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It is being realized that identification of subgroups within normal controls corresponding to contrasting disease susceptibility is likely to lead to more effective predictive marker discovery. We have previously used the Ayurvedic concept of Prakriti, which relates to phenotypic differences in normal individuals, including response to external environment as well as susceptibility to diseases, to explore molecular differences between three contrasting Prakriti types: Vata, Pitta, and Kapha. EGLN1 was one among 251 differentially expressed genes between the Prakriti types. In the present study, we report a link between high-altitude adaptation and common variations rs479200 (C/T) and rs480902 (T/C) in the EGLN1 gene. Furthermore, the TT genotype of rs479200, which was more frequent in Kapha types and correlated with higher expression of EGLN1, was associated with patients suffering from high-altitude pulmonary edema, whereas it was present at a significantly lower frequency in Pitta and nearly absent in natives of high altitude. Analysis of Human Genome Diversity Panel-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) and Indian Genome Variation Consortium panels showed that disparate genetic lineages at high altitudes share the same ancestral allele (T) of rs480902 that is overrepresented in Pitta and positively correlated with altitude globally (P < 0.001), including in India. Thus, EGLN1 polymorphisms are associated with high-altitude adaptation, and a genotype rare in highlanders but overrepresented in a subgroup of normal lowlanders discernable by Ayurveda may confer increased risk for high-altitude pulmonary edema. high-altitude pulmonary edema | Prakriti | Indian Genome Variation Database | phenotype | hypoxia doi/ 10.1073/pnas.1006108107

Abstract: The physiological role of NPFF/FMRFa family of peptides is complex and exact mechanism of action of these peptides is not yet completely understood. In same line of scrutiny, previously we reported an enzymatically stable chimeric analog of YGGFMKKKFMRFamide (YFa) i.e., [d-Ala2]YAGFMKKKFMRFamide ([d-Ala2]YFa) which have a role in antinociception and modulatory effect on opioid analgesia. In continuation, presently we investigated using tail-flick test whether [d-Ala2]YFa on systemic administration induced any antinociception in rats and if so then which specific opioid receptor(s) μ, δ or κ mediated it. Further, the antinociceptive effect of [d-Ala2]YFa on 6 days chronic intra-peritoneal (i.p.) treatment in rats was examined and finally, effect of this chronic treatment on the differential expression of opioid receptors was assessed. [d-Ala2]YFa on i.p. administration induced dose dependent antinociception which was mainly mediated by δ (DOR) and partially by μ (MOR) and κ (KOR) opioid receptors. Moreover, its antinociceptive effect remained comparable throughout the chronic treatment even during insufficient availability of DOR1. Importantly, during this treatment the mRNA expression of all three opioid receptors (MOR1, KOR1 and DOR1) was increased as assessed by real-time RTPCR though subsequent western blot analysis revealed a selective increase in the protein level of DOR1, only. Thus, pharmacological behavior of [d-Ala2]YFa suggests that competency of an opioid agonist to bind with multiple opioid receptors may enhance its potency to induce tolerance free analgesia. [Copyright &y& Elsevier]