The Nobel Prize for Economics in 2021 was awarded to three economists for their work on the lessons that natural experiments provide. These arise from comparisons between population groups that experience outcomes of real-life exposures that were not planned as an intervention trial. In health, migration of people produces a large natural experiment, which enables us to observe the effects of a changed living environment on their health. It creates an excellent platform to study gene-environment interactions.
In the 1980s, there was high global interest in the observation that the Japanese had a very low incidence of coronary heart disease in contrast to the very high rates in Europe and the US. So a study was conducted to see if persons of Japanese ethnicity would still retain low risk propensity if they migrated to regions with a higher risk of heart attacks. The Ni-Hon-San study compared Japanese living in Japan (Nippon) with those living in Honolulu (Hawaii) and San Francisco (California).
Japanese migrants in San Francisco were found to have higher rates of heart disease than those in Japan. Their rates were intermediate between heart disease rates seen in the country of origin and the country of adoption. Those in Honolulu too had higher levels than the Japanese in the home country but lower than the migrants to California, corresponding to the level of their acculturation to a different social environment. Body weight and blood cholesterol levels rose as the migrants moved closer to the Golden Gate Bridge of San Francisco (and the golden arches of American fast food joints). In contrast, the risk of bleeding brain strokes, high in Japan, fell with migration. This was possibly an effect of high fat consumption, which reduces the risk of bleeding but increases the risk of clotting.
There was also interest in persons of African ethnicity having high levels of hypertension and blood pressure-related organ damage when they were studied outside the African continent, especially in America. It was observed that African Americans had much higher rates of blood pressure-related disorders and diabetes than Africans in the mother continent. African migrants to Europe too had high levels of blood pressure and diabetes but lower than that of African Americans. Persons of African ethnicity in the Netherlands had higher risk of hypertension and diabetes than those in England, reflecting the patterns seen in the white populations of those two countries.
In Kenya, blood pressure patterns of Luo tribesmen were studied. Among these subsistence farmers, those who migrated to Nairobi had higher blood pressure levels than their rural counterparts. The level of rise corresponded to the years of urban residence in Nairobi. These studies made it clear that hypertension and diabetes among persons of African ethnicity were related to acculturation to urban environments, propelled by altered diets, lower physical activity, greater stress and higher levels of air pollution.
In the second half of the 20th century, diabetes and coronary heart disease were noted to be high among Indian migrants the world over. In the 1950s, early reports came in from Uganda and Malaya. Later, reports poured in from studies conducted in the UK, US, Singapore, Canada, South Africa and Mauritius. From the first to third generation, Indian and other South Asian migrants had higher heart attack rates compared to local and other migrant population groups. This was associated with increased body fat, abdominal obesity, lower muscle mass, glucose intolerance, insulin resistance, high levels of triglyceride and low levels of the cardio-protective HDL fraction of blood cholesterol. Even if not overtly obese or even actually thin, the potbellied Indian was an advertisement for high risk of diabetes and heart disease.
While this sparked theories of genetic susceptibility, no genetic marker of high predictive value has been identified. While it may indicate a polygenic origin rather than a single gene disorder, even a cluster of multiple candidate genes had a low explanatory power in various studies. Community-based epidemiological studies conducted by our research group showed a rising gradient of risk from rural to urban to migrant Indians. A comparison of urban migrant industry workers in three Indian cities with their siblings who stayed behind in rural homes revealed that the migrants exhibited a sharp rise in all heart disease and diabetes risk factors within a few years of their relocation to cities.
These studies provide proof—across ethnicity, time and geography—that environmental factors greatly influence the risk and disease outcomes like hypertension, diabetes and coronary heart disease. Genetic susceptibility or metabolic programming by early-life malnutrition may predispose one to these conditions. Whether, when and to what extent that susceptibility is triggered depends on the living environment to which the individual is exposed during the course of their life. We as a society create those living conditions. We can make them conducive to good health, rather than blame our genes. This is the lesson from the largest natural experiment of all-human migration.
(Views expressed are personal)
Dr K Srinath Reddy
Cardiologist, epidemiologist and President, Public Health Foundation of India (PHFI)
(ksrinath.reddy@phfi.org)