Khan, J. (Javed)

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    Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.
    (Nature Research, 2018) Machiela, M.J. (Mitchell J.); Wyatt, K. (Kathleen); Bhatia, S. (Smita); Patiño-García, A. (Ana); Armstrong, G.T. (Gregory T.); Zaidi, S. (Sakina); Cox, D.G. (David G.); Zhou, W. (Weiyin); Grünewald, T.G.P. (Thomas G. P.); Tirode, F. (Franck); Hartmann, W. (Wolfgang); Dirksen, U. (Uta); Kirchner, T. (Thomas); Kulozik, A. (Andreas E.); Khan, J. (Javed); Hoover, R.N. (Robert N.); Laurence, V. (Valérie); Freedman, N.D. (Neal D.); Kontny, U. (Udo); Alonso, J. (Javier); Delattre, O. (Olivier); Surdez, D. (Didier); Mirabeau, O. (Olivier); Pierron, G. (Gaelle); Manning, M. (Michelle); Grossetete-Lalami, S. (Sandrine); Mirabello, L. (Lisa); Burdett, L. (Laurie); Leisenring, W.M. (Wendy M.); Ballet, S. (Stelly); Strauch, K. (Konstantin); Kovar, H. (Heinrich); Gaspar, N. (Nathalie); Dagnall, C. (Casey); Kriebel, J. (Jennifer); Chanock, S.J. (Stephen J.); Michon, J. (Jean); Metzler, M. (Markus); Jones, K. (Krisitine); Reynaud, S. (Stephanie); Corradini, N. (Nadege); Picci, P. (Piero); Morton, L.M. (Lindsay M.); Karlins, E. (Eric); Rubio, R.A. (Rebeca Alba); Meitinger, T. (Thomas); Lapouble, E. (Eve); Yeager, M. (Meredith); Bérard, P.M. (Perrine Marec); Robison, L.L. (Leslie L.); Tucker, M. (Margaret); Gonzalez-Neira, A. (Anna); Rothman, N. (Nathaniel)
    Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.
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    The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial
    (Oxford University Press, 2021) Cleland, J.G. (John G.); Ferreira, J.P. (João Pedro); Mariottoni, B. (Beatrice); Pellicori, P. (Pierpaolo); Cuthbert, J. (Joe); Verdonschot, J.A.J. (Job A. J.); Petutschnigg, J. (Johannes); Ahmed, F.Z. (Fozia Z.); Cosmi, F. (Franco); Brunner-La-Rocca, H.P. (Hans-Peter); Mamas, M.A. (Mamas A.); Clark, A.L. (Andrew L.); Edelmann, F. (Frank); Pieske, B. (Burkert); Khan, J. (Javed); McDonald, K. (Ken); Rouet, P. (Philippe); Staessen, J.A. (Jan A.); Mujaj, B. (Blerim); Gonzalez, A. (Arantxa); Diez, J. (Javier); Hazebroek, M.R. (Mark R.); Heymans, S. (Stephane); Latini, R. (Roberto); Grojean, S. (Stéphanie); Pizard, A. (Anne); Girerd, N. (Nicolas); Rossignol, P.(Patrick); Collier, T.J. (Tim); Zannad, F. (Faiez)
    Aims: To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results: Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone. Conclusions: Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.