Genetic Risk Factors


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Cholesterol

Dyslipidemia is well documented as one of the main risk factors of ASCVD. The effects of hypertriglyceridemia, hyperglycemia, and increased free fatty acid levels, both fasting and postprandial, on endothelial dysfunction may be mediated through oxidative stress.11 Although dyslipidemia does not occur at a higher rate in South Asians, the type of dyslipidemia does differ. When compared with Chinese and European populations, South Asians have higher total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, and lower high-density lipoprotein (HDL) cholesterol levels.12 South Asians also have genetic polymorphisms causing higher levels of elevated lipoprotein (a) and defective apolipoprotein B.13 Both of these polymorphisms are independently and highly correlated with the presence and severity of ASCVD.

Hypertension

South Asians have upregulated angiotensin-converting enzyme (ACE) activity that is directly correlated with the development of hypertension.14,15 Das et al16 describe polymorphism of the ACE gene in adult Asians as a probable genetic risk factor for developing hypertension. A replication study and meta-analysis of >21,000 Japanese adults with hypertension confirmed the relationship of the genetic link and hypertension in the Asian population.17 Based on the genetic predisposition for development of hypertension, ACE inhibitors should be considered in therapeutic treatment regimens for the South Asian population.

Hyperglycemia

Individuals with diabetes die on average 10 years before individuals without diabetes, and two-thirds of those deaths are attributed to ASCVD.9 According to the International Diabetes Federation, more than 21 million Asian Indians have prediabetes.18 South Asians have a higher incidence of diabetes compared with non-Hispanic whites. However, even without overt diabetes, South Asians have reduced insulin sensitivity, up to 4-fold higher18 compared with other racial and ethnic groups, which can be explained by increased visceral fat and genetic polymorphisms.13 Older age, female sex, physical activity, and adiposity are strong indicators of insulin sensitivity, and each of these may alter the relationship of hyperglycemia to oxidative stress and ASCVD risk. The prevalence of type 2 diabetes is more than 4 times higher in South Asians than in other ethnic groups, and the onset is as much as 10 years earlier.4 South Asians have more insulin resistance in fasting and postprandial states than other ethnic groups,19 and one-third of South Asians have metabolic syndrome,9 possibly a consequence of increased obesity and ectopic fat deposition.

Adiposity

Among nations categorized as “major” by the Organisation for Economic Co-operation and Development, India has the lowest rate of obesity in the world.9 However, South Asians are much more susceptible to the deleterious metabolic effects of visceral adiposity. Visceral adiposity is well established as a direct risk factor associated with ASCVD globally but is more prevalent in the South Asian population in any body size.20 Visceral adipocytes, not subcutaneous adipocytes, are directly linked to increased inflammatory cytokines and the development of a proinflammatory state.21 South Asians exhibit the unique and deleterious obesity phenotype of increased visceral adipose tissue and lower lean body mass independent of waist circumference or body mass index.20

Although the most accurate measurement of visceral adiposity is computed tomography, this option is not feasible, equitable, or efficient. Visceral adiposity is often measured with a waist-to-hip ratio. Healthy waist circumferences for most adult populations are <88 cm for women and <102 cm for men. However, recent guidelines specify that people of South Asian ethnicity should have waist circumferences <85 cm for women and <90 cm for men.9

The greater prevalence of visceral adiposity when compared with generalized obesity suggests rapid fat gain in a previously lean individual.5 This type of fat gain places these individuals at higher risk for diabetes and metabolic syndrome and is thought to contribute significantly to ASCVD risk.8

Tumor Necrosis Factor

With increased insulin resistance, there is a subsequent increase in circulating proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin 6, and interleukin 18.11 South Asians have significantly increased high-sensitivity C-reactive protein (hs-CRP), which indicates a chronic low-grade state of inflammation.4

Nonalcoholic Fatty Liver Disease

South Asians have a genetic predisposition to development of nonalcoholic fatty liver disease (NAFLD), or hepatic steatosis, which is a significant risk factor for ASCVD. NAFLD is exacerbated by a high-sugar diet and abdominal adiposity, which are also prevalent in the South Asian culture.9 Because NAFLD is often asymptomatic, the majority of individuals are unaware of their condition. The prevalence of NAFLD (approximately 30%) is similar between South Asian and Western populations; individuals are predisposed to not only ASCVD and cirrhosis but to hepatic and other extrahepatic malignancies.9 The increased ASCVD risk associated with NAFLD is independent of standard ASCVD risk factors.

Regression and resolution of NAFLD is primarily accomplished through exercise, abstention from alcohol, weight loss through intra-abdominal fat mobilization, and a diet low in sugar and refined carbohydrates. These behavioral modifications are often the first-line treatment for other comorbid conditions that commonly affect South Asians.