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doi:10.1038/nindia.2014.40 Published online 25 March 2014

'Ayurgenomics' unravel new rheumatoid arthritis genes

T. V. Padma

Indian geneticists are combining modern and ancient sciences to unravel new genes linked to rheumatoid arthritis. They are drawing from both genome wide association studies (GWAS) and the ancient Indian system of medicine Ayurveda, making for a new hybrid discipline — 'Ayurgenomics'.

A genomics symposium in February 2014 at Thiruvananthapuram, Kerala saw Bittianda Kuttapa Thelma, head of Delhi University's genetics department, unravel some previously unreported genes linked to rheumatoid arthritis. The disease, leading to progressive degeneration of joint tissues and deformities, is caused by the inter-play of multiple genes.

Thelma's team had begun its hunt for novel rheumatoid arthritis genes in Indian patients on two premises. One, Indian population groups not part of the international HapMap project could harbour some hitherto unreported genes. And two, the Ayurvedic system of sub-classifying rheumatoid arthritis patients according to their body constitution — vata, pita and kapha — for treatment could be a basis for genetic differences that needs scientific testing and validation.

The scientists found limited replication of the genetic variations seen in Caucasian populations in the HapMap project in a north Indian cohort . The team first tested their hunch that the prior risk implicit in the three constitution types described in Ayurveda could uncover genetic variance and lead to predictive medicine.

They designed a study involving 350 patients diagnosed as amvata (the Ayurvedic equivalent of rheumatoid arthritis) alongside 376 controls. The scientists studied the clinical and immunological profiles of the patients, measuring, for example, the body mass index (BMI), haeomoglobin b, erthrocyte sedimentation rate (ESR) to gauge amount of inflammation and a confirmatory test for rheumatoid arthritis based on 'anti-CCP antibodies' (anti-cyclic citrinullated antibody) factor.

Simultaneously, they isolated genetic material or DNA from the patients and studied variations and possible candidate genes linked to rheumatoid arthritis. Next, they performed statistical test associations between the clinical, immunological and genetics data on one hand and the three sub-types of the patients on the other.

They reported notable differences between the five immunological factors, including BMI, pain, swelling, stiffness, ESR, anti-CCP antibodies, and rheumatoid arthritis factor, among the three sub-groups .

The disease profiles were most pronounced in the vata subgroup, tallying with the Ayurveda principle that vata people were susceptible to arthritis. Narrowing down to the vata group led to two new associated genes — CD40 and PON2. CD40 is linked to higher rate of joint destruction, also seen in the vata sub-group.

Overall, the study found 12 candidate genes from the three sub-groups.

The scientists also found that genes linked to inflammatory pathways influenced arthritis in the vata group but in another sub-group (pitta), genes involved with oxidative stress showed up. This meant different gene interactions and mechanisms led to the arthritis condition, and in turn needed different treatment approaches, Thelma reported.

The theory of possible presence of novel genes in the Indian population got a further boost when a separate group of geneticists reported a novel gene ARL15 in a north Indian population linked to rheumatoid arthritis .

Thelma says they have now found 17 novel genes in the vata, 24 in the pitta and 35 in the kapha sub-groups. Some of these genes were reported in the Caucasian groups part of the HapMap study but were not linked to rheumatoid arthritis. Some of the novel genes were not previously reported as linked to rheumatoid arthritis.

The scientists also found that some of the new genes in each sub-group were associated with high risk of developing the disease. For instance, some genes put patients at 3, 4 or even 5 times more at risk. This is considerably higher than risks with some of the published rheumatoid arthritis-linked genes, they say. Thelma says this sub-grouping is helping scientists identify novel genes and biomarkers that will ultimately help understand disease biology better.

The Ayurvedic system of sub-classification has evoked some interest. The European Institute of Systems Biology and Medicine (EISBM) and New Delhi-based Institute of Genomics and Integrative Biology (IGIB) are already planning a research exchange programme and will soon apply for a European Commission funding to pursue 'Ayurgenomics'.

Charles Auffrey, founder of EISBM and professor at University of Lyon, France, says the most difficult hurdle in predictive and personalised medicine is to fine-tune treatment according to individual predispositions. Auffrey says traditional medicine systems in China and India could offer some leads in personalised medicine.


References

  1. Prasad, P. et al. Caucasian and Asian specific rheumatoid arthritis risk loci reveal limited replication and apparent allelic heterogeneity in North Indians. PLOS ONE (2013) doi: 10.1371/journal.pone.0031584
  2. Juyal, R. C. et al. Potential of Ayurgenomics approach in complex trait research: leads from a pilot study on rheumatoid arthritis. PLOS ONE. (2012) doi: 10.1371/journal.pone.0045752
  3. Negi, S. et al. A genome-wide association study reveals ARL15, a novel non-HLA susceptibility gene for rheumatoid arthritis in north Indians. Arthritis Rheum. (2013) doi: 10.1002/art.38110