Does economic development contribute to sex differences in ischaemic heart disease mortality? Hong Kong as a natural experiment using a case-control study

At older ages women are as vulnerable to heart disease as men. However, men are more vulnerable to premature mortality from ischemic heart disease (IHD) [1, 2]. Estrogens undoubtedly play a part, but geographic differences [2], the lack of inflection in coronary heart disease mortality at menopause [3], and the essentially null results of hormone replacement therapy trials [4] suggest estrogens may not be the only factor [2]. The excess IHD risk in men is currently smallest in economically undeveloped locations, such as rural China [2], whilst it increased during the first half of the 20^th century in some industrialised countries [1, 2]. These geo-temporal differences suggest that some as yet unidentified environmental factors [1] possibly associated with economic development may be relevant. Migration from less developed to more economically developed countries provide a parallel with socio-economic development. Migration studies, such as the Honolulu Heart Study have been instrumental in understanding the trends in and environmental determinants of IHD [5]. Migration to more economically developed countries is usually associated with increased IHD risk, although, migration studies have not provided consistently converging scientific viewpoints [6]. The many different factors involved, i.e. ethnicity, country of origin and destination, acculturation, age at migration and generations since migration may all contribute to these disparate interpretations [7–11]. To our knowledge, no previous study has examined sex differences in IHD mortality with migration to a more economically developed location within an ethnically homogenous population. We took advantage of a natural experiment provided by migration into Hong Kong and a large population-based case-control study to examine if male excess risk of IHD mortality was associated with living in an economically developed location.

Most Chinese people in Hong Kong are first or second generation migrants from the neighbouring province of Guangdong in southern China. The main waves of migration took place in the late 1940s and early 1950s [12]. Industrialization and economic growth started in the first half of the 20^th century in Hong Kong [13], by 1952 per capita gross domestic product (GDP) was half that of western Europe and by 1995 had overtaken western Europe [14]. In contrast, China had a GDP per head similar to pre-industrialized western Europe until the 1970s [15]. Economic development in Guangdong province was not a priority until the establishment of the Special Economic Zones near Hong Kong in 1978, and despite substantial economic growth thereafter Guangdong GDP per head in US dollars was less than a tenth of levels in Hong Kong in 2001 [16]. The population of Hong Kong is ethnically (>95% Chinese), culturally and most likely genetically homogeneous, with the main difference between migrants and non-migrants being the duration and number of generations of economic development experienced, making Hong Kong unlike many other seminal migration studies [17], whilst fortuitously uniquely suited to examining the impact of economic development alone. Hong Kong also has a low prevalence of IHD compared with western countries or other developed Chinese communities, such as Singapore [18], whose population has a longer history of economic development. We hypothesised that if male excess risk of premature IHD mortality is driven by economic development and possibly also the associated nutritional transformation, we should observe a larger male excess risk of IHD mortality in people born and brought up in Hong Kong than in people who migrated to Hong Kong from China Guangdong province mainly as young adults [19]. To allow for the possibility of "salmon bias" [20] (i.e. unhealthy migrants returning home to die), or "healthy migrant" bias (i.e. self-selection of healthy people as migrants) disproportionately affecting male 'breadwinners' we also examined sex differences in risk of mortality from a cause where no differences would be expected, i.e. pneumonia. We used pneumonia in preference to all respiratory deaths to avoid changing patterns of tuberculosis and chronic obstructive pulmonary disease. In the present study we examined whether the male excess risk of premature mortality from IHD, but not pneumonia, was higher with birth in an economically developed environment.

Taking advantage of a unique natural experiment, we found male excess risk of premature IHD mortality was related to environmental factors. Men, who were born and brought up in the economically developed environment of Hong Kong, had an excess risk of premature IHD mortality compared to women, but there was no such difference for Hong Kong residents who had migrated from Guangdong. On the other hand at older ages men and women had more similar risks of dying from IHD regardless of place of birth. To our knowledge, these findings are unique. They confirm our hypothesis that consistent with findings from ecological studies [1, 2] a lifetime spent in an economically developed environment increases the risk of premature mortality from IHD in men but not women. Given, that most migration into Hong Kong took place in the late 1940s and early 1950s our findings also suggest that the relevant environmental influence is in the first two or three decades of life.

Nevertheless, factors other than environmental exposures across the life course may be relevant. First, unhealthy migrant men from Guangdong may have preferentially returned home, whilst such women did not. However, political differences between China and the former colonial power, the provision of Hong Kong residency to migrants, the much higher living standards in Hong Kong and the universal access to health care, education and social welfare in Hong Kong make large-scale migration back to China prior to 1998 is extremely unlikely. Alternatively, men from Guangdong may have migrated as self-selected healthy workers, whilst women migrated as unselected family members, although why a healthy migrant effect should be specific to IHD is difficult to explain. Due to historical circumstances, there was no census in Hong Kong between 1931 and 1961 and very little control on migration into Hong Kong during that period. The only source we have been able to identify which describes the main post-war influx of migrants into Hong Kong describes them as mainly young people looking for work, however the basis for that observation is impressionistic [19]. Second, in adult life men and women may respond differently to living in an economically developed region depending on their childhood location. Possibly men, but not women, from Guangdong continued a protective 'Guangdong' lifestyle, whilst men, but not women, of Hong Kong had a more 'westernized' lifestyle with its corresponding risks. Alternatively, men and women may have responded differently to the stresses of migration and living in Hong Kong, with corresponding increases in IHD risk [30]. Although, stress has similar effects on IHD risk in men and women [30], it is possible that life in Hong Kong was particularly stressful for migrant women and Hong Kong born men. There could also be differential residual confounding in men and women. However, if either of these were the case there should also have been differences in pneumonia mortality by sex and place of birth, which were not observed. Third, case-control studies are subject to recall bias, however simple information appropriate to proxy recall was collected [31, 32]. Moreover, cause of death was obtained from a well-maintained registry. There is universal access to health care in Hong Kong and most Hong Kong residents die in modern hospitals providing western medical care, so ascertainment of cause of death cause of is generally very good. However, inevitably some deaths may be misclassified, which would make our results conservative. Finally, using decedent controls in a mortality case control study would under-estimate male excess IHD risk if exposure to an economically developed environment preferentially increased risk of death from non-IHD causes in men, and would conversely over-estimate male excess IHD risk if the same exposure preferentially increased risk of death from non-IHD causes in women. However, we obtained similar results after removing from the controls deaths from causes which might have a sex-specific relationship with economic development, such as diabetes or cancer of the breast, prostate, uterus or ovary.

Given that we took advantage of a natural experiment, we are not showing precise point estimates of differences by sex with economic development, although they are broadly consistent with estimates in populations at different stages of economic development [2]. In particular, our estimates may be conservative. Age at migration and duration of residence in Hong Kong were not collected in the study. Some people born in Guangdong undoubtedly migrated to Hong Kong as children or adolescents. On the other hand some Hong Kong born people may have grown up elsewhere and returned later to Hong Kong. Men and women probably had essentially similar and comparable experiences, but the exposures to different livings conditions were diluted in some people, making our results conservative. In addition economic differentials between Hong Kong and Guangdong province were not consistent across the 20^th century, and specifically may have been smaller in the early 20^th century when the older people were growing up. Thus, it is possible that the lack of sex difference in IHD mortality at older ages may be partially artifactual due to smaller differences in living conditions between Hong Kong and Guangdong in the early 20^th century. Nevertheless, our study provides aetiologically significant evidence that male excess risk of premature IHD mortality is partially generated by a macro-environmental influence associated with economic development operating in the first few decades of life, which might increase the risk of IHD in men, decrease the risk of IHD in women or increase the risk of death from other causes in women.

Notwithstanding these provisos our study suggests that a factor in the first few decades of life contributes to the higher male risk of premature IHD mortality that emerges with economic development. Several aspects of pre-adult life are associated with increased cardiovascular risk, such as accelerated growth [33, 34], shorter legs and lower leg to trunk ratios [35, 36]. There is little indication that these factors have different associations by sex. On the other hand, puberty is the specific period of life when sex differences become much more pronounced due to the action of testosterone in males and estrogen in females. Increased testosterone in males at puberty also increases some IHD risk factors, such as reduced HDL-cholesterol [37–39], and possibly higher ApoB and more male fat patterning [39]. Conversely, higher estrogen levels at puberty promote a more female shape [40] with a lower waist-hip-ratio and corresponding lower IHD risk, but possibly also a higher risk of some hormone related cancers [41, 42]. Moreover, sex-differences in HDL-cholesterol appear to be contextually specific and smallest in least developed locations, such as China [43], suggesting they are environmentally driven, although these findings have not always been replicated in small studies [44].

In animal experiments under-feeding reduces testosterone [45–47] and estrogen levels [48] at puberty. Even in universally well-fed human populations, slight changes in diet affect sex-steroids in girls [49] although not in boys [50], where larger nutritional differences are needed [51]. We speculate that nutritionally driven differences in pubertal development seen in developed environments [52] but not very poor environments [51], may permanently increase sex differences in IHD risk, through higher levels of sex-steroids at puberty generating more detrimental lipids and body shape in men, whilst generating a more female body shape in women. Such differences would be expected to track into adult life [53]. Moreover, consistent with the much less marked change with economic development in the sex ratio for diabetes [27] than for IHD, such environmentally driven effects on pubertal sex-steroids would not be expected to affect pubertal pre-cursors of diabetes, which appear to be more strongly related to another hypothalamic-pituitary-endocrine axis, i.e. growth hormone [54–59].

Rather than being entirely an intrinsic sex-specific property, increased male risk of premature IHD mortality was associated with living in an economically developed environment in the first few decades of life. We speculate that a better pre-adult environment increases sex-steriods at puberty, which permanently increases IHD mortality risk in men whilst possibly decreasing IHD risk in women but possibly also increasing risks of other diseases, thus providing a socio-biological explanation for the emergence of increased male risk of premature IHD mortality following economic development. Our findings highlight the importance of investigating the long-term effects of early life environment on cardiovascular risk in the large proportion of the global population under-going rapid epidemiologic transition.