Precision medicine aims to move from traditional reactive medicine to a system where risk groups can be identified before the disease occurs. However, phenotypic heterogeneity amongst the diseased and healthy poses a major challenge for identification markers for risk stratification and early actionable interventions. In Ayurveda, individuals are phenotypically stratified into seven constitution types based on multisystem phenotypes termed “Prakriti”. It enables the prediction of health and disease trajectories and the selection of health interventions. We hypothesize that exome sequencing in healthy individuals of phenotypically homogeneous Prakriti types might enable the identification of functional variations associated with the constitution types. Exomes of 144 healthy Prakriti stratified individuals and controls from two genetically homogeneous cohorts (north and western India) revealed differential risk for diseases/traits like metabolic disorders, liver diseases, and body and hematological measurements amongst healthy individuals. These SNPs differ significantly from the Indo-European background control as well. Amongst these we highlight novel SNPs rs304447 (IFIT5) and rs941590 (SERPINA10) that could explain differential trajectories for immune response, bleeding or thrombosis. Our method demonstrates the requirement of a relatively smaller sample size for a well powered study. This study highlights the potential of integrating a unique phenotyping approach for the identification of predictive markers and the at-risk population amongst the healthy.

https://www.mdpi.com/2075-4426/12/3/489/pdf?version=1647588271

Whole Exome Sequencing in Healthy Individuals of Extreme Constitution Types Reveals Differential Disease Risk: A Novel Approach towards Predictive Medicine

Autonomic modulation is critical during various physiological activities, including orthostatic stimuli and primarily evaluated by heart rate variability (HRV). Orthostatic stress affects people differently suggesting the possibility of identification of predisposed groups to autonomic dysfunction‐related disorders in a healthy state. One way to understand this kind of variability is by using Ayurvedic approach that classifies healthy individuals into Prakriti types based on clinical phenotypes. To this end, we explored the differential response to orthostatic stress in different Prakriti types using HRV. HRV was measured in 379 subjects(Vata = 97, Pitta = 68, Kapha = 68, and Mixed Prakriti = 146) from two geographical regions(Vadu and Delhi NCR) for 5 min supine (baseline), 3 min head‐up‐tilt (HUT) at 60°, and 5 min resupine. We observed that Kapha group had lower baseline HRV than other two groups, although not statistically significant. The relative change (%Δ1&2) in various HRV parameters in response to HUT was although minimal in Kapha group. Kapha also had significantly lower change in HR, LF (nu), HF (nu), and LF/HF than Pitta in response to HUT. The relative change (%Δ1) in HR and parasympathetic parameters (RMSSD, HF, SD1) was significantly greater in the Vata than in the Kapha. Thus, the low baseline and lower response to HUT in Kapha and the maximum drop in parasympathetic activity of Vata may indicate a predisposition to early autonomic dysfunction and associated conditions. It emphasizes the critical role of Prakriti‐based phenotyping in stratifying the differential responses of cardiac autonomic modulation in various postures among healthy individuals across different populations.

Heart rate variability during head‐up tilt shows inter‐individual differences among healthy individuals of extreme Prakriti types

Differences in human phenotypes and susceptibility to complex diseases are an outcome of genetic and environmental interactions. This is evident in diseases that progress through a common set of intermediate patho-endophenotypes. Precision medicine aims to delineate molecular players for individualized and early interventions. Functional studies of lymphoblastoid cell line (LCL) model of phenotypically well-characterized healthy individuals can help deconvolute and validate these molecular mechanisms. In this study, LCLs are developed from eight healthy individuals belonging to three extreme constitution types, deep phenotyped on the basis of Ayurveda. LCLs were characterized by karyotyping and immunophenotyping. Growth characteristics and response to UV were studied in these LCLs. Significant differences in cell proliferation rates were observed between the contrasting groups such that one type (Kapha) proliferates significantly slower than the other two (Vata, Pitta). In response to UV, one of the fast growing groups (Vata) shows higher cell death but recovers its numbers due to an inherent higher rates of proliferation. This study reveals that baseline differences in cell proliferation could be a key to understanding the survivability of cells under UV stress. Variability in baseline cellular phenotypes not only explains the cellular basis of different constitution types but can also help set priors during the design of an individualized therapy with DNA damaging agents. This is the first study of its kind that shows variability of intermediate patho-phenotypes among healthy individuals with potential implications in precision medicine.

Baseline cell proliferation rates and response to UV differ in lymphoblastoid cell lines derived from healthy individuals of extreme constitution types

Differences in human phenotypes and susceptibility to complex diseases are an outcome of genetic and environmental interactions. This is evident in diseases that progress through a common set of intermediate patho-endophenotypes. Precision medicine aims to delineate the molecular players for individualized and early interventions. Functional studies in Lymphoblastoid Cell Line (LCL) model of phenotypically well characterized healthy individuals can help deconvolute and validate these molecular mechanisms. We developed LCLs from eight healthy individuals belonging to three extreme constitution types, deep phenotyped on the basis of Ayurveda. LCLs were characterized by karyotyping and immunophenotyping. Growth characteristics and response to UV was studied in these LCLs. We observed significant differences in cell proliferation rates between the contrasting groups such that one type (Kapha) proliferates significantly slower than the other two (Vata, Pitta). In response to UV, one fast growing group (Vata) shows higher cell death but recovers its numbers due to inherent higher rates of proliferation. The baseline differences in cell proliferation are key to understanding the survival of cells in UV stress. Variability in baseline cellular phenotypes not only explains the cellular basis of different constitutions types but can also help set priors during designing an individualized therapy with DNA damaging agents. This is the first study of its kind that shows variability of intermediate patho-phenotypes amongst healthy individuals that have implications in precision medicine.

/pdf/baseline-cell-proliferation-rates-and-response-to-uv-differ-e40wckkcv8.pdf

Baseline cell proliferation rates and response to UV differ in Lymphoblastoid Cell Lines derived from healthy individuals of extreme constitution types

Sunanda Singhmar

Papers

Baseline cell proliferation rates and response to UV differ in lymphoblastoid cell lines derived from healthy individuals of extreme constitution types

Baseline cell proliferation rates and response to UV differ in Lymphoblastoid Cell Lines derived from healthy individuals of extreme constitution types