Response to Letter Regarding Article, “Quantifying and understanding the increased risk of coronary artery disease among South Asians — results from the UK Biobank prospective cohort study”

We very much appreciate the comments by Drs. Enas and Varkey – who led several seminal efforts related to increased cardiovascular risk among South Asians – on our recent manuscript.¹

They propose consideration of a reduced threshold for consideration of statin therapy for physicians engaged in shared decision making with patients of South Asian ancestry. This proposal is well-aligned with current U.S. guidelines, which suggests ‘risk discussion regarding moderate-intensity statin therapy’ for those with a 10-year risk of atherosclerotic cardiovascular disease (ASCVD) as predicted by the Pooled Cohort Equations of 5 to 7.5% in whom a risk enhancer – such as South Asian ethnicity – is present.² The QRISK3 calculator recommends a conceptually similar approach, recommending multiplying the calculated risk by factors ranging from 1.3 to 1.7 for specific South Asian countries of origin.³ While we applaud both of these efforts to help motivate risk factor mitigation in the short-term, we emphasize an urgent need to move towards risk stratification based on underlying biologic differences as opposed to uniformly up-classifying risk for an entire ethnic group.

To that end, we agree that improved recognition and understanding of risk associated with lipoprotein(a) in individuals of South Asian ancestry is warranted. We recently confirmed that median lipoprotein(a) concentrations were approximately 60% higher in South Asian as compared to European ancestry individuals, thus accounting for greater population attributable risk.⁴ Prioritizing representation of South Asians within ongoing trials of lipoprotein(a)-lowering therapies will enable assessment of efficacy within this group.

Additional areas of scientific priorities include improved understanding of the increased risk of diabetes even in the absence of obesity, differences in body fat distribution, and culturally-specific dietary and environmental influences, as well as uncovering new pathways driving increased risk.

In addition to underrepresentation within cohort studies and clinical trials, we note that South Asians are the most under-represented major ancestral group within human genetic analyses – accounting for 23% of the global population but only 1.3% of these studies.⁵ This translates into reduced accuracy of genetic risk prediction tools such as polygenic scores and limits discovery of population-specific variants that may have important clinical or therapeutic relevance.

Moving forward, we look forward to joining Drs. Enas, Varkey, and a range of scientific and patient stakeholders in coming years to enable enhanced biologic understanding and improved clinical implementation of efforts to attenuate the important current disparities in rates of cardiovascular disease as compared to most other ethnicities.