The Cleft Palate–Craniofacial Journal 51(2) pp. 234–239 March 2014 Ó Copyright 2014 American Cleft Palate–Craniofacial Association

ORIGINAL ARTICLE Investigation of Parental Transmission of RUNX2 Single Nucleotide Polymorphism and Its Association With Nonsyndromic Cleft Lip With or Without Palate Seung Hee Jung, M.D., D.D.S., Ah-Young Lee, D.D.S., Ji Wan Park, Ph.D., Seung-Hak Baek, D.D.S., M.S.D., Ph.D., Young Ho Kim, D.D.S., M.S., Ph.D. Objective: To investigate the association and parental transmission of RUNX2 single nucleotide polymorphisms (SNPs) with risk of nonsyndromic cleft lip with or without cleft palate (NS-CL6P). Design: Four RUNX2 SNPs in 142 Korean NS-CL6P families (nine cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 76 trios and 66 dyads) were genotyped. The minor allele frequency, heterozygosity, and chi-square test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as D 0 and r2 for all SNPs. Both allelic and genotypic transmission disequilibrium tests (TDTs) were performed for individual SNPs using a family-based association test program. Sliding windows of haplotypes consisting of two to four SNPs were tested using a haplotype-based association test program. Genotypic odds ratios (GORs) were calculated from conditional logistic regression models. Parent-of-origin effects were assessed using transmission asymmetry test and parent-of-origin likelihood ratio test. Results: The family-based TDT showed significant evidence of linkage and association at rs1934328 (P ¼ .001). In the haplotype analysis, two, three, and four haplotypes containing rs1934328 revealed significant associations (P ¼ .0017, P ¼ .0022, and P ¼ .0020, respectively). The genotypes A/T and T/T at rs1934328 were significantly associated with NS-CL6P compared with the genotype A/A (GOR ¼ 2.75, 95% confidence interval [CI] ¼ 1.39–5.45, P ¼0.0019 in the dominant model; GOR ¼ 5.38, 95% CI ¼ 1.34–21.68, P ¼ .0046 in the additive model). However, no parent-of origin effect was observed. Conclusion: These findings suggest possible involvement of RUNX2-rs194328 in the etiology of NS-CL6P in Korean cleft-parent trios without excess parental transmission. KEY WORDS:

association, nonsyndromic cleft, parental transmission, RUNX2 SNP

A cleft condition usually has lifelong implications for the affected persons and their families despite the interdisciplinary interventions (Cobourne, 2004). Extensive research in genetic epidemiology over the past decades has identified a number of candidate genes of cleft, such as muscle segment homeo box 1 (MSX1), interferon regulatory factor 6 (IRF6), transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGF-B3), Treacher Collins syndrome gene (TCOF1), poliovirus receptor

related 1 (PVRL 1), methylenetetrahydrofolate reductase (MTHFR), and T-box transcription factor 22 (TBX22) (Lidral et al., 1998; Vieira et al., 2003; Zucchero et al., 2004; Jugessur and Murray, 2005; Turhani et al., 2005; Carinci et al., 2007; Sull et al., 2008a; Sull et al., 2009; Kantaputra et al., 2011; Luo et al., 2012). The Runt-related transcriptions factors 2 (RUNX2) gene at chromosome 6p21, also known as core-binding factor subunit alpha-1 (CBFA1), is a member of the RUNX

Dr. Jung is graduate student (MS), Department of Orthodontics, The Institute of Oral Health Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Dr. Lee is private practice Seoul, South Korea. Dr. Park is Associate Professor, Department of Medical Genetics, College of Medicine, Hallym University, Chuncheon, Gangwon Province, South Korea. Dr. Baek is Professor, Department of Orthodontics, School of Dentistry, Dental Research Institute, Seoul National University, Seoul, South Korea. Dr. Kim is Professor and Chair, Department of Orthodontics, The Institute of Oral Health Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. This research was supported by the Basic Science Research Program, the National Research Foundation of Korea [NRF 2009-0069859] funded by the Ministry of Education, Science and Technology. Submitted December 2012; Revised March 2013; Accepted June 2013. Address correspondence to: Dr. Young Ho Kim, Department of Orthodontics, The Institute of Oral Health Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50, Irwon-dong, Gangnam-Gu, Seoul, 135-710, South Korea, E-mail: [email protected], or Dr. Seung-Hak Baek, Department of Orthodontics, School of Dentistry, Dental Research Institute, Seoul National University, Yeonkun-dong #28, Jongro-ku, Seoul, 110-768, South Korea. E-mail: [email protected]. DOI: 10.1597/12-312 234

Jung et al., TRANSMISSION/ASSOCIATION: RUNX2 SNP AND CLEFT

TABLE 1 Demographic Information for Sex and Cleft Type in Patients With Nonsyndromic Cleft Lip With and Without Cleft Palate (NS-CL6P)* CL

CLA

CLP

3 1

11 3

34 24

48 28

Dyad (N¼66) Male Female

2 3

8 4

32 17

42 24

26 (18.3%)

107 (75.4%)

142

9 (6.3%)

AND

METHODS

Subjects

Sum

Trio (N¼76) Male Female

Sum

MATERIALS

235

* CL ¼ cleft lip only; CLA ¼ cleft lip and alveolus; CLP ¼ cleft lip and palate. Numbers indicate patients with CL, CLA, or CLP.

family. RUNX2 encodes a nuclear protein with a RUNT DNA-binding domain and is a key transcription factor associated with osteoblast differentiation and tooth morphogenesis (Komori et al., 1997; Aberg et al., 2004; Stein et al., 2004; Terry et al., 2004). Mutations in RUNX2 gene in humans and mice are associated with cleidocranial dysplasia, an autosomal dominant disorder characterized by partially or completely missing clavicles, dental anomalies, and craniofacial abnormalities, including submucous cleft palate and cleft lip (Lee et al., 1997; Mundlos et al., 1997; Otto et al., 1997; Cooper et al., 2001; Yamachika et al., 2001). Recently, several studies have reported that the RUNX2 gene is associated with development of nonsyndromic cleft lip with or without cleft palate (NS-CL6P). In previous animal and human studies, Aberg et al. (2004) reported that fusion failure between the shelves of the secondary palate occurred in RUNX2 homozygote-null mutant mice. Yamachika et al. (2001) reported a stop codon mutation in RUNX2 from a patient with cleidocranial dysplasia and cleft lip. Khan et al. (2006) suggested that CBFB, a heterodimer with RUNX2, may be associated with cleft palate. Only a few studies have investigated parent-of-origin effect of RUNX2 on NS-CL6P susceptibility, and these had controversial results. Sull et al. (2008b), in a caseparent trio study of four populations (146 from Taiwan, 77 from Maryland, 40 from Korea, and 35 from Singapore), reported that RUNX2 appears to influence the risk of NS-CL6P through a parent-of-origin effect with excess maternal transmission (rs910586 and rs2819861) and paternal transmission (rs1934328). However, Wu et al. (2012), in a case-parent trio study of 326 Chinese families, did not find any evidence for an imprinting effect of these single nucleotide polymorphisms (SNPs). Therefore, the purpose of the present study was to investigate the parental transmission of the RUNX2 SNPs and its association with risk of NS-CL6P among Korean cleft-parent trios, whose samples are independent from those of Sull et al. (2008b).

A total of 142 Korean NS-CL6P families (nine cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 90 males and 52 females; 76 trios and 66 dyads) were recruited from Seoul National University Dental Hospital (SNUDH) and Samsung Medical Center (SMC) (Table 1). All probands were classified as isolated NS-CL6P by clinical genetics evaluation. The research protocols were approved by the Institutional Review Board (IRB) at each institution (SNUDH IRB CRI-G07002 and SMC IRB #2007-08-086). SNP Selection, DNA, and Genotyping SNP markers in and around the RUNX2 gene were obtained from the NCBI dbSNP database (http://www. ncbi.nlm.nih.gov/SNP/). Four SNP markers (rs16873348, rs910586, rs2819861, and rs1934328) were selected using the Web browser, TAG SNP selection (TagSNP) (http://snpinfo.niehs.nih.gov/guide. htm#snptag) with the criteria of high design scores (a predictor of usable genotypes provided by Illumina Inc.), heterozygosity greater than 0.1 in Asian populations, and HapMap validation ver. 4.2 (Broad Institute, Cambridge, MA, USA) (Xu and Taylor, 2009). Peripheral venous blood samples of patients and their parents were collected at either SNUDH or SMC with written informed consent. Genomic DNA was extracted from peripheral venous blood lymphocytes using a commercial DNA extraction kit (Quiagen Inc., Valencia, CA). Primers for each SNP were synthesized using Oligator technology (Illumina Inc., San Diego, CA). DNA samples were genotyped using Illumina’s VeraCode Technology at SNPGenetics Inc. (Seoul, Korea). Genotype call rates and sample call rates at 95% or greater were considered acceptable. Statistical Analysis The minor allele frequency (MAF), heterozygosity, and chi-square test for Hardy-Weinberg equilibrium (HWE) at each SNP were computed using parent genotypes. Pairwise linkage disequilibrium (LD) was computed as both D 0 and r2 for all SNPs using the Haploview program ver. 4.2 (Broad Institute, Cambridge, MA, USA) (Ardlie et al., 2002). The transmission disequilibrium test (TDT) was used to test for excess transmission of particular alleles from parents to affected children. Both allelic and genotypic TDTs were performed for individual SNPs using a family-based association test program (Thomson, 1995). Sliding windows of haplotypes consisting of two to four SNPs were also tested to increase the power of the

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(Horvath et al., 2001). Because the Bonferroni correction for multiple comparison was applied, a P value less than .0125 was considered statistically significant. RESULTS Demographic Information for Sex and Cleft Type of the Probands A total of 142 probands (90 males and 52 females), which were collected from 76 trios and 66 dyads, consisted of 6.3% cleft lip, 18.3% cleft lip and alveolus, 75.4% cleft lip and palate patients (Table 1). MAF, Heterozygosity, HWE, and LD Analyses FIGURE 1 Linkage disequilibrium between SNPs in the RUNX2 gene among parents of patients with NS-CL6P.

Although MAFs for rs910586 and rs2819861 were lower than 5% (0.041 and 0.039, respectively), MAFs for rs16873348 and rs1934328 were higher than 20% (0.304 and 0.226, respectively) (Table 2). Genotype frequencies of any SNPs did not deviate from HWE (P . .010; Table 2). Among the groups made from four SNPs, one group of markers (rs910586-rs2819861) showed especially complete LD (D 0 ¼ 1, r2 ¼ 0.94; Figure 1).

association study using a haplotype-based association test (http://www.biostat.harvard.edu/fbat/default.html) (Rabinowitz and Laird, 2000). Genotypic odds ratios (GORs) for heterozygotes and homozygotes under additive, dominant, and recessive models were calculated separately for individual SNPs. The 3:1 case-control data set was generated with each NS-CL6P case matched to three possible pseudocontrol subjects created from the nontransmitted parental allele. GORs were obtained from conditional logistic regression models for matched sets using publicly available subroutines using STATA/MP v. 11.1 (http://stata.com). Parent-of-origin effects were assessed using the transmission asymmetry test (TAT), conditioning on parental genotypes (CPG) analysis, parent-of-origin likelihood ratio test (PO-LRT), and conditioning on exchangeable parental genotypes (CEPG) analysis (https://www-gene.cimr.cam.ac.uk/staff/clayton/ courses/florence11/lectures/lecture13-4up.pdf) (Weinberg et al., 1998; Weinberg, 1999; Cordell et al., 2004). Empirical P values for observed versus expected transmission were calculated using a permutation test

TDT Analyses for Single Markers and Haplotypes Single-marker analysis showed preferential overtransmission of rs1934328, which was still significant after Bonferroni correction (P ¼ .001; Table 2). The P values of two strongly correlated SNPs, rs910586 and rs2819861, were not statistically significant in individual SNP analysis (P ¼ .248 and P ¼ .366, respectively; Table 2). In haplotype analysis including rs1934328, the twoSNP haplotype (rs2819861 and rs1934328), the threeSNP haplotype (rs910586, rs2819861, and rs1934328), and the four-SNP haplotype (rs16873348, rs910586, rs2819861, and rs1934328) showed significant values (P ¼ .0017, P ¼ .0022, and P ¼ .0020, respectively).

TABLE 2 Information About Single Nucleotide Polymorphisms (SNPs) and Transmission Disequilibrium Test (TDT) Results for SNPs in the RUNX2 Gene Showing Evidence of Linkage and Linkage Disequilibrium in Nonsyndromic Cleft Lip With and Without Cleft Palate Trios Haplotype (P Value) || SNP

M/m†

MAF‡

HWE (P Value)

T/NT§

Allele (P Value)

rs16873348 rs910586 rs2819861 rs1934328

T/C C/T C/T A/T

0.304 0.041 0.039 0.226

.414 1.000 1.000 .575

34:25 8:4 7:4 40:16

.249 .248 .366 .001*

2

3

4 .0020**

.0022** .0017**

† Overtransmitted alleles are bolded. M/m denotes major allele/minor allele. ‡ MAF ¼ minor allele frequency; HWE ¼ Hardy-Weinberg equilibrium. § Transmission/nontransmission (T/NT) counts are from heterozygous parents. || Significant P values for individual SNPs and global P values for sliding windows of haplotypes of the two to four SNPs from TDT analyses. Tests significant after SNPSpD correction are bolded. * P , .0125 and ** P , .0025 after Bonferroni correction for multiple comparison.

Jung et al., TRANSMISSION/ASSOCIATION: RUNX2 SNP AND CLEFT

237

TABLE 3 Genotypic Odd Ratios (GORs) for Genotypes in rs1934328 of the RUNX2 Gene Showing Significant Evidence of Linkage and Linkage Disequilibrium in Nonsyndromic Cleft Lip With and Without Cleft Palate Groups Additive Model

Dominant Model

Recessive Model

SNP/Genotype

N†

GOR (95% CI)

P Value‡

GOR (95% CI)

P Value‡

GOR (95% CI)

P Value‡

rs1934328 A/A A/T T/T

n ¼ 75 211 133 16

1.0 (Reference) 2.68 (1.35–5.34) 5.38 (1.34–21.68)

.0046*

2.75 (1.39–5.45)

.0019**

2.43 (0.68–8.64)

.1760

† N ¼ the number of subjects carrying the genotype; n ¼ the number of case/pseudo-control sets generated; CI ¼ confidence interval. ‡ P values are for chi-square tests in the conditional logistic regression model for each SNP. * P , .0125 and ** P , .0025 after Bonferroni correction for multiple comparison.

However, increasing the number of SNPs adjacent to rs1934328 from the two-SNP haplotype to the threeSNP haplotype and the four-SNP haplotype did not improve statistical significance (P ¼ .0017 versus P ¼ .0022 and .0020; Table 2). Genotypic Odds Ratios In genotypic comparison, the genotype A/T at rs1934328 showed a significantly increased risk of NSCL6P compared with the genotype A/A (GOR ¼ 2.75, 95% confidence interval [CI] ¼ 1.39–5.45, P ¼ .0019 in the dominant model; GOR ¼ 2.68, 95% CI ¼ 1.35–5.34, P ¼ .0046 in the additive model; Table 3). In addition, the additive model showed that the genotype T/T at rs1934328 was associated with a significantly increased risk of NS-CL6P compared with the genotype A/A (GOR ¼ 5.38, 95% CI ¼ 1.34–21.68, P ¼ .0046; Table 3). Parent-of-Origin Effect The SNPs rs16873348, rs910586, and rs2819861 did not show significant parental transmission in TAT, CPG analysis, PO-LRT, and CEPG analysis (all P . .05; Table 4). Although rs1934328 showed meaningful values of maternal and paternal transmission (P ¼ .0124 and P ¼ .0164, respectively; Table 4), CPG analysis did not exhibit significant differences (P . .05; Table 4) and PO-LRT and CEPG analysis did not indicate significant

TABLE 4 Groups†

parental transmission (all P . .05; Table 4). Therefore, none of the four SNPs showed parent-of-origin effects. DISCUSSION To avoid the bias of population stratification confounding and to elucidate parent-of-origin effects, case-parent trios design was applied to the present study of NS-CL6P having heterogeneous etiology similar to studies by Beaty et al. (2002), Cordell et al. (2004), Sull et al. (2008b), and Wu et al. (2012). We found significant association between rs194328 and NS-CL6P in 76 Korean cleft-parent trios in single marker analysis (P ¼ .001; Table 2) and haplotype analyses (twohaplotype, P ¼ .0017; three-haplotype, P ¼ .0022; and fourhaplotype, P ¼ .0020; Table 2). However, the SNPs rs16873348, rs910586, and rs2819861 did not show significant associations with NS-CL6P (Table 2). Sull et al. (2008b) reported a similar result, which showed a significant association between rs1934328 and NS-CL6P at the 1% level among 40 Korean trios when parent-oforigin was not considered. However, other population trios (146 from Taiwan, 77 from Maryland, and 35 from Singapore) did not yield evidence of linkage and association between rs1934328 and NS-CL6P.22 In addition, Wu et al. (2012) found no evidence of association between rs194328, rs16873348, rs910586, and rs2819861 and NS-CL6P in 326 Chinese trios. These findings suggest that genetic susceptibility might be different in different populations.

Analysis Results of Parent-of-Origin Effects of the RUNX2 Gene in Nonsyndromic Cleft Lip With and Without Cleft Palate

TAT

rs16873348 rs910586 rs2819861 rs1934328

PO-LRT

Maternal Transmission

Paternal Transmission

.3359 .6547 .6547 .0164*

.4328 .2568 .4142 .0124*

CPG

Test of Parent-of-Origin Effects

Test of Parent-of-Origin Effects With Maternal Genotype

CEPG

0.8779 0.6800 0.8192 0.9002

.8500 .4800 .7000 .5900

.9000 .6800 .8200 .9600

.7185 .4843 .7064 .8638

† TAT ¼ transmission asymmetry test; CPG ¼ conditioning on parental genotype; PO-LRT ¼ parent-of-origin likelihood ratio test; CEPG ¼ conditioning on exchangeable parental genotype. * P , .05.

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In the present study, allelic association was detected for the T allele of rs1934328, which significantly increased the risk of NS-CL6P compared with the A allele (GOR¼ 2.75, 95% CI ¼ 1.39–5.45, P ¼ .0019 in the dominant model; Table 3). In the additive model, the genotype T/T showed a twofold increased risk for NS-CL6P compared with the genotype A/T (T/T: GOR ¼ 5.38, 95% CI ¼ 1.34-21.68 versus A/T: GOR ¼ 2.68, 95% CI ¼ 1.35–5.34, P ¼ .0046; Table 3), showing a dose-response relationship with risk increasing through overtransmission of the T allele. Sull et al. (2008b) also reported that the GOR of rs1934328 was 1.4 (P ¼ .014) in a combined data set from four populations when parent-of-origin was not considered. The finding that rs1934328, rs910586, and rs2819861 did not show a parent-of-origin effect differed from the results of Sull et al. (2008b), which reported that rs1934328 exhibited excess paternal transmission (P ¼ .002) and rs910586 and rs2819861 had excess maternal transmission (P ¼ .003 and P ¼ .007, respectively) in a combined data set of four populations (number of case-parent trios: 146 from Taiwan, 77 from Maryland, 40 from Korea, and 35 from Singapore). However, the results from Wu et al. (2012) showed no parent-of-origin effect for rs1934328, rs910586, or rs2819861, which is similar to our results. They reported that only one SNP (rs675613) showed marginally significant maternal overtransmission after considering maternal genotypic effects in 326 Chinese trios (P¼ 0.046) (Wu et al., 2012). The reasons for the difference in SNPs showing parent-of-origin effect seem to be differences in ethnic background, sample size, or cleft type distribution. These results indicate that, although RUNX2 might influence the risk of NS-CL6P, the possible maternal-specific and paternal-specific effects are still controversial. In addition, if these analyses are done by cleft types and by gender, different results can be obtained. Therefore, further studies will be needed to confirm the pattern of parental transmission by gender and cleft types. Wu et al. (2012) suggested that genetic variation in RUNX2 might influence susceptibility to NS-CL6P through interaction with environmental tobacco smoking in Chinese case-parent trios. Investigation of gene-environment interaction could identify additional risk loci, lead to better understanding of underlying biologic mechanisms, and provide information for designing effective preventive strategies (Wu et al., 2012). Therefore, further studies with a larger sample size and more markers are needed to determine the interaction between environment and genetic factors and to uncover the functional polymorphisms responsible for NS-CL6P. CONCLUSION The present findings suggest possible involvement of RUNX2-rs194328 in the etiology of NS-CL6P in Korean cleft-parent trios, without excess parental transmission. However, it is necessary to perform a functional study and

an animal model experiment to confirm that the RUNX2 SNP is directly related or indirectly connected with NSCL6P. Acknowledgments. This research was supported by the Basic Science Research Program, the National Research Foundation of Korea [NRF 2009-0069859], funded by the Ministry of Education, Science and Technology. We thank all participants, patients, their families, and the staffs at each participating site and institution for this multicenter study of oral clefts. We especially thank Yong Ick Ji, Eunhyun Jung, Se Young Cho, and Duk-Hwan Kim for assistance with laboratory work at the Center for Genome Research, Samsung Biomedical Research Institute, Seoul, Korea.

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Investigation of Parental Transmission of RUNX2 Single Nucleotide Polymorphism and Its Association With Nonsyndromic Cleft Lip With or Without Palate.

To investigate the association and parental transmission of RUNX2 single nucleotide polymorphisms (SNPs) with risk of nonsyndromic cleft lip with or w...
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