LETTER TO JMG

Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension

Ana Carolina Braga Marçano¹, Beverley Burke¹, Johannie Gungadoo¹, Chris Wallace¹, Pamela J Kaisaki², Peng Y Woon², Martin Farrall³, David Clayton⁴, Morris Brown⁴, Anna Dominiczak⁵, John M Connell⁵, John Webster⁶, Mark Lathrop⁷, Mark Caulfield¹, Nilesh Samani⁸, Dominique Gauguier², Patricia B Munroe¹

¹ Clinical Pharmacology and The Genome Centre, Barts and The London School of Medicine and Dentistry, London, UK
² The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
³ Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK
⁴ Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
⁵ BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, UK
⁶ Medicine and Therapeutics, Aberdeen Royal Infirmary, Aberdeen, UK
⁷ Centre National de Genotypage, Evry, France
⁸ Cardiology, University of Leicester, Glenfield Hospital, Leicester, UK

Correspondence to:
Patricia B Munroe
PhD, Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ; p.b.munroe{at}qmul.ac.uk

Background: Inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension.

Objective and methods: To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort.

Results: We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1).

Conclusion: These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically.

Abbreviations: BRIGHT, British Genetics of Hypertension; CEPH, Centre d’Etudes du Polymorphisme Humain; DIF, Diabetes in Families; EH, essential hypertension; GK, Goto–Kakizaki; HWE, Hardy–Weinberg equilibrium; SHR, spontaneously hypertensive rat; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test

Keywords: hypertension; diabetes; association; INPPL1

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