documented 280 cases of incident CRC; each case was matched for age to 2 randomly selected participants without cancer (controls). Information on anti-inflammatory drug (aspirin and NSAIDs) use was collected biennially. Results: Compared with women in the lowest quartile of plasma levels of sTNFR-2, women in the highest quartile had an increased risk of CRC (multivariate relative risk [RR], 1.67; 95% confidence interval [CI], 1.052.68; P for trend = .03). Among women with high baseline levels of sTNFR-2, those who initiated aspirin/NSAID use after blood collection had significant reductions in subsequent risk of CRC (multivariate RR, 0.39; 95% CI, 0.180.86). In contrast, among women with low baseline levels of sTNFR-2, initiation of aspirin/NSAID use was not associated with significant risk reduction (multivariate RR, 0.86; 95% CI, 0.411.79). Plasma levels of CRP and IL-6 were not significantly associated with CRC risk. Conclusions: Plasma levels of sTNFR-2, but not CRP or IL-6, are associated with an increased risk of CRC. Anti-inflammatory drugs appear to reduce risk of CRC among women with high, but not low, baseline levels of sTNFR-2. Certain subsets of the population, defined by inflammatory markers, may obtain different benefits from anti-inflammatory drugs. © 2011 AGA Institute.


Mendivil C.O.,Harvard University | Mendivil C.O.,University of Los Andes, Colombia | Rimm E.B.,Harvard University | Rimm E.B.,Channing Laboratory | And 4 more authors.
Circulation | Year: 2011

Background-: Low-density lipoprotein (LDL) that contains apolipoprotein (apo) C-III makes up only 10% to 20% of plasma LDL but has a markedly altered metabolism and proatherogenic effects on vascular cells. Methods and Results-: We examined the association between plasma LDL with apoC-III and coronary heart disease in 320 women and 419 men initially free of cardiovascular disease who developed a fatal or nonfatal myocardial infarction during 10 to 14 years of follow-up and matched controls who remained free of coronary heart disease. Concentrations of LDL with apoC-III (measured as apoB in this fraction) were associated with risk of coronary heart disease in multivariable analysis that included the ratio of total cholesterol to high-density lipoprotein cholesterol, LDL cholesterol, apoB, triglycerides, or high-density lipoprotein cholesterol and other risk factors. In all models, the relative risks for the top versus bottom quintile of LDL with apoC-III were greater than those for LDL without apoC-III. When included in the same multivariable-adjusted model, the risk associated with LDL with apoC-III (relative risk for top versus bottom quintile, 2.38; 95% confidence interval, 1.54-3.68; P for trend <0.001) was significantly greater than that associated with LDL without apoC-III (relative risk for top versus bottom quintile, 1.25; 95% confidence interval, 0.76-2.05; P for trend=0.97; P for interaction <0.001). This divergence in association with coronary heart disease persisted even after adjustment for plasma triglycerides. Conclusions-: The risk of coronary heart disease contributed by LDL appeared to result to a large extent from LDL that contains apoC-III. © 2011 American Heart Association, Inc.


Yu Y.,New England Eye Center | Reynolds R.,New England Eye Center | Rosner B.,Channing Laboratory | Daly M.J.,Massachusetts General Hospital | And 3 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. Understanding the effect of genes on progression to different stages of age-related macular degeneration (AMD) may suggest stage-specific therapeutic targets and more precise prediction of the development of this disease. METHODS. Progression events and time to each stage of AMD were derived from the longitudinal data of 2560 subjects without advanced AMD. SNPs in 12 AMD risk loci were genotyped. A multistate Markov model for progression from normal to intermediate drusen, then to large drusen, and eventually to neovascular disease (NV) or geographic atrophy (GA) was applied to estimate stage-specific hazard ratios for each SNP. The effects of these genetic factors were also estimated by a multivariate multistate Markov model adjusted for baseline age, sex, smoking, body mass index (BMI), education, antioxidant treatment, and the status of AMD in the fellow eye. RESULTS. Controlling for demographic and behavioral factors and other SNPs, the TT genotype of rs10468017 in LIPC was associated with decreased risk of progression from large drusen to NV (HR = 0.57, P = 0.04) and tended to reduce the risk of progression from normal to intermediate drusen (HR = 0.72, P = 0.07). The SNP rs1883025 (T allele) in ABCA1 was associated with decreased risk of progression from normal to intermediate drusen (HR per allele = 0.82 per allele, P = 9.7 = 10 -3) and from intermediate drusen to large drusen (HR per allele = 0.77, P = 5.2 = 10 -3). The genes CFH, C3, CFB, and ARMS2/HTRA1 were associated with progression from intermediate drusen to large drusen and from large drusen to GA or NV. CONCLUSIONS. Genes in different pathways influence progression to different stages of AMD. © 2012 The Association for Research in Vision and Ophthalmology, Inc.


Seddon J.M.,Tufts Medical Center | Seddon J.M.,Tufts University | Reynolds R.,Tufts Medical Center | Shah H.R.,Tufts University | Rosner B.,Channing Laboratory
Ophthalmology | Year: 2011

Objective: We evaluated monozygotic twin pairs with discordant age-related macular degeneration (AMD) phenotypes to assess differences in behavioral and nutritional factors. Design: Case series. Participants: Caucasian male twin pairs from the United States Twin Study of Macular Degeneration. Methods: Twin pairs were genotyped to confirm monozygosity. Ocular characteristics were evaluated based on fundus photographs using the Wisconsin Grading System and a 5-grade Clinical Age-Related Maculopathy Staging System. We selected twin pairs discordant in each of the following phenotypic categories: Stage of AMD (n = 28), drusen area (n = 60), drusen size (n = 40), and increased pigment area (n = 56). The Wilcoxon signed-rank test and linear regression were used to assess associations between behavioral and nutritional characteristics and each phenotype within discordant twin pairs. Main Outcome Measures: Differences in smoking and dietary factors within twin pairs discordant for stage of AMD, drusen area, drusen size, and pigment area. Results: Representative fundus photographs depict the discordant phenotypes. Pack-years of smoking were higher for the twin with the more advanced stage of AMD (P = 0.05). Higher dietary intake of vitamin D was present in the twins with less severe AMD (P = 0.01) and smaller drusen size (P = 0.05) compared with co-twins, adjusted for smoking and age. Dietary intakes of betaine and methionine were significantly higher in the twin with lower stage of AMD (P = 0.009) and smaller drusen area (P = 0.03), respectively. Conclusions: The twin with the more advanced stage of AMD, larger drusen area, drusen size, and pigment area tended to be the heavier smoker. The twin with the earlier stage of AMD, smaller drusen size and area, and less pigment tended to have higher dietary vitamin D, betaine, or methionine intake. Results suggest that behavioral and nutritional factors associated with epigenetic mechanisms are involved in the etiology of AMD, in addition to genetic susceptibility. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2011 American Academy of Ophthalmology.


Reynolds R.,New England Eye Center | Rosner B.,Channing Laboratory | Seddon J.M.,New England Eye Center | Seddon J.M.,Tufts University
Ophthalmology | Year: 2010

Objective A genetic variant in the high-density lipoprotein (HDL) cholesterol pathway, hepatic lipase (LIPC), was discovered to be associated with advanced age-related macular degeneration (AMD) in a genome-wide association study. In this study, we evaluated whether LIPC is associated with serum lipids, and whether this gene and serum lipids are independently associated with AMD. Design Case-control study. Participants A total of 458 participants from the Progression Study of Macular Degeneration and the Age-Related Eye Disease Ancillary Biomarker Study, including 318 advanced AMD cases with either geographic atrophy (n = 123) or neovascular disease (n = 195) and 140 controls. Methods Participants were genotyped for 8 variants associated with AMD: 2 CFH variants, C2, CFB, C3, CFI, the ARMS2/HTRA1 gene region, and LIPC. Fasting blood specimens were obtained at study onset, and serum levels of total cholesterol, low-density lipoprotein (LDL), HDL, and triglycerides were determined. Logistic and linear regression were used to evaluate associations between serum lipids, LIPC genotype, and AMD. Main Outcome Measures LIPC and serum lipid associations with AMD. Results The minor T allele of the LIPC gene was associated with a reduced risk of AMD (odds ratio, 0.4; 95% confidence interval, 0.20.9; P = 0.01, trend for number of T alleles, controlling for age and gender). Mean level of HDL was lower (P = 0.05) and mean level of LDL (P = 0.03) was higher in cases of advanced AMD compared with controls. Higher total cholesterol and LDL levels were associated with increased risk of AMD, with P for trend = 0.01 for both, in models controlling for environmental and genetic covariates. The T allele of LIPC was associated with higher levels of HDL, although LIPC was associated with advanced AMD independent of HDL level. Conclusions The HDL-raising allele of the LIPC gene (T) was associated with a reduced risk of AMD. Higher total cholesterol and LDL levels were associated with increased risk, whereas higher HDL levels tended to reduce the risk of AMD. The specific mechanisms underlying the association between AMD and LIPC require further investigation. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references. © 2010 American Academy of Ophthalmology.


Reynolds R.,New England Eye Center | Rosner B.,Channing Laboratory | Seddon J.M.,New England Eye Center | Seddon J.M.,Tufts University
Ophthalmology | Year: 2013

Objective: To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD), and progression to geographic atrophy (GA). Design: Observational analysis of a prospective cohort. Participants: A total of 2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not. Methods: Eyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements, were collected at baseline using questionnaires. Dietary data were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids and interaction effects between dietary fat intake and genetic variation on risk of GA. Main Outcome Measures: Associations between dietary fat intake reported from FFQs, genetic variants, and incident GA. Results: Increased intake of DHA was significantly associated with reduced risk of progression to GA in models with behavioral factors (model A) plus genetic variants (model B) (P trend = 0.01 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in model B (P trend = 0.02). Monounsaturated fat was associated with increased risk in model A (P trend = 0.05). DHA intake was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002; P for interaction between gene and fat intake = 0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90). Conclusions: Increased self-reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA. © 2013 American Academy of Ophthalmology.


Schernhammer E.S.,Channing Laboratory | Schernhammer E.S.,Harvard University | Razavi P.,University of Southern California | Li T.Y.,Channing Laboratory | And 4 more authors.
Journal of the National Cancer Institute | Year: 2011

Night shift work is associated with increased risk of several cancers, but the risk of skin cancer among night shift workers is unknown. We documented 10799 incident skin cancers in 68336 women in the Nurses' Health Study from June 1988 to June 2006 and examined the relationship between rotating night shifts and skin cancer. We used Cox proportional hazard models, adjusted for confounding variables (phenotypic and established risk factors of skin cancer), and performed stratified analysis to explore the modifying effect of hair color. Working 10 years or more on rotating night shifts was associated with a 14% decreased risk of skin cancer compared with never working night shifts (age-standardized incidence rate: 976 per 100000 person-years (PY) vs 1070 per 100000 PY, respectively; adjusted hazard ratios = 0.86, 95% confidence interval = 0.81 to 0.92, Ptrend <. 001). This association was strongest for cutaneous melanoma; working 10 years or more of rotating night shifts was associated with 44% decreased risk of melanoma, after adjustment for melanoma risk factors (age-standardized incidence rate: 20 per 100000 PY vs 35 per 100000 PY, respectively; adjusted hazard ratios = 0.56, 95% confidence interval = 0.36 to 0.87, Ptrend =. 005). Hair color, a surrogate for an individual's susceptibility to skin cancer, was a statistically significant effect modifier for the observed associations; darker-haired women had the lowest risk (Pinteraction =. 02). © 2011 The Author.


Forman J.P.,Channing Laboratory | Williams J.S.,Harvard University | Fisher N.D.L.,Harvard University
Hypertension | Year: 2010

Vitamin D regulates the renin-angiotensin system (RAS) in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the RAS in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II (Ang II) and the renal plasma flow response to infused Ang II, which is an indirect measure of the intrinsic RAS activity in the kidney. Compared with individuals with sufficient 25-hydroxyvitamin D levels (≥30.0 ng/mL), those with insufficiency (15.0 to 29.9 ng/mL) and deficiency (<15.0 ng/mL) had higher circulating Ang II levels (P for trend=0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused Ang II (mean decrease of 115 mL/min per 1.73 m in renal plasma flow versus 145 mL/min per 1.73 m2 among those with sufficient vitamin D levels; P for trend=0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy humans. Copyright © 2010 American Heart Association. All rights reserved.

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