SUPPLEMENTARY MATERIAL

Supplementary Table 1. Results of gene-gene interaction analysis between the associated

variants in MMP3 and TIMP2. Analyses were performed comparing the presence of one or two

copies of each associated SNP alleles in cleft individuals and controls.

SNP Alleles
MMP3 rs522616 TIMP2 rs8179096 P-value*
CC and CT TT
AA and AG cases 421 7 0.0000001
controls 285 38
GG cases 64 2 0.38
controls 89 1
CC CT and TT
AA and AG cases 376 52 0.045
controls 267 56
GG cases 55 11 0.14
controls 82 8
CC and CT TT
AA cases 247 4 0.000001
controls 150 23
AG and GG cases 238 5 0.01
controls 2 16
CC CT and TT
AA cases 218 33 0.18
controls 142 31
AG and GG cases 213 30 0.65
controls 207 33

*Mantel-Haenszel test. P≤0.05 indicates statistical significance.

Supplementary Table 2. Details of the single nucleotide polymorphisms and minor allele
frequencies in the confirmation dataset, stratified by ethnic background and by the presence or
absence of family history of clefts.

Gene Bp* SNP Alleles MAF Caucasians MAF Hispanics

With Fx No Fx With Fx No Fx
MMP3 102705658 rs683878 C/G 0.28 (G) 0.29 (G) 0.42 (C) 0.47 (C)
MMP3 102707339 rs639752 T/G 0.49 (T) 0.49 (T) 0.30 (G) 0.33 (G)
MMP3 102709425 rs520540 A/G 0.49 (G) 0.49 (A) 0.30 (A) 0.34 (A)
MMP3 102713620 rs679620 G/A 0.49 (G) 0.49 (A) 0.30 (A) 0.33 (A)
MMP3 102715048 rs522616 G/A 0.21 (G) 0.22 (G) 0.50 (G) 0.44 (G)
TIMP2 76845245 rs6501254 A/G 0.14 (A) 0.20 (A) 0.08 (A) 0.10 (A)
TIMP2 76862105 rs9894295 T/C 0.10 (C) 0.13 (C) 0.14 (C) 0.12 (C)
TIMP2 76877655 rs6501257 A/G 0.17 (G) 0.20 (G) 0.17 (G) 0.17 (G)
TIMP2 76898633 rs4789860 C/T 0.47 (C) 0.44 (C) 0.33 (C) 0.37 (C)
TIMP2 76906085 rs6501265 A/C 0.45 (A) 0.45 (A) 0.47 (C) 0.46 (C)
TIMP2 76918131 rs7212662 G/T 0.47 (G) 0.45 (G) 0.38 (G) 0.40 (G)
TIMP2 76921649 rs8179096 T/C 0.08 (T) 0.08 (T) 0.07 (T) 0.07 (T)
* Bp, base pair position, according to NCBI Reference Assembly.
MAF, Minor allele frequency. Minor allele shown in parenthesis.
Fx, family history of clefts.

Supplementary Table 3. Results of association analysis for SNPs in MMP3 in US families with
CL/P. Analyses were performed stratified by ethnic background and by the presence or absence
of family history of clefts.
 All Families
Gene SNP Caucasian Hispanic
PDT Geno-PDT APL PDT Geno-PDT APL
P-value P-value P-value P-value P-value P-value
MMP3 rs683878 0.5495 0.2247 0.4498 0.6115 0.7489 0.7376
MMP3 rs639752 0.9064 0.1780 0.9274 0.8137 0.9724 0.7644
MMP3 rs520540 0.9687 0.2049 0.8801 0.8137 0.8929 0.8026
MMP3 rs679620 0.9063 0.1930 0.9343 0.6350 0.8817 0.9521
MMP3 rs522616 0.8599 0.4374 0.7778 0.3721 0.6534 0.2618

Families with Positive Family History

Gene SNP Caucasian Hispanic
PDT Geno-PDT APL PDT Geno-PDT APL
P-value P-value P-value P-value P-value P-value
MMP3 rs683878 1.0000 0.5879 0.1833 0.1116 0.2585 0.4108
MMP3 rs639752 0.8851 0.0495 0.4581 0.4913 0.4642 0.7711
MMP3 rs520540 0.8084 0.0442 0.4622 0.4484 0.5135 0.7571
MMP3 rs679620 0.6996 0.1074 0.4750 0.4404 0.5064 0.6759
MMP3 rs522616 0.6646 0.9004 0.6971 0.2773 0.2078 0.6860

Families with No Family History

Gene SNP Caucasian Hispanic
PDT Geno-PDT APL PDT Geno-PDT APL
P-value P-value P-value P-value P-value P-value
MMP3 rs683878 0.3840 0.3097 0.9154 0.3613 0.3556 0.8722
MMP3 rs639752 1.0000 0.9233 0.5457 0.6439 0.5952 0.5858
MMP3 rs520540 0.7902 0.8078 0.8063 0.5741 0.3637 0.6089
MMP3 rs679620 0.7355 0.9465 0.7345 0.8527 0.8505 0.9044
MMP3 rs522616 0.5218 0.1368 0.8882 0.0196 0.0197 0.1149
PDT, Pedigree Disequilibrium Test.
GenoPDT, Genotype-Pedigree Disequilibrium Test
APL, Association in the Presence of Linkage
P≤0.05 indicates statistical significance (in bold).
Supplementary Table 4. Results of association analysis for SNPs in TIMP2 in US families with
CL/P. Analyses were performed stratified by ethnic background and by the presence or absence
of family history of clefts.
All families

SNP Caucasian Hispanic

PDT GenoPDT APL PDT GenoPDT APL
P-value P-value P-value P-value P-value P-value
TIMP2 rs6501254 0.2813 0.4869 0.0409 0.7180 0.8838 0.8721
TIMP2 rs9894295 0.0573 0.0684 0.0331 0.7697 0.4589 0.5913
TIMP2 rs6501257 0.2582 0.4702 0.3105 0.1698 0.3451 0.0901
TIMP2 rs4789860 0.3023 0.6298 0.0536 0.8273 0.9777 0.9702
TIMP2 rs6501265 0.8944 0.7203 0.0897 0.6773 0.9243 0.5936
TIMP2 rs7212662 0.4671 0.7529 0.7413 0.7911 0.3439 0.5205
TIMP2 rs8179096 0.0314 0.0524 0.0635 0.1699 0.2346 0.0165
Families with Positive family history

Gene SNP Caucasian Hispanic

PDT GenoPDT APL PDT GenoPDT APL
P-value P-value P-value P-value P-value P-value
TIMP2 rs6501254 0.8840 0.4015 0.0211 0.7728 0.3350 0.6602
TIMP2 rs9894295 0.2579 0.2232 0.0781 0.4576 0.0298 0.3832
TIMP2 rs6501257 0.3519 0.5601 0.2240 0.1278 0.2375 0.7828
TIMP2 rs4789860 0.5394 0.6617 0.5390 0.8685 0.9541 0.6416
TIMP2 rs6501265 0.0542 0.2361 0.9672 0.7098 0.7435 0.6780
TIMP2 rs7212662 0.0172 0.0846 0.2187 0.9432 0.2530 0.5503
TIMP2 rs8179096 0.0997 0.1639 0.7042 0.2249 0.1637 0.4471
Families with No family history

Gene SNP Caucasian Hispanic

PDT GenoPDT APL PDT GenoPDT APL
P-value P-value P-value P-value P-value P-value
TIMP2 rs6501254 0.0229 0.0504 0.3165 0.3232 0.6281 0.9522
TIMP2 rs9894295 0.0313 0.0495 0.2554 0.2348 0.4251 0.2073
TIMP2 rs6501257 0.5485 0.3948 0.8410 0.0234 0.0381 0.0269
TIMP2 rs4789860 0.0262 0.0940 0.0438 0.6583 0.9072 0.7455
TIMP2 rs6501265 0.0309 0.0477 0.0318 0.8461 0.9764 0.7162
TIMP2 rs7212662 0.4153 0.1823 0.2548 0.5735 0.1654 0.6793
TIMP2 rs8179096 0.1957 0.3378 0.0577 0.5371 0.3484 0.0134
PDT, Pedigree Disequilibrium Test
GenoPDT, Genotype-Pedigree Disequilibrium Test
APL, Association in the Presence of Linkage
P≤0.05 indicates statistical significance (in bold).