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Focused panel sequencing points to genetic predisposition in non-cirrhotic intrahepatic portal hypertension patients in India

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Indian Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Objective

Non-cirrhotic intrahepatic portal hypertension (NCIPH), a portal microangiopathy affecting small portal vein radicles, is a disease of Indian sub-continent. NCIPH appears to be a complex disease with interactions between inherited and acquired factors, though the exact pathophysiological mechanism is unknown. We aimed at investigating the genetic variants that might contribute to susceptibility to NCIPH.

Methods

In this case-control study, we analyzed genes associated with microangiopathy—VWF-ADAMTS13 (von Willebrand factor and its cleavase enzyme — a disintegrin and matrix metalloprotease with thrombospondin type-1 motifs member 13) and alternative complement system vitamin B12 metabolism and with familial NCIPH.

Result

Eighty-four Indian patients with liver biopsy–proven NCIPH (cases) and 103 healthy controls (matched for residential region of India) were included in the study. Targeted next-generation sequencing (NGS) panel, comprising 11 genes of interest, was done on 54 cases. Genotyping of selected variants was performed in 84 cases and 103 healthy controls. We identified variants in MBL2, CD46 and VWF genes either associated or predisposing to NCIPH. We also identified a single case with a novel compound heterozygous mutation in MBL2 gene, possibly contributing to development of NCIPH.

Conclusion

In this first of a kind comprehensive gene panel study, multiple variants of significance have been noted, especially in ADAMTS13-VWF and complement pathways in NCIPH patients in India. Functional significance of these variants needs to be further studied.

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Funding

We received funds from Department of Science and Technology, Government of India (EMR/ 2015/000570).

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Authors and Affiliations

  1. Wellcome Trust Research Laboratory, Division of GI Sciences, Christian Medical College, Vellore, 632 004, India

    Rekha Aaron, Kalpana Premkumar, B. Vijayalekshmi & K. A. Balasubramanian

  2. Department of Endocrinology, Christian Medical College, Vellore, 632 004, India

    Aaron Chapla & Nihal Thomas

  3. Department of Hepatology, Christian Medical College, Vellore, 632 004, India

    Uday Zachariah, Elwyn Elias, C. E. Eapen & Ashish Goel

  4. Department of Pathology, Christian Medical College, Vellore, 632 004, India

    Thomas Alex Kodiatte, Sukesh C. Nair & Banumathi Ramakrishna

  5. Department of Transfusion Medicine and Immuno-Haematology, Christian Medical College, Vellore, 632 004, India

    Dolly Daniel & John Jude

  6. Department of Microbiology, Christian Medical College, Vellore, 632 004, India

    John Jude

  7. Department of Pathology, SRM Institutes for Medical Science, Chennai, 600 083, India

    Banumathi Ramakrishna

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  1. Rekha Aaron
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  2. Kalpana Premkumar
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  14. C. E. Eapen
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  15. Ashish Goel
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Contributions

RA, AC, UZ, EE, JJ, KAB, SCN, NT, CEE and AG contributed to the study concept and design. UZ, AG and CEE recruited the patients and obtained informed consent. RA, KP, AC, BV, DD, JJ, KAB, SCN and NT performed the laboratory experiments. TAK and BR contributed to the pathology part. All were involved in data collection, interpretation and conclusion, preparation of the manuscript, critical revision and review of the manuscript and approved the final version of the manuscript.

Corresponding author

Correspondence to Ashish Goel.

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Conflict of interest

RA, KP, AC, BV, UZ, EE, TAK, DD, JJ, KAB, SCN, NT, BR, CEE and AG declare no competing interests.

Consent to participate

Obtained from all study participants.

Ethics statement

 The study was performed conforming to the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning human and animal rights, and the authors followed the policy concerning informed consent as shown on Springer.com.

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The authors are solely responsible for the data and the contents of the paper. In no way, the Honorary Editor-in-Chief, Editorial Board Members, the Indian Society of Gastroenterology or the printer/publishers are responsible for the results/findings and content of this article.

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Aaron, R., Premkumar, K., Chapla, A. et al. Focused panel sequencing points to genetic predisposition in non-cirrhotic intrahepatic portal hypertension patients in India. Indian J Gastroenterol 43, 434–442 (2024). https://doi.org/10.1007/s12664-023-01454-5

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