Introduction

An estimated 17.5 million deaths in 2012 were attributed to cardiovascular disease (CVD), 7.4 million of which were due to coronary heart disease (CHD) alone [1]. While the global burden of CVD and its associated age- and disability-adjusted life years (DALY) is on the decline, it is on the rise in several developing countries [2].

South Asia, a region that comprises middle- and low-income countries (Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka), is no different. The region has seen an epidemiological shift from communicable to non-communicable diseases in the last few decades due to improved socioeconomic conditions and high rates of rural to urban migration. In 1990, CVD accounted for 15% of all deaths in South Asia. By 2013, this estimate increased to 27% [2]. The region is projected to have more individuals with atherosclerotic disease than any other region by the year 2020 [3, 4].

South Asians are also believed to have an earlier presentation of coronary artery disease (CAD) compared with other ethnicities [5]. The economic repercussions of this earlier onset of CAD or premature coronary artery disease (PCAD) are greater due to a higher loss of productive and profitable years. This is not limited to South Asians living in the region. South Asian immigrants around the world have also demonstrated a higher burden and an earlier presentation of CHD when compared with their respective local populations [6].

In this review, we discuss the burden and angiographic presentation of PCAD among immigrant and non-immigrant South Asians and compare them with other ethnicities. We also examine data exploring the determinants of PCAD among South Asians.

Burden of Premature Coronary Artery Disease among South Asians

While a family history of PCAD is defined as the onset of a cardiovascular event before the age of 55 years in males and 65 years in females, personal history of PCAD is usually defined as 10 years younger in each gender, i.e., onset of a cardiovascular event before the age of 45 years in males and 55 years in females [7,8,9]. Overall, the burden of premature ischemic heart disease (non-fatal acute myocardial infarction (MI), angina pectoris, ischemic heart failure) has been found to be higher in South Asians. The INTERHEART study, which compared CHD risk factors in 52 countries, found that the mean age of first presentation of acute MI in South Asians was 53.0 (SD ± 11.4) years [10]. This was similar to the mean age reported in the Bangladesh Risk of Acute Vascular Events (BRAVE) study (52.6 ± 10.4 years) for patients who presented with their first MI [11]. In comparison, the mean age of first presentation of acute MI was 63.0 years among patients in Western Europe, China, and Hong Kong, and 62.0 years in Central and Eastern Europe in the INTERHEART study [10]. South Asians was also found to have one of the highest proportions of patients presenting with acute MI before 40 years of age (8.9%). In comparison, 2.7% of patients in Western Europe and 2.9% of patients in Central and Eastern Europe were less than 40 years of age when they presented with acute MI [10]. The Global Burden of Disease 2010 study reported that among all South Asians who developed ischemic heart disease (IHD), 29% males and 24% females were less than 50 years of age [12]. This estimate was even higher in Bangladesh where 46% of the participants in the BRAVE cohort had their first MI before 50 years of age [11].

Premature Coronary Artery Disease Burden Among the Immigrant South Asian Population

Variation in the burden of CAD among different ethnicities has given rise to an interest in examining its burden in immigrant populations. There are an estimated 20 million South Asians settled in different parts of the world [13]. When these immigrants have been compared with local populations, they have often demonstrated a higher burden of CAD. In a study of 416 patients in the USA aged 40 years or younger, 33% of the cohort had PCAD (symptomatic CAD before age 40) [14]. The patients included multiple ethnicities comprised of African Americans, Hispanics, White, and Asian Indians (AIs). The prevalence of PCAD was found to be highest in the AIs (50%) and Whites (50%) compared with Hispanics (20%) and African Americans (30%).

Other studies comparing overall CAD burden and age of onset of CAD between South Asian immigrants and the local population have also found an earlier age of CAD onset among South Asians. Although these studies did not specifically recruit patients with PCAD, lower mean age of South Asians in the cohorts would suggest a higher prevalence of PCAD. A study of the prevalence of CHD and its risk factors in 1688 first-generation Asian Indian (AI) physicians living in the USA reported the mean age at the time of diagnosis of CHD to be 46.3 (± 6.9) years [15]. Similarly, in a comparison of 645 AI physicians with a mean age of 48.0 years (± 5.5 years) and 22,071 US physicians with a mean age of 53.2 years (± 9.5 years), the crude prevalence of angina was nearly double in AIs compared with that in US physicians (2.2 vs. 1.2%, p = 0.03) [15].

Thus, it is reasonable to conclude that the burden of PCAD is higher among South Asians regardless of their residence in South Asia or otherwise. There is, however, a need for larger studies that directly compare the burden in immigrant and non-immigrant South Asian populations.

Angiographic Findings and Markers of Subclinical Atherosclerosis

Studies on angiographic profiles of South Asians with PCAD have shown a high prevalence of single-vessel disease (SVD) [16•, 17, 18]. A study conducted at the National Academy of Medical Sciences in Nepal recruited 115 patients less than 45 years of age diagnosed with acute MI between 2014 and 2015 and reported that a majority of patients (53.8%) had SVD on angiography [16•]. Findings were similar in a study conducted in Gujarat, India, that recruited 820 patients less than 40 years of age with acute coronary syndrome (ACS) (611 patients with ST-elevation MI and 209 with non-ST-elevation MI or unstable angina) [17]. SVD was present in 56.6% of patients with STEMI and 36.6% in the NSTEMI group. Tewari et al. compared angiographic findings of 1971 patients with angiographically proven atherosclerotic CAD in different age groups and found participants aged less than 40 years had a high prevalence of SVD [18]. These findings, however, are not unique to South Asians and have been demonstrated in young patients of other ethnicities [19, 20]. This may be explained by a greater likelihood of acute thrombosis in a single vessel in young patients rather than diffuse atherosclerosis accumulating over a period of time in older patients. Future studies need to compare angiographic findings of immigrant and non-immigrant South Asians with other ethnicities to draw meaningful conclusions from angiographic findings of PCAD in South Asians.

Another study evaluated calcium scores in South Asians. The study compared coronary artery calcium (CAC) scores (a marker of subclinical atherosclerosis) between 13,501 Caucasians and 935 South Asians who underwent electron beam computed tomography (ECT) in London, UK. The study found that Caucasians had lower mean CACs than South Asians (males < 50 years 23.8 ± 104.2 vs. 36.1 ± 277.8; females < 50 years 12.9 ± 32.03 vs. 27.3 ± 135.5) [21]. While differences in mean CAC may indicate the influence of ethnicity on CAC, limited conclusions can be drawn regarding its clinical significance without taking into consideration its association with risk factors of CVD.

Determinants of Coronary Heart Disease in South Asians

Even though a higher prevalence of PCAD among South Asians is well-documented, the underlying etiology is not well-understood. Both genetic and non-genetic risk factors may play a role [22]. Data related to the prevalence of traditional (hypertension, diabetes mellitus, dyslipidemia, smoking, obesity, physical activity, and family of premature CVD) and non-traditional (dysfunctional HDL, lipoprotein, (a) and genetics) cardiovascular risk factors that may account for a higher burden of PCAD among South Asians are explored below.

Traditional Risk Factors

The INTERHEART study compared cardiovascular risk factors in 52 different countries including India, Pakistan, Bangladesh, Nepal, and Sri Lanka [10]. This case-control study recruited 15,152 patients with acute MI (cases) and 14,820 healthy controls. Of these, 3936 participants were from South Asia while 23,159 participants belonged to other countries. Current and former smoking (61.6% in cases vs. 40.8% in controls, odds ratio (OR) 2.57 [95% confidence interval (CI) 2.22–2.96]), history of hypertension (29.6 vs. 12.7%, OR 2.92 [2.46–3.48]), history of diabetes mellitus (20.2 vs. 9.5%, OR 2.52 [2.07–3.07]), high waist-to-hip ratio (44.0 vs. 9.6%, OR 2.44 [2.05–2.91]), elevated ApoB100/ApoA-I ratio (top vs. lowest tertile) (61.5 vs. 43.8%, OR 2.57 [2.03–3.26]), and adverse psychosocial factors (stress or depression) (86.0 vs. 82.0%, OR 2.62 [1.76–3.90]) were strongly associated with increased risk of AMI (p < 0.001 for all) in native South Asians. The prevalence of protective risk factors like leisure time physical activity (cases 4.6% in South Asia vs. 15.8% in other countries, controls 6.1% in South Asia vs. 21.6% in other countries), regular alcohol intake (cases 13.3 vs. 25.7%, controls 10.7 vs. 26.9%), and daily intake of fruits and vegetables (cases 20.0 vs. 38.3%, controls 20.0 vs. 26.5%) was markedly lower (p < 0.001 for all), while that of harmful risk factors such as elevated ApoB100/ApoA-I ratio (61.5 vs. 48.3% in cases, 43.8 vs. 31.8% in controls) was higher in South Asian cases and controls compared with other countries. In further analysis, when participants younger than 40 years of age from South Asia and other countries were compared, the prevalence of the 3 metabolic risk factors (ApoB100/ApoA-I ratio, diabetes, and waist-to-hip ratio) was higher in South Asian cases and controls, and consumption of fruits and vegetables, physical activity, and alcohol use were lower compared with their counterparts from other areas [3].

In another analysis from the INTERHEART study comparing the lipids and lipoproteins among participants from South Asia and other Asian countries enrolled in INTERHEART, several important observations were made. First, for any given LDL-C, South Asians tended to have higher Apo B levels compared with other Asians. This indicates that South Asians on average have a higher number of LDL particles and a pattern of small dense LDL particles. Second, HDL-C levels were the lowest among South Asians (for example, mean HDL-C levels in South Asian cases with MI were 32.5 mg/dL compared with 41.9 mg/dL for those with MI from China or Hong Kong). Third, the mean levels of triglycerides were higher among South Asians compared with other Asian groups (163.3 mg/dL among South Asian cases with MI compared with 139.3 mg/dL among MI cases from China or Hong Kong). These results indicate a particular pattern of dyslipidemia among South Asians with MI characterized by low HDL-C, higher triglyceride levels, and a higher LDL particle burden for any given LDL-C level [23].

The Bangladesh Risk of Acute Vascular Events (BRAVE) study enrolled 4500 patients after their first MI, and 4500 age- and sex-matched controls (visitors at the hospital) [11]. The study not only investigated traditional risk factors, but also risk factors inherent to Bangladesh and other South Asian countries such as use of smokeless tobacco (jarda or gul) and cooking oils commonly used in South Asia (banaspati or palm oil). The study found that current tobacco consumption (79 vs. 63%), diabetes mellitus (17 vs. 8%), hypertension (24 vs. 10%), and family history of MI (13 vs. 6%) were higher in the group with MI compared with controls (p < 0.001 for all). HDL-C levels were lower in patients with MI (0.85 mmol/l [32.9 mg/dL]) than controls (0.87 mmol/l [33.6 mg/dL]) while the following were higher in patients with MI compared with controls: total cholesterol (TC) (5.14 mmol/l [198.8 mg/dL] in patients with MI vs. 4.77 mmol/l [184.5 mg/dL] in controls), and LDL-C (3.19 mmol/l [123.4 mg/dL] vs. 2.76 mmol/l [106.7 mg/dL]) (p < 0.001 for all).

Studies that have compared immigrant South Asians with the local population have provided insights into the relative influence of the different risk factors (genetic vs. non-genetic) of CVD. The London Life Sciences Prospective Population Study (LOLIPOP) recruited 16,774 Asian Indians (AIs) and 7032 European Whites (EWs) aged 35–75 years from a clinic-based cohort from West London, UK [24]. The AIs had a lower mean age (50.5 years in AIs vs. 52.3 years in EWs) and a higher prevalence of diabetes (18.5% in AIs vs. 7.4% in EWs) and hypertension (29.4 vs. 20.3%). HDL-C levels (1.25 mmol/l [48.3 mg/dL] in AIs vs.1.39 mmol/l [53.8 mg/dL] in EWs), mean BMI (27 ± 4.7 vs. 27 ± 5.3 kg/m2), and smoking prevalence (18.7 vs. 57.2%) were lower in AIs compared with EWs. Other than smoking, all other traditional risk factors were more prevalent in AIs compared with EWs.

Patel et al. compared CHD risk factors among immigrant and non-immigrant South Asian populations by enrolling 242 British Gujaratis settled in Sandwell, UK, and 295 Gujaratis from their native rural village in Navrasi, Gujarat, India [25]. Mean ages of the cohort for Navrasi were 49.1 years for men and 48.5 years for women. The mean ages for the Sandwell cohort were 49.0 for men and 49.2 years for women. The researchers found a higher prevalence of known diabetes (14.5% in Indian Gujaratis vs. 9.1% in British Gujaratis for men; 7.7 vs. 3.9% for women), impaired glucose tolerance (17.7 vs. 3.3% for men; 16.3 vs. 7.5% for women), plasma homocysteine levels (17 vs. 10 μmol/l for men; 13 vs. 9 μmol/l for women), and smoking (40 vs. 10% for men; 3.2 vs. 0% for women) in Indian Gujaratis compared with their British counterparts. On the other hand, mean BMI, dietary energy intake, fat intake, hypertension, total cholesterol, apolipoprotein B, triglycerides, non-esterified fatty acids (NEFA), and C-reactive protein (CRP) levels were higher among the British Gujaratis compared with their counterparts in India in both men and women. The authors concluded that most of the risk factors found higher in the Sandwell cohort were likely the result of adopted lifestyles and dietary habits.

In a cross-sectional study of randomly selected 1428 immigrant South African Asian Indians (mean age 45.5 ± 13 years) settled in Durban, South Africa, high rates of traditional risk factors were observed [26]. The prevalence of hypertension was as high as 47.5% with another 17.1% being pre-hypertensive, while the prevalence of diabetes was 20.1% with another 29.1% classified as pre-diabetic (impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (fasting glucose 5.6–7.0 mmol/l [100–126 mg/dL]). Increased waist circumference (men > 90 cm, women > 80 cm) was found in 73.1% of participants while 64.5% were either overweight or obese (BMI > 25 kg/m2). Around 52.3% of males and 14.6% of females were current smokers.

Thus, it is fair to conclude that South Asians have a higher prevalence of traditional risk factors. The effects of migration and changes in dietary pattern appear to contribute significantly to a higher risk factor burden as seen in the study on Gujaratis in Sandwell.

Non-traditional Risk Factors

Dysfunctional HDL

The inverse correlation between HDL-C and CAD is well-established. HDL-C reduces the cholesterol content of macrophage foam cells, through its antioxidant and anti-inflammatory properties, and transports it back to the liver for excretion through the process of reverse cholesterol transport. However, oxidization of HDL particles during systemic and vascular inflammatory states may make it pro-inflammatory and pro-oxidant. This reversal of functional to dysfunctional HDL may lead to a loss of protective effect of high levels of HDL-C on CAD [27].

A study examining the association of subclinical atherosclerosis with dysfunctional HDL recruited 129 South Asians between the ages of 35 and 65 years (mean age 51.3 ± 9.23 years) from Hindu temples in the State of Georgia [28••]. Subclinical atherosclerosis was measured using common carotid artery intima-media thickness (CCA-IMT) and dysfunctional HDL was assessed using a novel cell-free assay and HDL inflammatory index. The HDL inflammatory index was calculated by normalizing the cell-free assay values obtained for LDL alone as 1.0. If the addition of a test HDL resulted in a value of 1.0 or greater, the test HDL was classified as pro-inflammatory (dysfunctional). The index was found to be > 1.00 in 50% of the participants suggesting a pro-inflammatory or dysfunctional HDL (95% CI 0.87–1.43). Subclinical atherosclerosis defined as CCA-IMT > 0.80 mm was found in 41.4% of participants (95% CI: 0.23–0.59). A positive association was found between subclinical atherosclerosis and dysfunctional HDL after adjusting for age, hypertension, and family history of CAD (OR 4.25, 95% CI 1.68–10.78).

Bhalodkar et al. compared various lipoprotein concentrations and sizes in 211 AI immigrant men with those in 1684 Caucasian men enrolled in the Framingham Heart Offspring Study [29]. The prevalence of angiographically determined CAD was approximately 5.8% in AI men and 2.5% in the Framingham Heart Study population. Mean age of participants was lower in the AI men (50.0 ± 11.2 vs. 51.6 ± 10.1 years, p = 0.03). HDL subclass distribution was determined by gradient gel electrophoresis and nuclear magnetic resonance spectroscopy. Mean HDL-C levels were 41.0 ± 10 mg/dL in AI men and 41.0 ± 11 mg/dL in Caucasian men. However, concentrations of large HDL subclasses (H3 + H4 + H5) were significantly lower (21.4 ± 13.9 mg/dL in AI men vs. 23.8 ± 11.5 mg/dL in Caucasians, p < 0.005), and those of small HDL cholesterol subclasses (H1 + H2) significantly higher (19.7 ± 6.5 mg/dL in AI vs. 17.4 ± 4.8 mg/dL in Caucasians, p < 0.0001) in AI men compared with Caucasian men. It is hypothesized that large HDL particles may be more efficient at reverse cholesterol transport compared with small HDL particles [30]. Therefore, the findings presented above could play an important role in explaining aggressive CAD in SAs.

Superko et al. had a similar design where they recruited 173 AI males with no history of CAD and compared them with 239 non-AI healthy males in the Berkeley Health Lab database [31]. HDL subclass distribution was determined by gradient gel electrophoresis. Electrophoretic bands representing the HDL sub-fractions HDL2b, HDL2a, HDL3a, HDL3b, and HDL3c were identified and densitometrically scanned using a computer-assisted scanning procedure. The study revealed no significant differences in HDL-C levels between AI and non-AI males (44.0 ± 9.9 vs. 42.5 ± 12.6 mg/dL p = 0.19), but the large HDL2b component was significantly lower in the AI group (11.6 ± 5.0 vs. 14.3 ± 8.3 mg/dL, p = 0.0002) than the non-AI group. Another finding from the study was that the combination of elevated lipoprotein(a) levels (Lp(a) > 20 mg/dL) and low HDL2b (HDL2b < 20%) was found in 42.1% of the AI men compared with 18.8% in the non-AI men (p < 0.0001). The authors concluded that these findings could identify a group at higher risk of CAD.

Lipoprotein(a)

High levels of Lp(a) have been identified to be a causal risk factor for atherosclerotic CAD, stroke, and peripheral vascular disease. Levels of Lp(a) are mostly determined by genetics [32]. Numerous studies have been conducted on its role in CAD. Studies from South Asia have mainly focused on the role of Lp(a) in the premature onset of CAD. Some of these studies are discussed here [33, 34].

In a Mendelian randomization study conducted on the Pakistan Risk of Myocardial Infarction Study (PROMIS) cohort, apolipoprotein size and concentration were measured in 9015 patients and 8629 controls from 7 centers in 5 cities in Pakistan [35••]. The study identified the minor allele rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size and the minor allele rs3777392 as a variant associated with Lp(a) concentration. The odds ratio for MI was 0.93 (95% CI 0.90–0.97, p < 0.0001) per 1 SD increase in Lp(a) size, and 1.10 (95% CI 1.05–1.14; p < 0.0001) per 1-SD increment in Lp(a) concentration after adjusting for several cardiovascular risk factors. The study concluded that small apolipoprotein(a) isoform size and high Lp(a) concentration were independently associated with CHD among Pakistani patients. The study also analyzed concentrations of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) using chemiluminescent ELISA in relation to genome-wide genotypes. Lp(a) gene variants (rs10455872 and rs3798220) were found to be strongly associated with OxPL-apoB concentration. This would suggest that oxidative damage could mediate the pathological effects of Lp(a) in coronary heart disease.

Bansal et al. examined 30 Indian patients with PCAD (age less than 45 years in males and age less than 55 years in females) and 30 Indian controls to identify advanced lipid parameters that correlate with PCAD [36]. The mean ages of the cases and controls were 42.5 and 41.1 years, respectively. Mean Lp(a) level was 43.17 ± 10.23 mg/dL in cases and 17.62 ± 3.18 in controls (p < 0.0001). Lipoprotein(a) levels were also found to correlate strongly with PCAD (correlation coefficient = + 0.86).

Individuals with high concentration of Lp(a) due to genetic susceptibility are prone to developing PCAD due to accelerated atherosclerosis. Studies have suggested a strong association of Lp(a) with CAD with higher concentrations associated with progression of disease in South Asians.

Genetic Markers

Genetic studies have been conducted among immigrant and non-immigrant South Asian populations to determine the effect of gene-gene and gene-environment interactions. These cohorts include the PROMIS cohort in Pakistan, the BRAVE cohort in Bangladesh, and LOLIPOP (immigrant SAs and EWs in UK) [11, 24, 35••]. In addition, the South Asian Birth Cohort (START), an Indian-Canadian collaboration (urban and rural Indians, Canadian Indians), has been initiated to study the genetic interactions and other factors that may lead to increased risk of diabetes and CVD in the South Asian population [37]. Large genome projects such as the 1000 Genome Project include multiethnic cohorts to better understand genetic differences between different ethnicities [38]. Some of the recent genetic studies conducted in South Asian cohorts are discussed here.

In 2011, The Coronary Artery Disease (C4D) Genetics Consortium reported a meta-analysis of 4 large Genome Wide Association Studies (GWAS) of CAD that included 2 South Asian cohorts (PROMIS and LOLIPOP) and two European ancestry (PROCARDIS and HPS) cohorts [39]. The study comprised of 15,420 individuals (8424 Europeans and 6996 South Asians) with CAD and 15,062 controls. Prior genotyping of these individuals yielded a total of 574,919 single nucleotide polymorphisms (SNPs) that were tested for association with CAD. The meta-analysis identified 59 SNPs (41 from pooled European and South Asian studies and 6 from South Asian studies alone) at 50 loci that were potentially associated with CAD. These SNPs were tested for replication in 21,408 cases of CAD and 19,185 controls largely by de novo genotyping. After replication, 5 of these SNPs (rs1412444, rs974819, rs4380028, rs10953541, and rs2505083)—all from pooled European and South Asian meta-analysis—achieved the predetermined threshold for replication (p < 8.5 × 10−4) and conventional genome-wide significance (p < 5.0 × 10−8). These SNPs implicate new pathways for CAD susceptibility.

Even with the discovery of 58 genomic regions associated with CAD, most of the heritability cannot be explained. Therefore, efforts to discover additional susceptibility loci need to be made. Researchers set out to perform GWAS to evaluate promising associations and genotyped 56,309 participants using targeted gene array from earlier GWAS, and conducted a meta-analysis of 194,427 participants (88,192 CAD cases and 162,544 controls) of a multiethnic cohort [40••]. A total of 7 cohorts (EPIC-CVD, CHS, CIHDS/CGPS, TAICHI, ARIC, WHI, and MIGEN) from non-South Asian ancestry and 2 cohorts (PROMIS and BRAVE) from South Asian ancestry were used. In addition, data from the CARDIoGRAMplusC4D (European and South Asian cohorts) were also used. Meta-analysis of studies with de novo genotyping was performed. South Asian samples contributing to the meta-analysis were 3950 CAD cases and 3581 controls. They found 25 SNP CAD associations from 15 genomic regions (p < 5 × 10–8, in fixed-effects meta-analysis). The SNPs found to have association with CAD were found in or near genes involved in cellular adhesion, leukocyte migration, and atherosclerosis (PECAM1, rs1867624), vascular smooth muscle cell differentiation (LMOD1, rs2820315), and coagulation and inflammation (PROCR, rs867186 (p Ser219Gly), which shed light on arterial wall-specific mechanism regulation effected by these polymorphisms.

Monocytes have many functions including initiation of adaptive immunity and clearance of dead cells and pathogens, and they can contribute to the pathogenesis of atherosclerosis as well. Chemokine receptors CCR2, CRR5, and CX3CR1A organize monocytes in homeostatic and inflammatory states [41]. A growing body of evidence links SNPs in the genes for these receptors to cardiometabolic diseases including atherosclerotic cardiovascular disease. A study investigating common and low frequency variation in 9058 MI cases and 8379 controls from the PROMIS cohort in Pakistan identified 6 variants in CX3CR1 associated with MI, which were unique to South Asians. These variants were not found in large (mostly European) cohorts of CARDIoGRAM plus C4D of 60,801 cases and 123,504 controls, the MIGen and CARDIoGRAM Exome consortia of 42,335 cases and 78,240 controls, and the Exome Sequencing Project and Early-Onset Myocardial Infarction of 4703 cases and 5090 controls.

The tumor suppressor gene (p53) affects smooth muscle proliferation, an important step in atherogenesis. A study of 284 South African Indians with 100 CAD cases, 100 controls, and 84 Black controls with mean age 37.5 years found significant differences in genotype distribution among Indian CAD patients and Indian controls (p = 0.0025) [42••]. A higher frequency of the p53 Arg72 allele was found in Indian CAD cases than Indian controls (52 vs. 39.5%, p = 0.015). Considering the young age of the cohort, this study is important in identifying the Arg72 variant of the p53 functional polymorphism (rs1042522) as a contributory factor for the development of PCAD in this population.

Epigenetic factors alter gene function by histone binding and methylation of DNA at cytosine residues. The pattern of gene regulation is influenced by environmental insults making it susceptible to disease. These insults can be maternal undernutrition resulting in in-utero or early-life nutritional deficiency which can produce low birth-weight babies. Studies have demonstrated these factors to be associated with increased risk of adult-onset CHD [43]. Studies have been conducted on the effect of epigenetic factors on various medical conditions such as metabolic diseases and psychiatric disorders among South Asian immigrants but no large-scale investigation has been conducted on the influence of epigenetic factors and development of PCAD in South Asian immigrants [44]. Flowers et al. enrolled 22 cases and 22 controls to study the association of atherogenic dyslipidemia with microRNA (miR), a structural component of an epigenetic mechanism of post-transcriptional regulation of mRNA, on South Asian men. Cases were defined as South Asian men with HDL-C < 40 mg/dL and TG > 150 mg/dL. Cases had lower HDL-C levels (33 vs. 47 mg/dL, p < 0.05) and higher triglycerides (237 vs. 109 mg/dL, p < 0.05) than controls [45]. Cases also had higher fasting blood glucose (97 vs. 88 mg/dL, p < 0.05) and higher mean BMI (26.1 vs. 23.9 kg/m2, p < 0.05). There were no statistically significant differences between cases and controls in total cholesterol (197 mg/dL in cases vs. 194 mg/dL in controls, p < 0.8) or LDL-C (116 vs. 123 mg/dL, p < 0.3). Out of 74 miR which met quality control measures, 3 miR (miR-214, miR-885-5p, miR-205) displayed increased expression in cases compared with controls, while 15 miR (miR-374a, miR-100, miR-7, miR-18a, miR-125b, miR-148a, miR-17, miR-21, miR-221, miR-93, miR-143, miR-17, miR-106b) had a 2-fold decreased expression in cases than controls (p < 0.05). Among the 6 miR (miR-100, miR-106b, miR-125b, miR-148a, miR-21, miR-7), previously shown to regulate the expression of gene pathways that regulate lipoprotein metabolism, the only miR that remained statistically significant when measuring individual samples was miR-21 (p < 0.05). This study identifies miR as a potential diagnostic and/or prognostic marker of atherogenic dyslipidemia in South Asians.

While meaningful work has been initiated, more is needed to understand epigenetic gene regulation in South Asians and the unexplained heritability of atherosclerosis in the South Asian population.

Conclusion

South Asians have demonstrated a higher burden of PCAD compared with other ethnicities. These findings are consistent among both the immigrant and non-immigrant South Asian population. In addition to a higher prevalence of traditional risk factors, studies have now also started to focus on risk factors inherent to the South Asian population (gutka, use of banaspati/palm oil). While studies have been conducted to evaluate genetics to explain a higher burden in South Asians, they do not allow definitive conclusions, especially with regard to how these could impact therapy. Large-scale studies are needed to identify how this information can be rationally utilized for early identification of risk among South Asians, and how currently available therapies can mitigate this increased risk.