NEWS & VIEWS CORONARY ARTERY DISEASE
Complex association between height and CHD—size matters Pekka J. Karhunen and Tuula Meinander Refers to Nelson, C. P. et al. Genetically determined height and coronary artery disease. N. Engl. J. Med. 372, 1608–1618 (2015)
Meta-analyses and large population-based studies have linked shorter body height with increased risk of coronary heart disease (CHD). This complex association is now confirmed at the gene level, indicating that genetic variants affecting body height and associated with short stature seem to have independent roles as risk factors for CHD. human body height might increase by 5–10 cm in 100 years. The first report on the inverse association between coronary heart disease (CHD) and height was published in 1951. Since then, the association between short stature and cardiovascular diseases has been reported in >1,900 papers according to a database search.4 Although negative and even controversial studies have been published, a metaanalysis4 and two large population-based studies3,5 indicate that this link does exist. In the meta-analysis, the mean relative risk of cardiovascular morbidity and mortality was 1.46 among individuals in the shortest height category compared with those in the tallest category, regardless of sex.4 The hazard ratios were slightly lower in population studies.3,5 Notably, the mechanisms underlying the inverse association between 190
350 300
Height (cm)
185
250
180
200
175
150
170 Male CHD mortality Average height among Finnish conscripts
165 0
100 50
Mortality per 100,000 male population
Adult height is an indicator of overall health and economic well-being and differs substantially between populations, even within the same country. Adult height has increased only slowly through history owing to limited nutritional resources. Wars and famines have had a negative effect, causing a temporary decrease in the average height of populations (Figure 1). The average height of mummies from several thousands of years ago is estimated to be 160–165 cm. On the basis of skeletal data, the average height in northern Europe in the Middle Ages was 173.4 cm during the period of warm climate in 900–1300 AD, which was bene ficial for agriculture.1 Subsequently, a period of colder climate (the Little Ice Age), which lasted for the following 400–500 years, led to a decrease in average height to 167 cm during the 17th and 18th centuries.1 In the first half of the 18 th century, the average height of English men was still only 165 cm.2 The estimated mean height of English, German, and Scottish soldiers ranged from 163.6 cm to 165.9 cm.2 Most histor ical height data are collected on conscripts for military purposes, meaning that data on female heights are scarce. Improved nutrition owing to advances in agricultural technologies and division of labour after the Industrial Revolution accelerated the increase in height in the 20th century: in many industrialized countries, the average body height is now close to 180 cm among men. In an extensive study on 1 million people, the mean adult height was found to increase by 0.5–1.0 cm with each successive decade of birth for people born between 1900 and 1960. 3 If this trend continues,
adult height and the risk of coronary artery disease are unclear. In a new, large study comprising 65,066 patients with CHD and 128,383 controls of European descent, Nelson and colleagues from the CARDIoGRAM+C4D Consortium used a genetic approach to test the association between height and CHD.6 They studied the association between CHD and 180 height-associated genetic variants identified in a previous study, and which explained about 10% of the variation in height. They also performed bioinformatics analyses of the height-associated variants to identify potential biological mechanisms that might link shorter height with an increased risk of CHD. Interestingly, none of these 180 variants lay in a locus previously implicated in genome-wide association studies into susceptibility to CHD. A significant association between the heightassociated single nucleotide polymorphisms (SNPs) and CHD existed among men (OR 0.88), but not among women.6 This association translated to a relative increase of 13.5% in the risk of CHD for each standard deviation decrease in height. Typically for genome-wide association studies, the association between each individual SNP and the risk of CHD was very small: the association was found only when all SNPs were combined. When the study population was divided into four groups on the basis of the number of height-increasing alleles, the odds ratio for quartile 4 (highest number
0 1700 1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2012
Year
Figure 1 | Trends among conscripts in average body height and male Nature CHD mortality 100,000 Reviewsper | Cardiology male population in Finland. Decrease in body height was caused by a period of cold climate ending in several famines starting in 1857. The last big famine was in 1866–1868, during which 150,000 people died. Height data obtained from Nummela, I. Shorty or not? About the history of Finnish population heights. In The Famine Years in the History of Finland. Department of History, Jyväskylä University: Publications on the History of Finland 19, 93–153 (1994) and http://en.wikipedia.org/wiki/Human_height. CHD mortality data obtained from Statistics Finland. Abbreviation: CHD, coronary heart disease.
NATURE REVIEWS | CARDIOLOGY
VOLUME 12 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of alleles) compared with quartile 1 was 0.74 (P 4,000 years.7 Severe atherosclerosis was already common in pre-industrial populations, including pre-agricultural hunter– gatherers who died aged
Complex association between height and CHD—size matters Pekka J. Karhunen and Tuula Meinander Refers to Nelson, C. P. et al. Genetically determined height and coronary artery disease. N. Engl. J. Med. 372, 1608–1618 (2015)
Meta-analyses and large population-based studies have linked shorter body height with increased risk of coronary heart disease (CHD). This complex association is now confirmed at the gene level, indicating that genetic variants affecting body height and associated with short stature seem to have independent roles as risk factors for CHD. human body height might increase by 5–10 cm in 100 years. The first report on the inverse association between coronary heart disease (CHD) and height was published in 1951. Since then, the association between short stature and cardiovascular diseases has been reported in >1,900 papers according to a database search.4 Although negative and even controversial studies have been published, a metaanalysis4 and two large population-based studies3,5 indicate that this link does exist. In the meta-analysis, the mean relative risk of cardiovascular morbidity and mortality was 1.46 among individuals in the shortest height category compared with those in the tallest category, regardless of sex.4 The hazard ratios were slightly lower in population studies.3,5 Notably, the mechanisms underlying the inverse association between 190
350 300
Height (cm)
185
250
180
200
175
150
170 Male CHD mortality Average height among Finnish conscripts
165 0
100 50
Mortality per 100,000 male population
Adult height is an indicator of overall health and economic well-being and differs substantially between populations, even within the same country. Adult height has increased only slowly through history owing to limited nutritional resources. Wars and famines have had a negative effect, causing a temporary decrease in the average height of populations (Figure 1). The average height of mummies from several thousands of years ago is estimated to be 160–165 cm. On the basis of skeletal data, the average height in northern Europe in the Middle Ages was 173.4 cm during the period of warm climate in 900–1300 AD, which was bene ficial for agriculture.1 Subsequently, a period of colder climate (the Little Ice Age), which lasted for the following 400–500 years, led to a decrease in average height to 167 cm during the 17th and 18th centuries.1 In the first half of the 18 th century, the average height of English men was still only 165 cm.2 The estimated mean height of English, German, and Scottish soldiers ranged from 163.6 cm to 165.9 cm.2 Most histor ical height data are collected on conscripts for military purposes, meaning that data on female heights are scarce. Improved nutrition owing to advances in agricultural technologies and division of labour after the Industrial Revolution accelerated the increase in height in the 20th century: in many industrialized countries, the average body height is now close to 180 cm among men. In an extensive study on 1 million people, the mean adult height was found to increase by 0.5–1.0 cm with each successive decade of birth for people born between 1900 and 1960. 3 If this trend continues,
adult height and the risk of coronary artery disease are unclear. In a new, large study comprising 65,066 patients with CHD and 128,383 controls of European descent, Nelson and colleagues from the CARDIoGRAM+C4D Consortium used a genetic approach to test the association between height and CHD.6 They studied the association between CHD and 180 height-associated genetic variants identified in a previous study, and which explained about 10% of the variation in height. They also performed bioinformatics analyses of the height-associated variants to identify potential biological mechanisms that might link shorter height with an increased risk of CHD. Interestingly, none of these 180 variants lay in a locus previously implicated in genome-wide association studies into susceptibility to CHD. A significant association between the heightassociated single nucleotide polymorphisms (SNPs) and CHD existed among men (OR 0.88), but not among women.6 This association translated to a relative increase of 13.5% in the risk of CHD for each standard deviation decrease in height. Typically for genome-wide association studies, the association between each individual SNP and the risk of CHD was very small: the association was found only when all SNPs were combined. When the study population was divided into four groups on the basis of the number of height-increasing alleles, the odds ratio for quartile 4 (highest number
0 1700 1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2012
Year
Figure 1 | Trends among conscripts in average body height and male Nature CHD mortality 100,000 Reviewsper | Cardiology male population in Finland. Decrease in body height was caused by a period of cold climate ending in several famines starting in 1857. The last big famine was in 1866–1868, during which 150,000 people died. Height data obtained from Nummela, I. Shorty or not? About the history of Finnish population heights. In The Famine Years in the History of Finland. Department of History, Jyväskylä University: Publications on the History of Finland 19, 93–153 (1994) and http://en.wikipedia.org/wiki/Human_height. CHD mortality data obtained from Statistics Finland. Abbreviation: CHD, coronary heart disease.
NATURE REVIEWS | CARDIOLOGY
VOLUME 12 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of alleles) compared with quartile 1 was 0.74 (P 4,000 years.7 Severe atherosclerosis was already common in pre-industrial populations, including pre-agricultural hunter– gatherers who died aged
