Luc Djoussé

Lifestyle Risk Factors and New-Onset Diabetes Mellitus in Older Adults: The Cardiovascular Health Study

BACKGROUND The combined impact of lifestyle factors on incidence of diabetes mellitus later in life is not well established. The objective of this study was to determine how lifestyle factors, assessed in combination, relate to new-onset diabetes in a broad and relatively unselected population of older adults. METHODS We prospectively examined associations of lifestyle factors, measured using repeated assessments later in life, with incident diabetes mellitus during a 10-year period (1989-1998) among 4883 men and women 65 years or older (mean [SD] age at baseline, 73 [6] years) enrolled in the Cardiovascular Health Study. Low-risk lifestyle groups were defined by physical activity level (leisure-time activity and walking pace) above the median; dietary score (higher fiber intake and polyunsaturated to saturated fat ratio, lower trans-fat intake and lower mean glycemic index) in the top 2 quintiles; never smoked or former smoker more than 20 years ago or for fewer than 5 pack-years; alcohol use (predominantly light or moderate); body mass index less than 25 (calculated as weight in kilograms divided by height in meters squared); and waist circumference of 88 cm for women or 92 cm for men. The main outcome measure was incident diabetes defined annually by new use of insulin or oral hypoglycemic medications. We also evaluated fasting and 2-hour postchallenge glucose levels. RESULTS During 34,539 person-years, 337 new cases of drug-treated diabetes mellitus occurred (9.8 per 1000 person-years). After adjustment for age, sex, race, educational level, and annual income, each lifestyle factor was independently associated with incident diabetes. Overall, the rate of incident diabetes was 35% lower (relative risk, 0.65; 95% confidence interval, 0.59-0.71) for each 1 additional lifestyle factor in the low-risk group. Participants whose physical activity level and dietary, smoking, and alcohol habits were all in the low-risk group had an 82% lower incidence of diabetes (relative risk, 0.18; 95% confidence interval, 0.06-0.56) compared with all other participants. When absence of adiposity (either body mass index <25 or waist circumference < or =88/92 cm for women/men) was added to the other 4 low-risk lifestyle factors, incidence of diabetes was 89% lower (relative risk, 0.11; 95% confidence interval, 0.01-0.76). Overall, 9 of 10 new cases of diabetes appeared to be attributable to these 5 lifestyle factors. Associations were slightly attenuated, but still highly significant, for incident diabetes defined by medication use or glucose level. CONCLUSION Even later in life, combined lifestyle factors are associated with a markedly lower incidence of new-onset diabetes mellitus.

Association of C-reactive protein with markers of prevalent atherosclerotic disease

Recent prospective studies have demonstrated that elevated C-reactive protein (CRP) is a marker of increased risk of atherothrombotic clinical events. We examined in a large, cross-sectional family-based study (n = 875 men, 948 women) whether serum CRP was associated with prevalent coronary heart disease (CHD), the ankle/brachial blood pressure index, or carotid intima-media thickness, an indicator of subclinical atherosclerosis as assessed by B-mode ultrasound. CRP was associated with many other cardiovascular risk factors, particularly markers of obesity and insulin resistance, markers of inflammation and acute phase reaction, and hormone replacement therapy. Adjusted for age and family type, there was a weak positive association of CRP with carotid intima-media thickness in both genders and with prevalent CHD in women. However, adjustment for other risk factors completely eliminated the associations. For example, among women, the risk factor-adjusted mean values of intima-media thickness across quartiles of CRP were 0.76, 0.74, 0.75, and 0.76 mm (p >0.5). In men there was a weak inverse association between CRP and ankle/brachial blood pressure index, independent of other risk factors, but no such association in women. Our findings indicate that CRP is not strongly and independently associated with prevalent atherosclerosis. Because CRP has been associated with clinical events, it could be that elevated CRP may be a stronger marker of thrombotic risk than of the degree of atherosclerosis.

Weight loss in early stage of Huntington's disease.

Background: Huntington’s disease (HD) is an autosomal dominant disease with neurologic manifestations. In transgenic mouse models of HD, weight loss is recognized as a feature associated with the disease onset. It is unclear whether a similar pattern occurs in humans. Methods: Data from the Huntington Study Group were used to evaluate whether HD is associated with lower body mass index (BMI) at the earliest stage of the disease. There were 361 case subjects in whom HD had been diagnosed with an independence scale rating of 100 (no special care needed), a total functional capacity score of ≥11, and HD duration of <4 years. For each case subject, five sex- and age-matched control subjects were selected from the National Heart, Lung, and Blood Institute Family Heart Study or the Framingham Offspring Study. Results: Among case subjects, neither disease duration, nor dystonia, nor chorea score was significantly associated with BMI. BMI was significantly lower among case than among control subjects. Among men, age-adjusted BMI (±SE) was 25.90 ± 0.34 kg/m2 for case subjects with HD and 27.68 ± 0.16 kg/m2 for control subjects. Among women, corresponding values were 24.34 ± 0.43 for case subjects with HD and 26.63 ± 0.21 kg/m2 for control subjects. Conclusions: At an early stage of the disease, subjects with Huntington’s disease had lower body mass index than matched controls from the general population. The cause of weight loss is unknown but the parallel to observations in Huntington’s disease transgenic mice suggests that it is a significant hallmark of Huntington’s disease gene expression.

Alcohol Consumption and Risk for Congestive Heart Failure in the Framingham Heart Study

Regular, heavy consumption of alcohol is associated with subclinical impairment of left ventricular function (1-3) and occasionally results in overt cardiomyopathy (4). This may be a consequence of direct toxic effects of alcohol or its metabolites (5); coexisting malnutrition (6); associated hypertension (7, 8); increased ventricular mass (9) or, rarely, toxic additives to alcoholic beverages (10). Conversely, moderate alcohol consumption appears to be protective against coronary heart disease (11-14). Myocardial infarction is an important risk factor for congestive heart failure (15-18). By preventing coronary heart disease, moderate alcohol consumption may indirectly protect against congestive heart failure secondary to myocardial infarction. Thus, the relation of alcohol consumption to the risk for congestive heart failure is probably complex, reflecting the interplay of its coronary protective effects and its myocardial toxic effects. Little is known about the effect of alcohol consumption on the incidence of congestive heart failure in community-based populations. We therefore sought to determine the relation between alcohol consumption and risk for congestive heart failure in participants in the Framingham Heart Study. Methods Study Sample The Framingham Heart Study is a prospective epidemiologic cohort study established in 1948 to evaluate potential risk factors for coronary heart disease. The original cohort consisted of 5209 residents of Framingham, Massachusetts, 28 to 62 years of age at entry, who have undergone follow-up evaluations every 2 years. In 1971, 5124 additional participants (the offspring of the original participants and their spouses) were enrolled into the Framingham Offspring Study. These participants undergo follow-up evaluations every 4 years. The study design and entry criteria for both cohorts are described elsewhere (19-22). The study sample was drawn from members of the original cohort who attended examination 12, 15, 17, 20, or 22 (1971 to 1994) and members of the offspring cohort who attended examination 2, 4, or 5 (1979 to 1995). Each of these examinations served as the baseline for subsequent follow-up intervals. Participants with complete information on alcohol consumption at a baseline examination and an examination 6 to 10 years earlier (to identify former drinkers) were eligible for the analysis. All examinations and procedures were approved by the institutional review board of Boston University School of Medicine, and all participants gave informed consent. Ascertainment of Alcohol Consumption At examinations 12 through 15 and 17 through 22 of the original cohort and at all examinations of the offspring cohort, participants were asked about the number of 1.5-oz cocktails, 12-oz glasses (or cans) of beer, and 4-oz glasses of wine they consumed in 1 week. Alcohol intake (g/wk) among participants who consumed at least 1 drink/wk was computed by using the following equation: 28.35 + (0.57 + the number of cocktails per week + 0.44 + the number of beers per week + 0.40 + the number of glasses of wine per week) (23). For each participant, the number of drinks consumed per week was calculated by assuming that each drink contains 13 g of alcohol (24). Men who consumed 15 drinks/wk or more and women who consumed 8 drinks/wk or more were considered to be heavy drinkers in accordance with definitions established by the National Institute of Alcohol Abuse and Alcoholism (25). Participants who reported consuming less than 1 drink/wk at the index examination were further separated into two groups on the basis of reported alcohol consumption at an examination 6 to 10 years before the index examination. Participants who reported consumption of less than 1 drink/wk at the index examination but more than 1 drink/wk at the previous examination were classified as former drinkers. Participants who reported consumption of less than 1 drink/wk at both examinations were classified as nondrinkers and served as the reference group. Baseline Measurements Medical histories and physical examinations were performed for each participant at every clinic visit. Systolic and diastolic blood pressure were measured twice in the left arm of each participant. The average of the two readings was used for each blood pressure variable. The diagnosis of hypertension was based on a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or current use of antihypertensive drugs (26). Total and high-density lipoprotein (HDL) cholesterol levels were measured at each examination except examination 17 of the original cohort. For participants attending examination 17, total and HDL cholesterol levels measured at examination 15 were used. Body mass index was calculated as weight in kilograms divided by the square of the height in meters. Participants were separated according to smoking status into nonsmokers, former smokers, and current smokers (those who smoked cigarettes regularly within 1 year of the index examination). The number of cigarettes smoked per day was recorded for current smokers. Diabetes was defined as a nonfasting blood glucose level of 11.1 mmol/L or greater ( 200 mg/dL), a fasting blood glucose level of 7.8 mmol/L or greater ( 140 mg/dL), or use of insulin or an oral hypoglycemic agent (27). Diagnostic criteria for coronary heart disease (including myocardial infarction, coronary insufficiency, and angina pectoris) are described elsewhere (22). Valvular heart disease was defined as the presence of a systolic murmur louder than II/VI or any diastolic murmur. Electrocardiographic left ventricular hypertrophy was diagnosed if a participant had voltage criteria for left ventricular hypertrophy accompanied by lateral repolarization changes (28). Outcome Measurements The primary outcome of interest was incident congestive heart failure. Participants were monitored for the development of congestive heart failure and other cardiovascular events by using routine periodic clinic examinations and surveillance procedures. Information about such events was obtained through medical history, physical examination, and hospitalization records and by communication with personal physicians. All suspected new events were reviewed by a panel of three experienced investigators who evaluated all pertinent medical and hospital records and pathology reports. Table 1 shows criteria for diagnosis of congestive heart failure. Congestive heart failure was diagnosed if at least two major criteria or one major and two minor criteria were present. Minor criteria were acceptable only if they could not be attributed to another medical condition (such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or the nephrotic syndrome) (29). Table 1. Criteria for Congestive Heart Failure The criteria used to identify participants with congestive heart failure in the Framingham Heart Study compare favorably to other clinically based criteria used to identify persons with congestive heart failure (30) and left ventricular systolic dysfunction (31). Mosterd and colleagues (30) reported that the Framingham Heart Study criteria were 100% sensitive and 78% specific for identifying persons with definite congestive heart failure as determined by clinical assessment by a cardiologist. Statistical Analysis Separate analyses were performed for men and women. Because men and women differed markedly in reported alcohol intake, level of alcohol consumption was categorized differently for each sex. Baseline risk factors were computed for each level of alcohol consumption. Age-adjusted and multivariable-adjusted hazard ratios for congestive heart failure were calculated by using Cox proportional-hazards regression models (32), with pooled follow-up periods and reported alcohol intake at original cohort examinations 12, 15, 17, 20, and 22 and offspring cohort examinations 2, 4, and 5. Nondrinkers served as the reference group. The following covariates were included in the multivariable-adjusted models: age, smoking (cigarettes/d), body mass index, diabetes, valvular heart disease, HDL cholesterol level, and hypertension. The maximum duration of follow-up was 5 years. For participants attending consecutive examinations that were fewer than 5 years apart (original cohort examinations 15 and 17, and 20 and 22 and offspring examinations 4 and 5), follow-up was censored at the time of the repeated examination (approximately 4 years later). Participants who attended more than one index examination could contribute to multiple observations periods. We used the AndersonGill model for multiple failure times (33) to account for the potential for clustering of observations by participant. Because the effect of alcohol consumption on development of congestive heart failure may be mediated through the effects of alcohol on hypertension or HDL cholesterol level, we performed secondary analyses using multivariable-adjusted models, with and without hypertension status and HDL cholesterol as covariates. To determine the association between alcohol consumption and risk for congestive heart failure without interceding myocardial infarction, we calculated age-adjusted and multivariable-adjusted hazard ratios, censoring participants at the time of myocardial infarction that occurred during follow-up. To adjust for differences in medical therapy across alcohol consumption categories, models were constructed that adjusted for medications taken at the index examination (aspirin, -blockers, diuretics, calcium-channel blockers, and angiotensin-converting enzyme inhibitors) in addition to the covariates included in the model used for the primary analysis. For the final model, the proportional hazards assumption was tested and found to be appropriate. Analyses for length-selection biases showed that from the earliest ascertainment of alcohol consumption in the Framingham Study until the period of the current primary analysi

Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis.

The relationship between omega-3 polyunsaturated fatty acids (n-3 PUFA) from seafood sources (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or plant sources (alpha-linolenic acid, ALA) and risk of type 2 diabetes mellitus (DM) remains unclear. We systematically searched multiple literature databases through June 2011 to identify prospective studies examining relations of dietary n-3 PUFA, dietary fish and/or seafood, and circulating n-3 PUFA biomarkers with incidence of DM. Data were independently extracted in duplicate by 2 investigators, including multivariate-adjusted relative risk (RR) estimates and corresponding 95 % CI. Generalized least-squares trend estimation was used to assess dose-response relationships, with pooled summary estimates calculated by both fixed-effect and random-effect models. From 288 identified abstracts, 16 studies met inclusion criteria, including 18 separate cohorts comprising 540,184 individuals and 25,670 cases of incident DM. Consumption of fish and/or seafood was not significantly associated with DM (n = 13 studies; RR per 100 g/d = 1·12, 95 % CI = 0·94, 1·34); nor were consumption of EPA+DHA (n = 16 cohorts; RR per 250 mg/d = 1·04, 95 % CI = 0·97, 1·10) nor circulating levels of EPA+DHA biomarkers (n = 5 cohorts; RR per 3 % of total fatty acids = 0·94, 95 % CI = 0·75, 1·17). Both dietary ALA (n = 7 studies; RR per 0·5 g/d = 0·93, 95 % CI = 0·83, 1·04) and circulating ALA biomarker levels (n = 6 studies; RR per 0·1 % of total fatty acid = 0·90, 95 % CI = 0·80, 1·00, P = 0·06) were associated with non-significant trend towards lower risk of DM. Substantial heterogeneity (I²~80 %) was observed among studies of fish/seafood or EPA+DHA and DM; moderate heterogeneity ( < 55 %) was seen for dietary and biomarker ALA and DM. In unadjusted meta-regressions, study location (Asia vs. North America/Europe), mean BMI, and duration of follow-up each modified the association between fish/seafood and EPA+DHA consumption and DM risk (P-interaction ≤ 0·02 each). We had limited statistical power to determine the independent effect of these sources of heterogeneity due to their high collinearity. The overall pooled findings do not support either major harms or benefits of fish/seafood or EPA+DHA on development of DM, and suggest that ALA may be associated with modestly lower risk. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation.

Genetic loci associated with plasma phospholipid N-3 fatty acids: A Meta-Analysis of Genome-Wide association studies from the charge consortium

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10−64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10−58) and docosapentaenoic acid (DPA, p = 4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10−12) and DPA (p = 1×10−43) and lower docosahexaenoic acid (DHA, p = 1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Intake of Fruits, Vegetables, and Dairy Products in Early Childhood and Subsequent Blood Pressure Change

Background: Diets characterized by high intakes of fruits and vegetables and low-fat dairy products (for example, the DASH diet) have been shown to reduce blood pressure in adults. The effects of similar diets on childrens blood pressure are unknown. Methods: We used 8 years of follow-up data from 95 children, initially 3 to 6 years of age at enrollment in the prospective Framingham Childrens Study in 1986. The yearly clinic visits included 5 measures of blood pressure obtained with an automated device. Diet was assessed by means of replicate sets of 3-day food diaries during each year. Results: Children who consumed more fruits and vegetables (4 or more servings per day) or more dairy products (2 or more servings per day) during the preschool years had smaller yearly gains in systolic blood pressure throughout childhood. By the time of early adolescence, children with higher intakes of fruits and vegetables and dairy products had an adjusted mean (± standard deviation) systolic blood pressure of 106 ± 2.9 mm Hg, whereas those with lower intakes in both food groups had a mean systolic blood pressure of 113 ±1.5 mm Hg. Those with higher intakes of fruits and vegetables alone or dairy alone had intermediate levels of systolic blood pressure in adolescence. The effects on diastolic blood pressure were weaker. Conclusion: These results suggest that a diet rich in fruits, vegetables, and dairy products may have beneficial effects on blood pressure during childhood.

Serum Albumin and Risk of Myocardial Infarction and All-Cause Mortality in the Framingham Offspring Study

Background—Coronary disease remains the leading cause of death in the United States. The association between serum albumin and cardiovascular disease remains controversial. We used data collected prospectively from participants of the Framingham Offspring Study to assess whether a lower concentration of serum albumin was associated with an increased risk of myocardial infarction (MI) and all-cause mortality. Methods and Results—During 21.9 years of mean follow-up, 280 cases of MI occurred. From the highest to the lowest tertile of serum albumin, crude incidence rates of MI were 26.7, 46.7, and 67.8 cases per 10 000 person-years, respectively, for men and 5.9, 15.0, and 16.8 cases per 10 000 person-years, respectively, for women. In a Mantel-Haenszel method adjusting for age, total cholesterol, and hypertension, lower serum albumin was associated with an increased risk of MI in both sexes. From the highest to the lowest tertile of albumin, the adjusted hazard ratios (95% CI) of MI were 1.0 (reference), 1.25 (0.84 to 1.84), and 1.49 (1.01 to 2.21), respectively, for men and 1.0, 1.79 (0.88 to 3.65), and 2.12 (1.06 to 4.27), respectively, for women. The albumin-MI association was stronger among hypertensive subjects in both sexes. In addition, low albumin was associated with an increased rate of all-cause mortality in women. Conclusions—Lower serum albumin concentrations appear to be associated with an increased risk of coronary disease in both sexes and with all-cause mortality in women and could help along with traditional risk factors in identifying people at risk of MI.

A Genome Scan for Modifiers of Age at Onset in Huntington Disease: The HD MAPS Study

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21-23 (LOD=2.29), and 6q24-26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.

Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes

BACKGROUND Although dietary omega-3 (n-3) fatty acids may confer some cardiovascular benefits, it is unclear whether these nutrients may also unfavorably affect risk of type 2 diabetes (T2D). OBJECTIVE We evaluated whether dietary omega-3 fatty acids and fish consumption were associated with increased risk of T2D. DESIGN This was a prospective study of 36,328 women (mean age: 54.6 y) who participated in the Womens Health Study and who were followed from 1992 to 2008. Incident T2D was self-reported and validated primarily through the collection of supplementary information from participants. Information on omega-3 and fish intakes was obtained by using a validated food-frequency questionnaire. We used Cox proportional hazard models to estimate adjusted relative risks. RESULTS During an average follow-up of 12.4 y, 2370 women developed T2D. Marine but not plant-based omega-3 fatty acids were positively associated with incident T2D. From the lowest to highest quintiles of marine omega-3 intake, the multivariable-adjusted hazard ratios (95% CIs) for T2D were 1.0 (referent), 1.17 (1.03, 1.33), 1.20 (1.05, 1.38), 1.46 (1.28, 1.66), and 1.44 (1.25, 1.65), respectively (P for trend < 0.0001). A similar association was observed with fish intake, but additional adjustment for docosahexaenoic acid led to the elimination of the association. The relation between marine omega-3 fatty acids and T2D was observed in hypertensive and nonhypertensive subjects and in women who reported infrequent fish consumption. CONCLUSION Our data suggest an increased risk of T2D with the intake of long-chain omega-3 fatty acids, especially with higher intakes (≥ 0.20 g omega-3/d or ≥ 2 servings of fish/d). The Womens Health Study was registered at clinicaltrials.gov as NCT00000479.