The South Asian Enigma: Solving a Puzzle of Global Importance

Individuals of South Asian (Bangladeshi, Bhutanese, Indian, Maldivian, Nepalese, Pakistani, and Sri Lankan) ancestry account for almost a quarter of the world’s population, and the South Asian diaspora is one of the largest and most widespread across the globe. Studies from Europe and North America have consistently shown that South Asians experience significant atherosclerotic cardiovascular disease (ASCVD) disparities, as evidenced by increased risk factor burden, higher hospitalization, and mortality rates compared to White populations.^1–3 Additionally, this high risk exists in native settings as well, with a higher ASCVD incidence reported in India, Pakistan, and Bangladesh despite overall lower risk factor burden compared to middle and high income countries.⁴ Research efforts over the last 50 years have yielded tremendous insights into the pathophysiology, prevention, and clinical care of ASCVD. However, racial/ethnic disparities in ASCVD persist, and the underlying reasons for the increased risk of South Asians remains elusive.

In this issue of Circulation, Patel et al conducted a prospective analysis of the UK Biobank cohort to determine the incidence of ASCVD in 8,124 South Asian individuals compared to 449,349 individuals of white European ancestry within the context of contemporary medical care.⁵ The UK Biobank study enrolled over 500,000 individuals between the ages of 40 and 69 years between 2006 and 2010, who underwent extensive phenotyping, including physical examination, detailed questionnaires that included self-reported ancestry, behavioral, psychosocial, and clinical information, and collection of biological specimens. For this analysis, individuals with prevalent ASCVD by self-report or hospitalization records were excluded, and the primary endpoint was incidence of ASCVD defined based on hospitalization records indicating a diagnosis of acute myocardial infarction, ischemic stroke, or their acute complications, coronary revascularization procedures, and death registry data. After a median follow-up of 11 years, South Asian individuals across age-, sex-, and immigrant status were at 2-fold higher risk for ASCVD than White individuals. The excess risk associated with South Asian ancestry was attenuated but remained independent after accounting for a wide range of demographic, socioeconomic, behavioral, psychological, and clinical risk factors (fully adjusted HR 1.45, 95% CI 1.28-1.65).⁵ The authors posit that genetic factors may account for this residual increased risk.

This study also confirmed findings from prior cohort studies showing that ASCVD risk in South Asians was primarily driven by hypertension, diabetes, and central adiposity, and not more novel risk factors. Yet these established risk factors do not fully explain South Asians’ higher risk. Other studies in immigrant South Asian populations in Canada, Singapore, Spain, the United Kingdom, and the United States have also highlighted the higher rates of diabetes and hypertension in South Asians compared with other race/ethnic groups. Data from a community-based prospective cohort of South Asian Americans showed a high burden of several ASCVD risk factors, including a higher prevalence of diabetes (23%),⁶ hypertension (42%), and higher levels of abdominal visceral fat and liver fat⁷ compared to White, Black, Hispanic, and Chinese Americans. South Asians may have particular vulnerability to developing type 2 diabetes both due to evolutionarily-determined and lifestyle-related factors that have been reviewed previously.⁸ Metabolic and pro-inflammatory derangements that occur with insulin resistance have long been theorized to be underlying drivers for both the higher type 2 diabetes burden and ASCVD in South Asians. However, newer data have demonstrated distinct subtypes of type 2 diabetes,⁹ with South Asians having a higher prevalence of both a severe insulin resistant with obesity subtype and a less recognized severe insulin deficient subtype.¹⁰ Importantly, both of these more prevalent diabetes subtypes in South Asians were associated with a higher incidence of coronary artery calcium, a marker of subclinical atherosclerosis and strong predictor of future ASCVD, compared to other diabetes subtypes.¹¹ These insights provide evidence for why diabetes may have a stronger association with ASCVD among South Asians than in other race/ethnic groups, and support the need for early recognition of prediabetes along with diabetes prevention efforts as fundamental strategies to prevent ASCVD among South Asians. Epidemiologic and electronic health record-based studies, such as this analysis from the UK Biobank, are often unable to account for insulin resistance or insulin deficiency. Moreover, current ASCVD clinical risk prediction scores do not adequately capture the increased risk due to insulin resistance or deficiency in South Asians.

An important finding in this paper was that incident ASCVD risk was not uniform across South Asian subgroups; individuals of Bangladeshi and Pakistani origin were at higher risk than those of Indian or other South Asian origin. Higher risk factor burden and lower socioeconomic status in Bangladeshi and Pakistani participants appeared to partially explain subgroup differences. The INTERHEART case-control study examined risk factors for heart attack among South Asians from 1999-2003. Among the five South Asian countries studied, Bangladeshis had the highest prevalence of most risk factors.¹² More recent evidence from several diaspora countries also demonstrated that cardiovascular health disparities vary across immigrant South Asian subgroups. For example, Pakistani and Bangladeshi immigrants in Canada have higher age-standardized incidence of a major cardiovascular event compared to Indian immigrants.¹ In both the United Kingdom and in Catalonia, Spain, cardiovascular risk factors and ASCVD incidence is not uniform among South Asians, and Bangladeshis had worse risk profiles than Pakistanis and Indians.^{2, 13} Although the high prevalence of ASCVD in people of South Asian ancestry overall may be bolstered in part by genetic variation, the patterns of genetic diversity within South Asians do not follow recently constructed national boundaries, and there is little evidence to support genetic heterogeneity as the main driver of differences in ASCVD between South Asian subgroups.

We now have several prospective cohort studies showing that cardiovascular health disadvantages of South Asians in Europe and North America cannot be explained by traditional risk factors, and that there are important differences by country of origin. There is now the need to advance a unified, global effort to fully understand and address ASCVD disparities in South Asians. Studying the health of South Asian immigrants provides a key opportunity to understand how heterogeneity in socio-cultural, environmental, interpersonal, and individual factors underlie ASCVD disparities by country of origin, but very few studies have examined these relationships in large samples and with more detailed socioecological measures. The paper by Patel et al showed that Bangladeshi and Pakistani individuals lived in areas with greater economic deprivation, and it is well known that ASCVD risk and outcomes are patterned by socioeconomic position, with socioeconomic adversity being associated with worse health. In addition to differences in socioeconomic position between South Asian groups, Bangladeshis and Pakistanis are predominantly Muslim and may have unique experiences with discrimination that impact their health outcomes.¹⁴ Mechanistic studies are needed to fill knowledge gaps about the multilevel risks that cause ASCVD disparities as well as protective factors that mitigate them.

Although there are important limitations of the study by Patel et al, including the use of self-reported risk factors, diagnostic codes from inpatient admissions, and respondent bias which led to under-representation of South Asians in the UK Biobank cohort, these study results underscore that individuals of South Asian origin in the UK are at enhanced risk for ASCVD compared to individuals of white European ancestry. Yet, the reasons underlying the increased risk of cardiovascular and metabolic disease are still not known, and solving this puzzle is of tremendous global importance. Future studies should enroll adequate samples to disaggregate South Asian subgroups and utilize a conceptual framework-driven approach to articulate and understand mechanisms that link drivers of cardiovascular health at the contextual, inter-personal, and individual level. The AHA’s 2030 Impact Goal is to “Equitably increase healthy life expectancy beyond current projections across the U.S. and worldwide.”¹⁵ Achieving this ambitious goal requires collaborative global and local research to better understand the complex, multilevel determinants of cardiovascular health disparities and accelerate equitable uptake of proven, evidence-based prevention and treatment for South Asians and other high risk populations.