PERSPECTIVES

1994, and the Omni 2 cohort in 2003. These

TIMELINE
cohorts consisted of individuals from ethnic
minorities, to improve the ethnic diversity
The Framingham Heart Study of the study sample. Finally, owing to the
long duration of follow‑up and the rich
— 67 years of discovery in and carefully collected phenotypic data,
the FHS is well positioned to study disease
metabolic disease trends over time, including insights into the
natural history of disease, and long-term
disease outcomes.
Michelle T. Long and Caroline S. Fox
Obesity
Abstract | The Framingham Heart Study (FHS), initiated in 1948, is the longest Body weight was recognized early in
running prospective cohort study in the USA. Through >65 years of discovery, the course of the FHS as a risk factor for
the FHS has contributed to our understanding of obesity, type 2 diabetes cardiovascular disease1. Individuals with
mellitus and prediabetes mellitus, the metabolic syndrome and nonalcoholic obesity had more than double the risk of
developing angina pectoris and coronary
fatty liver disease (NAFLD), and to how these conditions relate to our overall and heart disease over a 12‑year period
cardiovascular-related mortality. This Timeline gives an overview of the compared with individuals with normal
substantial role the FHS has played in advancing the understanding of obesity, weight 1. Increased risk of angina pectoris
diabetes mellitus and NAFLD, and considers the direction the FHS will take in and sudden death was associated with
the years to come. obesity alone in men, but with obesity in
combination with additional risk factors in
women. In 1981, obesity was shown to be
Major advances in the understanding of FHS design an independent marker for the prediction of
obesity, type 2 diabetes mellitus (T2DM) A number of design features have enabled future glucose intolerance2. Whereas other
and other metabolic diseases have been the FHS to be particularly well suited to studies typically focus on extremes of body
achieved over the past 60 years. The make substantial contributions to the weight, the community-based population
Framingham Heart Study (FHS) — a multi- understanding of metabolic diseases. sample of the FHS enables estimation
generational, community-based, prospective First, when the initial cohort of 5,209 of the relationships between various
cohort study — has been uniquely men and women between the ages of categories of BMI and risk of cardiovascular
positioned to lead to a number of important 30 and 62 years (the Original cohort) disease in a prospective fashion. In the
insights into the understanding of both was recruited, it included a large number Framingham experience of up to 44 years
cardiovascular and metabolic diseases. of spousal pairs and extended families. of follow‑up, compared with normal BMI,
Initiated in 1948 in response to the rapidly In 1971, the FHS was expanded and the overweight and obesity were associated
increasing incidence of cardiovascular- children of the Original cohort and their with incident hypertension, T2DM and
related death, the FHS is a long-running spouses were invited to participate in the angina pectoris3 (TABLE 1). Increased BMI
study of the epidemiology of chronic Offspring cohort in order to enhance has also been associated with increased
disease in the USA (FIG. 1). Initially the study of familial disease patterns (FIG. 1). risks of heart failure4 and new-onset atrial
planned as a 20‑year study to identify This design provided two generations of fibrillation5 (TABLE 1).
factors that predisposed people to participants for the study of familial and Early in the 1980s, obesity began to be
coronary heart disease (and more genetic influences on disease and phenotype recognized as a heterogeneous disease6.
broadly, cardiovascular disease) the FHS occurrence. Later, in 2002, the children A study of the importance of body-fat
is universally recognized in this field, of the Offspring cohort participants were distribution as a predictor of metabolic
especially for the development of the enrolled in the Third Generation cohort, disease demonstrated that women with
Framingham Risk Scores. Over the ensuing which provided additional opportunities central obesity had higher plasma glucose
decades, the study was continued and to explore the relation of genetic factors to and insulin levels during oral glucose loading
expanded to include other chronic diseases, various conditions. Second, individuals than women with obesity predominantly in
notably obesity, T2DM and other metabolic in the Original, Offspring and Third the lower body 6. In the biannual tests of the
diseases. This Timeline article reviews the Generation cohorts were predominantly FHS Original Cohort, individuals underwent
major findings and outcomes related to white and of European descent, which is detailed measures of skinfolds and waist
obesity, T2DM and nonalcoholic fatty liver not representative of the US population. circumference, enabling estimates to be made
disease (NAFLD) made in >65 years of In recognition of this limitation, the FHS of regional body-fat distribution. In 1991,
discovery through the FHS (FIG. 2). investigators recruited the Omni cohort in regional obesity (particularly abdominal

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PERSPECTIVES
Original
(n = 5,209; 55% female)
1945 1950 1955 1960 1965
Figure 1 | Cohorts of the Framingham Heart Study. The Offspring
cohort consists of children of individuals in the Original cohort, along with
their spouses.  The Omni and Omni 2 cohorts consist of individuals from
minority ethnic backgrounds, enrolled to reflect the diversity of the national
obesity) was found to be an independent
contributor to cardiovascular disease at a
given level of adiposity 7. After adjustment
for cardiovascular disease risk factors and
BMI, measures of central obesity were
associated with incident stroke and heart
failure in men and with incident coronary
heart disease, cardiovascular mortality and
all-cause mortality in men and women7.
Waist circumference is an easily obtained
but imprecise measure of abdominal
adiposity that is not able to distinguish
between visceral adipose tissue (VAT) and
subcutaneous adipose tissue (SAT) deposits;
the waist‑to‑hip ratio is a more reliable
predictor of cardiovascular measures than
waist circumference alone, but is still unable
to accurately distinguish between VAT
and SAT8. In recognition of this limitation,
beginning in 2002 individuals in the FHS
Offspring and Third Generation cohorts
were invited to participate in a sub-study to
measure coronary and aortic calcium and
ectopic fat by multi-detector CT (MDCT).
The availability of this information has
enabled the exploration of three radiographic
indices of ectopic fat: quantity, location
and quality 9. Although results from the
FHS show that both types of adipose tissue
are associated with metabolic risk factors,
VAT is more strongly associated than SAT
with an adverse metabolic risk profile10,
including levels of fasting plasma glucose,
triglycerides and HDL cholesterol, and
incidence of hypertension, diabetes mellitus
and the metabolic syndrome. The association
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Offspring
(n = 5,124; 52% female)
1970 1975 1980 1985
Time (year)
population. The Third Generation cohort Nature
in the Offspring cohort. The New Offspring Spouse cohort consists of
spouses of individuals in the Offspring cohort with at least two children in
the Third Generation cohort, and was added to improve statistical power.
between VAT and all risk factors examined
is consistently stronger for women than
for men (TABLE 2). These observations
support the hypothesis that VAT is a unique,
pathogenic fat depot. In a prospective study
involving 3,086 participants in the FHS, the
associations between the volume of VAT
and incident cardiovascular disease and
cancer were determined, after adjustment
for generalized and central adiposity 11. In
multivariable-adjusted models, VAT was
associated with incident cardiovascular
disease and cancer, whereas no significant
associations were demonstrated for other
fat depots (including SAT, periaortic fat and
pericardial fat). In addition to the quantity
of fat, the location of ectopic fat deposits has
important implications for cardiometabolic
risk. For example, in 1,155 individuals
who were enrolled in the FHS and free of
cardiovascular disease, pericardial fat rather
than intrathoracic fat was associated with
coronary artery calcium after multivariable
adjustment 12. This result suggests a paracrine
role for the ectopic (pericardial) fat depot
on the thoracic vasculature. Evidence
also suggests that indirect measures of
fat quality, such as adipocyte size13 and
adipocyte bed vascularity 14, could have
important implications for the evaluation of
cardiometabolic risk associated with ectopic
fat. In adipose tissue, high lipid content
and low vascularity are associated with low
attenuation on MDCT scans15. The FHS has
used attenuation in MDCT (measured in
Hounsfield units) as a noninvasive marker
© 2016 Macmillan Publishers Limited. All rights reserved
Omni
(n = 506; 58% female)
Third Generation
(n = 4,095; 53% female)
Omni 2
(n = 410; 57% female)
New Offspring Spouse
(n = 103; 54% female)
1990 1995 2000 2005 2010 2015
consistsReviews
of children of individuals
| Endocrinology
of fat quality. Low levels of attenuation in
VAT and SAT are associated with adverse
cardiometabolic risk above and beyond total
adipose tissue volume16. For example, in a
multivariable model with adjustment for
VAT volume, a decrease of 1 Hounsfield unit
in VAT was associated with increased risk of
having impaired fasting glucose (OR 1.48,
95% CI 1.18–1.85, P <0.001), the metabolic
syndrome (OR 1.53, 95% CI 1.20–1.95,
P <0.001) and insulin resistance (OR 1.46,
95% CI 1.13–1.89, P <0.001) in women;
similar trends were also seen in men16. In
contrast to the cross-sectional population
sampling, the results of a prospective study
of 3,324 individuals demonstrated that a
1 SD Hounsfield unit increase in VAT and
SAT was associated with increased all-cause
mortality (HR 1.99, 95% CI 1.47–2.69,
P <0.001) and cancer-related mortality
(HR 1.93, 95% CI 1.27–2.94, P = 0.002)
in multivariable-adjusted models17. This
association could be the result of systemic
inflammatory states characterized by
high levels of inflammatory macrophages,
proinflammatory cytokines and components
of the extracellular matrix, which can
promote fibrosis and vascularity of the fat
tissue, leading to increased attenuation
on MDCT18.
Trends in obesity
The long-running FHS is well suited to the
identification of trends in the occurrence of
disease in the community. For example, the
incidence rates for overweight and obesity
 PERSPECTIVES

in women were found to increase twofold Original cohort enrolment of two-thirds

(from 15.0% to 33.1%) and threefold (from
3.9% to 14.0%), respectively, over a 50‑year
period from 1950 to 2000 (REF. 19). Similar
increases were also observed in men19.
These changes have occurred progressively,
indicating that the trend is not just a recent
problem. Increasing prevalence of obesity
has also been observed in the National
Health and Nutrition Examination Survey
(NHANES), which included a sample
that was more representative of the US
population than that in the FHS20.
of the population of Framingham,
Massachusetts, by the US Public Health
Services, led by Gilcin Meadors and a
committee of community leaders
Framingham relative weight
index developed64
Results from the FHS showed that
physical activity reduces the risk
of heart disease, whereas obesity
increase this risk1
1948
National Heart Institute (now
known as the NHLBI) takes over
1949 the FHS and Thomas R. Dawber
becomes the director
1957
The term ‘risk factor’ (now part of
1961 everyday medical parlance) was
coined in relation to the FHS65
1967
1971 Children of the original cohort
(Offspring cohort) enrolled

Genetics of obesity Diabetes mellitus noted to be an

Over the past decade, technological advances
have introduced genetic screening into
population-based studies, such as the FHS.
Genome-wide association studies (GWAS)
constitute a high-throughput, unbiased
approach that has enabled identification
of dozens of genes that are associated with
fat deposition in compartments including
VAT21, SAT21, pericardial fat 22, fatty liver 23
and renal sinus fat 24. The FHS, through
participation in ‘big science’ projects and
genetic consortia, has contributed to the
identification of novel loci in genetic studies
of obesity 25,26, revealing new insights into the
relationships between adipose tissue, lipid
biology and body-fat distribution27.
T2DM
Similar to obesity, T2DM was recognized as
an important risk factor for cardiovascular
disease early in the course of the FHS.
Compared with unaffected individuals,
the presence of T2DM is associated with
a twofold to fourfold increased risk of
myocardial infarction28, as well as an
increased risk of congestive heart failure29,
peripheral artery disease30, stroke28 and
overall mortality 28. T2DM was consistently
noted to be a stronger relative risk factor
for cardiovascular disease in women than
in men, although men had higher absolute
event rates for cardiovascular disease
(age-adjusted average annual incidence
of cardiovascular disease per 1,000
cardiovascular disease events in individuals
with T2DM was 27.2 for women and 39.1
for men)28. The population attributable
fraction (PAF) of T2DM on cardiovascular
disease was 7.3 for women and 5.0 for men,
and the PAF of T2DM on cardiovascular-
disease-related death was 18.3 for women
compared with 7.1 for men28. In another FHS
investigation, compared with normal fasting
glucose, impaired fasting glucose levels
corresponding to prediabetes mellitus were
found to be associated with increased relative
important cardiovascular disease 1979
risk factor28
1980 Extraction of DNA from blood
samples of the Original
cohort and Offspring cohort
1990 for genetic analyses
Omni cohort
recruitment began 1994
Simple algorithm developed to enable
prediction of multivariate CHD risk in
1998
Quantitative brain MRI scans and results
patients without overt CHD
of a comprehensive neuropsychological
battery of tests obtained on ~3,000 of 1999
the Offspring cohort The metabolic syndrome
was formally acknowledged
2001 as a syndrome40
Third Generation Obesity found to be a risk
cohort recruited 2002 factor for heart failure4
Omni 2 cohort
recruited 2003 Lifetime risk of becoming
overweight found to be
>70%, risk of becoming
NHLBI and Boston 2005 obese ~50%
University launch SHARe
project to make GWAS data
Demonstration of relevance of network
available to researchers 2007 phenomena to obesity, and apparent
FHS contributes to identification of spread through social ties63
hundreds of genes underlying major 2009
heart disease risk factors, including BMI,
blood cholesterol, tobacco smoking,
blood pressure, glycaemia and T2DM 2015 Use of mobile technology
and digital data collection
(eHealth) initiated
Figure 2 | Selected milestones from the first 67 years of the FHS. CHD, coronary heart disease;
Nature
FHS, Framingham Heart Study; GWAS, genome-wide association study; Reviews
NHLBI, | Endocrinology
National Heart, Lung,
and Blood Institute; SHARe, SNP Health Association Resource, T2DM, type 2 diabetes mellitus.
risk of cardiovascular disease in women, of the increased incidence of T2DM was
but not in men31. These findings have also among individuals with obesity 33. However,
been confirmed in a meta-analysis of 37 no difference was observed between the
prospective cohort studies32. incidence of T2DM in the FHS in the 2000s
compared with the 1990s34. To determine the
Trends in T2DM as a risk factor effect of the rise in the incidence of T2DM
The long follow‑up duration and prospective on cardiovascular complications, rates of
design of the FHS have enabled the cardiovascular disease among participants
observation of changes in disease incidence with and without T2DM between 1950 and
over time. For example, the incidence of 1995 have been investigated35. Although
T2DM in adults aged 40–55 years in the the rate of incident cardiovascular disease
1990s was double that in the 1970s33. Most events in individuals with T2DM fell by

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PERSPECTIVES

Table 1 | BMI and cardiovascular risk in the FHS with 44 years of follow-up3–5 hypertension and T2DM were at greatest
risk of poor performance on tests of visual
Cardiovascular Women Men organization and memory 43. The association
disease outcome
Overweight Obesity Overweight Obesity between T2DM and cognitive decline has
Atrial fibrillation5*‡ 1.11 (0.83–1.50) 1.45 (1.03–2.05) 1.09 (0.82–1.43) 1.49 (1.06–2.09) subsequently been confirmed by a similar
observation in the Whitehall II cohort study 44.
CHF4*§ 1.50 (1.12–2.02) 2.12 (1.51–2.97) 1.20 (0.87–1.64) 1.90 (1.30–2.79)
In 1999, a substudy 45 utilizing brain
Angina pectoris3||¶ 1.42 (1.08–2.05) 1.63 (1.18–2.25) 1.47 (1.12–1.92) 1.81 (1.28–2.55) MRI scanning and a comprehensive
Myocardial infarction 3||¶
0.91 (0.61–1.36) 1.46 (0.94–2.28) 1.26 (0.98–1.61) 1.17 (0.82–1.67) neuropsychological test battery was
T2DM3||# 0.91 (0.72–1.15) 1.36 (1.03–1.78) 1.27 (0.97–1.67) 1.85 (1.31–2.61) conducted in order to establish baseline
measures of brain morphology and cognitive
Total cardiovascular 1.13 (0.96–1.33) 1.38 (1.14–1.68) 1.24 (1.07–1.48) 1.38 (1.12–1.69)
disease3||¶ function in nearly 3,000 individuals in the
FHS Offspring cohort. The availability of
Cardiovascular-disease- 0.77 (0.50–1.18) 1.56 (1.00–2.43) 1.05 (0.74–1.48) 0.98 (0.59–1.63)
related death3||¶
brain MRI data has enabled exploration of the
association between metabolic dysregulation
Overweight, BMI 25.0–29.9 kg/m2; obesity, BMI ≥30.0 kg/m2. Risks are relative to individuals with normal BMI
(18.5–24.9 kg/m2). *Hazard ratio (95% CI). ‡Adjusted for age, systolic blood pressure, use of antihypertensive and markers of cognitive performance and
therapy, type 2 diabetes mellitus (T2DM), electrocardiographic left ventricular hypertrophy (LVH), prior brain volume. Cross-sectionally, various
myocardial infarction or congestive heart failure (CHF), regular cigarette smoking in the prior year and indices of metabolic dysfunction, including
significant heart murmur. §Adjusted for age, alcohol consumption, total cholesterol, current cigarette
smoking, valve disease, T2DM, electrocardiographic LVH and myocardial infarction. ||Relative risk (95% CI). T2DM, insulin resistance as defined by
¶
Adjusted for age, cigarette smoking, hypertension, hypercholesterolaemia and T2DM. #Adjusted for age, HOMA and fasting insulin and HbA1c
cigarette smoking, hypertension, and hypercholesterolaemia. FHS, Framingham Heart Study.
levels, were all associated with lower total
cerebral brain volume, as measured by MRI45.
50% in this time period, the absolute risk than those with a fasting blood sugar level Measures of insulin resistance were inversely
of cardiovascular disease was still twofold <100 mg/dl31. The metabolic syndrome, associated with visual memory and executive
greater in those with T2DM than in a constellation of metabolic traits and a function, whereas glycaemic indices were
those without it35. Moreover, the burden measure of central obesity that have been only associated with impairments to executive
of cardiovascular disease resulting from observed to frequently cluster together, was function. The results of this study suggest
T2DM was greater in the period from the formally acknowledged as a syndrome in 2001 that insulin-resistant states accelerate brain
middle of the 1970s to the 1990s compared (REF. 40). In the FHS, the metabolic syndrome structural and cognitive ageing. In the FHS,
with the 1950s to the 1970s, demonstrating was found to be a strong predictor of incident the observed difference in total cerebral brain
the increasing importance of T2DM as a T2DM, conferring a nearly sevenfold increase volume between individuals with and without
contributor to cardiovascular disease risk36. in risk among those fulfilling the definition T2DM is equivalent to around 6 years of
Additionally, although morbidity has fallen of the metabolic syndrome compared with chronological ageing 45.
for both men and women with T2DM in the those who did not41. In order to better
FHS, mortality is approximately twice as high identify individuals with an increased risk of T2DM genetics and metabolomics
in those with T2DM as in those without it37. developing T2DM, a prediction equation for Family history of T2DM has long been
The higher mortality associated with T2DM incident disease was developed in the FHS42. recognized to contribute to the risk of the
might, in part, be the result of suboptimal The prediction equation consists of a ‘simple disease in offspring, and levels of fasting
reduction in risk factors. In a sample of clinical model’ that includes parental history glucose have been found to be heritable
individuals in the FHS with T2DM who of T2DM, obesity, hypertension, low HDL in the FHS cohort 46. Through GWAS, a
became 50 years old between 2000 and 2005, cholesterol levels, high triglyceride levels and number of genes associated with fasting
hypertension and LDL cholesterol levels were impaired fasting glucose42. With these readily glucose and T2DM have been identified47–49.
controlled in 14.8% and 23.1%, respectively, available clinical variables, this prediction To test whether knowledge of these genetic
17.1% were active smokers and 61.8% were model enables identification of individuals at loci can improve the ability to predict who
obese38. Among individuals without T2DM high risk of T2DM before they develop overt will develop T2DM, 18 well-validated
who became 50 years old between 2000 and disease (C‑statistic 0.881)42. single nucleotide polymorphisms that were
2005, blood pressure was under optimal previously associated with T2DM were
control in 36.0%, and only 23.5% were Neurocognitive markers genotyped in 2,377 individuals enrolled
obese, 19.2% were active smokers and LDL The FHS has included measures of cognitive in the FHS50. Knowledge of an individual’s
cholesterol levels were controlled in 19.9%38. function, as assessed by tests of learning, genotype score was not found to improve
Similar findings were observed in a study of memory, visual organization, verbal fluency on the simple clinical model previously
individuals enrolled in NHANES39. attention, concept formation and abstract developed in the FHS50,51. Using technologies
reasoning, which has enabled the evaluation that enable the high-throughput profiling
Risk factors for incident T2DM of risk factors for cognitive decline. In a of metabolic status from analysis of blood
An understanding of the risk factors for prospective analysis of around 30 years samples, the potential for metabolic profiling
T2DM is important for the early detection of FHS data, the duration of T2DM was to predict the development of T2DM
of disease. In the FHS, individuals with a associated with increased risk of poor has been investigated within the FHS52.
fasting blood sugar level in the prediabetes performance on tests of verbal memory and Measurement of a combination of three
mellitus range have a 4‑year risk of concept formation43. The results of this study amino acids (isoleucine, phenylalanine and
diabetes mellitus that is 12.7‑fold higher demonstrated an interaction between blood tyrosine) was found to improve prediction
(in men) and 22.3‑fold higher (in women) pressure and T2DM, as individuals with of future T2DM, and individuals in the top

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 PERSPECTIVES

Table 2 | The association of VAT with metabolic risk factors in the FHS9 visceral fat59 (TABLE 3). Liver fat could be an
important ectopic fat depot that confers
Risk factors Women Men Sex additional risk over other visceral fat
interaction
Effect size P Effect size or P
(P) depots. In the FHS, NAFLD defined by
or odds ratio odds ratio MDCT has been associated with multiple
Continuous risk factors* measures of vascular dysfunction, which
Systolic blood pressure‡ 4.8 ± 0.4 <0.0001 3.3 ± 0.4 <0.0001 <0.0001 highlights the importance of liver fat in the
atherosclerotic pathway 60. In particular, after
Diastolic blood pressure ‡
2.6 ± 0.3 <0.0001 2.6 ± 0.2 <0.0001 0.01
adjusting for cardiovascular disease risk
Fasting plasma glucose§ 4.8 ± 0.4 <0.0001 3.1 ± 0.5 <0.0001 <0.0001 factors and adiposity measures, NAFLD was
Log[triglycerides] ||
0.23 ± 0.01 <0.0001 0.22 ± 0.01 <0.0001 0.0002 correlated with measures of microvascular
HDL cholesterol|| −5.9 ± 0.4 <0.0001 −4.5 ± 0.7 <0.0001 <0.0001 dysfunction. Individuals with NAFLD had
higher resting blood-flow velocity in the
Dichotomous risk factors¶ brachial artery than those without NAFLD,
Hypertension 2.1 (1.8–2.4) <0.0001 1.9 (1.6–2.1) <0.0001 0.01 which might contribute to microvascular
Impaired fasting glucose 2.5 (2.1–2.9) <0.0001 1.8 (1.6–2.0) <0.0001 <0.0001 damage. Results from the FHS have also
T2DM 2.1 (1.6–2.6) <0.0001 1.6 (1.3–2.0) <0.0001 0.03
confirmed the association between physical
activity and NAFLD. Individuals in the
Metabolic syndrome 4.7 (3.9–5.7) <0.0001 4.2 (3.5–5.0) <0.0001 0.002 FHS who engaged in moderate-to‑vigorous
For all individuals, regression was adjusted for age, cigarette smoking, alcohol use and physical activity. physical activity at the level recommended
For women, regression was also adjusted for menopausal status and hormone replacement therapy.
*Data presented as effect size (average change in risk factor ± SE) per 1 SD in visceral adipose tissue. by the National Physical Activity guidelines
‡
Also adjusted for hypertension treatment. §Also adjusted for type 2 diabetes mellitus (T2DM) treatment. (as measured by an accelerometer) had a
||
Also adjusted for treatment for lipid disorders. ¶Data presented as odds ratio per 1 SD of adipose tissue reduced risk (OR 0.63, P = 0.007) of NAFLD
with 95% CI. FHS, Framingham Heart Study.
compared with those who did not adhere
to the guideline recommendations61. This
quartile of levels of this combination had a suggests that ALT is a potential biomarker finding is particularly important given
fivefold to sevenfold increased risk of T2DM for incident metabolic disease. Results that NAFLD is associated with subclinical
compared with individuals in the lowest obtained in the FHS have also shown that cardiovascular disease outcomes independent
quartile52. This finding has subsequently ALT levels are correlated with multiple of many metabolic diseases and traits62.
been validated in a large European cohort 53. cardiometabolic risk factors above and
Combining genetic and metabolic traits beyond VAT and insulin resistance58. Future directions
with clinical variables modestly improves NAFLD has also been characterized in In the FHS, the importance of personal
the predictive ability for incident T2DM the FHS by measurement of liver MDCT relationships and social networks as
compared with clinical variables alone54. attenuation in individuals in the Offspring, contributing factors to disease was
Third Generation and Omni cohorts. Cross- recognized early on. In 2007, results from
NAFLD sectionally, NAFLD was associated with the FHS showed that obesity apparently
Over the past decade, NAFLD has emerged dyslipidaemia, dysglycaemia, the metabolic spreads through a dense, interconnected
as the most common chronic liver syndrome, T2DM and hypertension; social network63, demonstrating the power
condition in the USA55. The use of serum these associations were independent of of social networks in the epidemiology of
aminotransferase levels as a surrogate for
liver inflammation has enabled a number of
important observations regarding NAFLD to
Table 3 | Association of NAFLD with cardiometabolic risk factors in the FHS59
be made within the FHS. Taking advantage
of the multi-generational design of the Cardiometabolic risk factor Effect* (95% CI) P
FHS, investigators had early insights into Blood glucose (mg/dl) 3.54 (1.54–5.64) 0.001
the familial inheritance of NAFLD, finding
Impaired fasting glucose ‡
1.58 (1.21–2.07) <0.001
that individuals with a history of early-onset
paternal obesity had significantly higher T2DM§ 1.64 (1.11–2.41) 0.012
alanine aminotransferase (ALT) levels Insulin resistance ||
2.79 (2.19–3.65) <0.001
than individuals without such a history Log[triglycerides] 0.22 (0.17–0.28) <0.001
(OR 1.75, 95% CI 1.06–2.89, P = 0.03)56. This
HDL (mg/dl) −2.48 (−3.89 to −1.06) <0.001
observation persisted after accounting for
the BMI of the offspring. The relationships Hypertension¶ 1.52 (1.17–1.97) 0.002
between ALT levels and the development of Metabolic syndrome #
1.95 (1.48–2.56) <0.001
incident T2DM, cardiovascular disease and The prevalence of cardiometabolic risk factors was compared in individuals with and without nonalcoholic
the metabolic syndrome have been studied fatty liver disease (NAFLD), with adjustment for age, sex, drinks per week, menopausal status, hormone
replacement therapy, cigarette smoking, BMI, waist circumference and visceral adipose tissue. *The effect
in the FHS with 20 years of follow‑up. is the change in a continuous dependent trait or in the odds ratio of having a dependent trait in
As ALT levels increase, the risks of incident individuals with NAFLD compared with those without NAFLD. ‡Fasting plasma glucose of 100–125 mg/dl.
metabolic syndrome and T2DM increase, Fasting plasma glucose of ≥126 mg/dl, or treatment for type 2 diabetes mellitus (T2DM). ||Top quartile of
§

insulin resistance as defined by HOMA. ¶Systolic blood pressure ≥140 mmHg, diastolic blood pressure
even in individuals with ALT levels within ≥90 mmHg or antihypertensive treatment. #Defined from the modified Adult Treatment Panel criteria40.
the ‘normal’ range (≤40 U/l)57, which FHS, Framingham Heart Study.

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PERSPECTIVES
disease. Going forward, FHS investigators are
beginning to incorporate mobile technology
and digital data collection (eHealth) into
their studies. Additionally, as technologies
continue to develop, the FHS will use
advances in areas such as metabolomics,
proteomics, high-throughput immunoassays,
gene expression and microRNAs to further
elucidate the mechanisms driving metabolic
diseases, and to uncover novel biomarkers.
Conclusions
Our understanding of obesity, diabetes
mellitus and other metabolic diseases has
progressed tremendously in the past century.
The FHS, with its prospective design, multi-
generational structure and long duration of
follow‑up, has contributed to this remarkable
increase in knowledge for the past 65 years.
In the future, as technological advances
become increasingly available to researchers
in the FHS and other population-based
studies, more unbiased, high-throughput
screens will be implemented. Through the
integration of data from multiple sources
with the existing high-quality phenotypic
and outcome data, we will work to discover
novel biomarkers and to determine the
mechanisms underlying metabolic disease
as it relates to cardiovascular disease.
Michelle T. Long is at the Division of Gastroenterology,
Boston Medical Center, Boston University School of
Medicine, 7th Floor, 85 East Concord Street, Boston,
Massachusetts 02118, USA.
Caroline S. Fox is at the National Heart, Lung, and
Blood Institute’s Framingham Heart Study,
Framingham, Massachusetts 01702–5827, USA.
Correspondence to M.T.L. mtlong@bu.edu
doi:10.1038/nrendo.2015.226
Published online 18 Jan 2016
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PERSPECTIVES
Acknowledgements
The authors acknowledge funding by the Boston University
School of Medicine and the National Heart, Lung, and Blood
I n s t i t u t e ’s F r a m i n g h a m H e a r t S t u d y ( c o n t r a c t
HHSN268201500001I) and the Division of Intramural
Research of the National Heart, Lung, and Blood Institute.
Author contributions
Both authors researched data for the article, contributed
substantially to discussion of the content and to writing the
article, and to reviewing and editing the manuscript
before submission.
Competing interests statement
The authors declare no competing interests.