Value of exploring disease biology by studying South Asian Cohorts in Type 2 Diabetes

Dr. Ramesh Menon, Senior Bioinformatics Scientist – II, MedGenome Labs

It’s widely believed that South Asians are born with a high risk for several non-communicable diseases (NCD) such as diabetes, cardiovascular diseases etc, which often points to unhealthy lifestyle and environmental factors. For example, higher prevalence of type 2 diabetes is often over-attributed to overweight/obesity in Indians. How many of us know that in India, there are higher incidence of type 2 diabetes reported even in people with lower BMI ? [1,2]

Compared to Europeans, South Asians, on an average have low muscle mass, which could be due to long-term adaptation to climate [2]. Genetic studies in South Asian population have found increased selection of a gene encoding myostatin – a protein that inhibits skeletal muscle growth in uterus through poor placental glucose uptake [3]. Can this be a factor for higher incidence for type 2 diabetes in South Asians? Recent studies answered yes to this question [3]. In fact, South Asians may have a specific tendency for fat accumulation in liver (ectopic hepatic fat) and for intramyocellular fat deposition, which cause further disruption in insulin action [2,4,5]. In addition, the conversion from pre-diabetes to diabetes is alarmingly rapid in South Asians, reported in a 10 year follow-up study by Madras Diabetic Research Foundation [6]. We are yet to completely understand the reason behind this completely, but hepatic fat accumulation is found to play an important role in post-dysglycaemia [6].

A typical genome-wide association study (GWAS) attempts to identify moderate or high frequent genetic variant by assaying several thousands to millions of genomic markers, screening large number of samples. One of the important study was from Saxena and collegues in 2013, where the GWAS analysis was performed in Punjabi Sikhs, a sub-population with high prevalence of type 2 diabetes and cardiovascular disease despite low obesity rates, moderate non-vegetarian diet, and strict tobacco abstinence [7]. The authors have identified a previously unreported genetic variant (rs9552911) in SGCG (skeletal muscle-expressed sarcoglycan) gene, which has a strong association to type 2 diabetes in Punjabi Sikhs. The findings were confirmed by a replication study.

In a larger study published very recently in Nature Genetics, Vujkovic collegues have discovered 558 independent SNPs associated with T2D in a multi-ethnic study. Interestingly, out of 558 markers, 21 SNPs were ancestry informative markers (AIM) present in Europeans [8]. However, they could not find a population-specific type 2 diabetes associated marker in South Asians, which may be due to limited South Asian sub-population representation in the public domain used in the study.
In India, the major limiting factor is the systematic recording of clinical/biochemical/anthropometric parameters of the patient visiting the clinic. Except few well-established hospitals or clinics which are active in research, our primary health centres where most patients get treatment are not equipped to capture this important information. This limits the application of current computation tools and statistical methods from a deeper analysis combining genotype and phenotype data. Models like UK Biobank are good examples that can be followed in India.

References

  1. Narayan and Kanaya (2020). Why are South Asians prone to type 2 diabetes? A hypothesis based on underexplored pathways. Diabetologia
  2. Pomeroy et.al (2019). Ancient origins of low lean mass among South Asians and implications for modern type 2 diabetes susceptibility. Scientific Reports
  3. Metspalu et. al. (2011). Shared and unique components of human population structure and genome-wide signals of positive selection in South Asia. American Journal of Human Genetics
  4. Trouwbors et.al. (2018). Ectopic Fat Accumulation in Distinct Insulin Resistant Phenotypes; Targets for Personalized Nutritional Interventions. Frontiers in Nutrition
  5. Gujral et.al. (2019). Diabetes in Normal-Weight Individuals: High Susceptibility in Nonwhite Populations. Diabetes Care
  6. Mohan et.al. (2015). Incidence of Diabetes and Prediabetes and Predictors of Progression Among Asian Indians: 10-Year Follow-up of the Chennai Urban Rural Epidemiology Study (CURES). Diabetes Care
  7. Saxena et. al. (2013). Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India. Diabetes
  8. Vujkovic et.al. (2020). Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nature Genetics

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