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BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related stem cell transplantation.

Ignazio Stefano Piras1, Andrea Angius1,2, Marco Andreani3, Manuela Testi3, Guido Lucarelli4, Matteo Floris1, Sarah Marktel5, Fabio Ciceri5, Giorgio La Nasa6,7, Katharina Fleischhauer8, Maria Grazia Roncarolo9,10, Alessandro Bulfone1, 11, Silvia Gregori9, *and Rosa Bacchetta9, *, #

* Equal contribution.

Running title: BAT2 and BAT3: two novel SNPs: new biomarkers of associated with rejection.

1Crs4, Biomedicine, Pula (CA), Italy; 2 IRGB, CNR, Monserrato (CA), Italy; 3Laboratory of Immunogenetics and Transplant Biology, IME Foundation, Polyclinic of Tor Vergata University, Rome, Italy; 4International Center for Transplantation in Thalassemia and Sickle Cell Anemia, IME Foundation, Polyclinic of Tor Vergata University, Rome, Italy; 5Pediatric Immuno-Hematology Unit and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Ospedale San Raffaele IRCCS, Milan; 6Centro Trapianti di Midollo Osseo, P.O. “R. Binaghi”, Cagliari, Italy; 7Department of Hematology, University of Cagliari, Cagliari, Italy; 8Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; 9San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; 10Universita’ Vita-Salute, San Raffaele Scientific Institute, Milano, Italy; 11bioflag Srl, Pula (CA), Italy.

# Corresponding Author

Dr. R. Bacchetta, at San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Via Olgettina 58, 20132 Milan, Italy.

Phone: +39 0226434669.

Fax: +39 0226434668.

e-mail:

Supplementary figure legends.

Figure 1S. Manhattan plot of nominal P values from the genome wide association study. The dot line indicates the putative threshold (P < 10-5)

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Table S1. Top ranked SNPs showing a nominal association (uncorrected P < 1x10-4)

Chr / SNP / Location (Bp) / Allelic Variants / P value / adj P value / Gene / Left Gene / Right Gene
4 / rs2067512 / 173026078 / T/C / 1.45x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
11 / rs1986684 / 111124487 / T/C / 2.01x10-5 / 1,000 / - / LOC120364 / C11orf53
13 / rs9530477 / 76457183 / C/T / 2.02x10-5 / 1,000 / FLJ35379 / LMO7 / LOC100132423
13 / rs9530481 / 76460332 / C/T / 2.0 x10-5 / 1,000 / - / FLJ35379 / LOC100132423
13 / rs9530484 / 76463084 / C/T / 2.02x10-5 / 1,000 / - / FLJ35379 / LOC100132423
1 / rs11162732 / 80021748 / C/T / 2.08x10-5 / 1,000 / - / ADH5P2 / LOC553139
1 / rs10493656 / 80054163 / C/T / 2.08x10-5 / 1,000 / - / ADH5P2 / LOC553139
4 / rs17058064 / 173028600 / T/C / 2.41x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
7 / rs6462846 / 38529384 / T/A / 2.56x10-5 / 1,000 / AMPH / TRG@ / KRT8P20
1 / rs2201453 / 80040353 / G/A / 2.71x10-5 / 1,000 / - / ADH5P2 / LOC553139
3 / rs1430009 / 5607917 / G/C / 3.01x10-5 / 1,000 / - / MRPS35P1 / MRPS36P1
6 / rs10484558 / 31615514 / T/C / 3.01x10-5 / 1,000 / BAT3 / BAT2 / APOM
14 / rs17756842 / 79041822 / A/G / 3.01x10-5 / 1,000 / NRXN3 / FRDAP / LOC100131497
12 / rs4842324 / 80321020 / A/G / 3.40x10-5 / 1,000 / PPP1R12A / LOC100133105 / LOC120872
12 / rs2895747 / 80344468 / T/C / 3.40x10-5 / 1,000 / - / PPP1R12A / LOC120872
13 / rs4245353 / 50444271 / T/G / 3.40x10-5 / 1,000 / - / KPNA3 / LOC220429
22 / rs9617104 / 50440651 / T/C / 3.40x10-5 / 1,000 / IL17REL / PIM3 / TTLL8
8 / rs4484667 / 77440302 / C/A / 3.43x10-5 / 1,000 / - / HNF4G / MRPL9P1
1 / rs9970802 / 57646661 / G/T / 4.05x10-5 / 1,000 / DAB1 / C8B / LOC729423
18 / rs16944053 / 2922900 / G/A / 4.81x10-5 / 1,000 / LPIN2 / EMILIN2 / LOC727896
8 / rs17586654 / 17025169 / A/G / 5.23 10-5 / 1,000 / ZDHHC2 / LOC100130392 / CNOT7
3 / rs9854367 / 102259425 / T/C / 5.28x10-5 / 1,000 / - / ZPLD1 / LOC644681
2 / rs4849017 / 126275423 / C/T / 5.77x10-5 / 1,000 / - / CNTNAP5 / LOC150554
2 / rs2421652 / 126299907 / G/A / 5.77x10-5 / 1,000 / - / CNTNAP5 / LOC150554
15 / rs11635236 / 90850762 / G/A / 5.77x10-5 / 1,000 / - / LOC728477 / GABARAPL3
14 / rs1147447 / 66460742 / G/A / 6.06x10-5 / 1,000 / LOC729850 / FTHL13 / YBX1P1
4 / rs7697010 / 173043154 / T/C / 6.49x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
4 / rs12506901 / 173052921 / T/G / 6.49x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
4 / rs6553610 / 173068658 / T/C / 6.49x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
4 / rs7377766 / 173071817 / T/A / 6.49x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
4 / rs6553611 / 173074650 / A/C / 6.49x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244
12 / rs9783424 / 80188841 / T/C / 7.11x10-5 / 1,000 / PPP1R12A / LOC100133105 / LOC120872
8 / rs3779936 / 134265748 / A/G / 8.05x10-5 / 1,000 / NDRG1 / WISP1 / LOC392271
8 / rs1060401 / 134270303 / C/T / 8.05x10-5 / 1,000 / NDRG1 / WISP1 / LOC392271
12 / rs10506820 / 80294654 / T/G / 8.05x10-5 / 1,000 / PPP1R12A / LOC100133105 / LOC120872
12 / rs7294440 / 80309122 / A/T / 8.05x10-5 / 1,000 / PPP1R12A / LOC100133105 / LOC120872
4 / rs10014481 / 173047655 / G/A / 9.93x10-5 / 1,000 / GALNT17 / LOC441052 / LOC100130244

Table S2. Frequencies of the allele A (rs11538264, BAT2) and of the allele C (rs10484558, BAT3)

Population / rs11538264 (BAT2) / rs10484558 (BAT3) / Reference
European / 0.05 / 0.009 / 1
Han Chinese / 0.044 / 0.025 / 1
Japanese / 0.078 / 0.076 / 1
Youruba Sout Africa / 0.15 / 0.155 / 1
African ancestry, Southwest USA / 0.071 / 0.102 / 1
Gujarati Indians, Houston, TX / 0.017 / 0.017 / 1
Luhya in Webuye, Kenya / 0.117 / 0.133 / 1
Mexican ancestry, Los Angeles, CA / 0.112 / 0.13 / 1
Maasai, Kinyawa, Kenya / 0.201 / 0.199 / 1
Toscans, Italy / 0.04 / 0.04 / 1
Bushman population, Northern Kalahari / 0.75 / 1 / 2

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References

1. Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F et al. Integrating common and rare genetic variation in diverse human populations. Nature 2010; 467(7311): 52-58. e-pub ahead of print 2010/09/03; doi: 10.1038/nature09298.

2. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29(1): 308-311. e-pub ahead of print 2000/01/11.

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