N. M. Scott. S. M. Weinberg. K. Neiswanger. College of Nursing Publications

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1 College of Nursing Publications Dermatoglyphic fingerprint heterogeneity among individuals with nonsyndromic cleft lip with or without cleft palate and their unaffected relatives in China and the Philippines N. M. Scott S. M. Weinberg K. Neiswanger Please see article for additional authors. Copyright Wayne State University Press, Posted by permission. Human biology, 77:2 (2005) pp Hosted by Iowa Research Online. For more information please contact:

2 Dermatoglyphic Fingerprint Heterogeneity Among Individuals with Nonsyndromic Cleft Lip With or Without Cleft Palate and Their Unaffected Relatives in China and the Philippines NICOLE M. SCOTT, 1 SETH M. WEINBERG, 1 KATHERINE NEISWANGER, 1 CARLA A. BRANDON, 1 SANDRA DAACK-HIRSCH, 2 JEFFREY C. MURRAY, 2 YOU-E LIU, 3 AND MARY L. MARAZITA 1,4 Abstract Cleft lip with or without cleft palate (CL/P) is a common birth defect (birth prevalence ranging from 1/500 to 1/2,000) with a complex etiology. Traits potentially related to CL/P, such as dermatoglyphics, may reflect the genetic and epidemiologic heterogeneity observed in CL/P. Such phenotypic heterogeneity in dermatoglyphic patterns may account for some of the variability in previously reported associations of dermatoglyphics and CL/P. To test this hypothesis, we took dermatoglyphic prints from individuals with nonsyndromic CL/P (n 460) and their unaffected relatives (n 254) from the Philippines and China. For both samples three raters designated the patterns as arch, ulnar loop, radial loop, whorl, or other. Chi-square analysis and standard ANOVA were used to investigate heterogeneity between Filipino and Chinese study subjects. The significant associations between particular pattern types and CL/P were not the same in both populations, demonstrating population-specific association of CL/P and dermatoglyphic pattern types. The ANOVA of pattern type included both CL/P cases and their relatives, with affection status, sex, and population group as variables. For each pattern type except arches, population was significant ( p ); for radial loops, affection status was additionally significant ( p ). When only CL/P cases were considered, population was again significant for the ulnar loop ( p ), whorl ( p ), and other ( p ) patterns. The ANOVAs demonstrate between-population heterogeneity in dermatoglyphic pattern types. These results support our hypothesis that population-specific associations and population heterogeneity in dermatoglyphic patterns exist for CL/P cases and their relatives. 1 Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Suite 500, Cellomics Building, 100 Technology Dr., Pittsburgh, PA Department of Pediatrics, University of Iowa, Ames, IA. 3 Zhabei Genetic Research Institute, Shanghai, China. 4 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. Human Biology, April 2005, v. 77, no. 2, pp Copyright 2005 Wayne State University Press, Detroit, Michigan KEY WORDS: DERMATOGLYPHICS, CLEFT LIP WITH OR WITHOUT CLEFT PALATE, POPULA- TION VARIATION, CHINA, PHILIPPINES.

3 258 / scott et al. Cleft lip with or without cleft palate (CL/P) is a heterogeneous congenital anomaly. It ranges in birth prevalence from approximately 1/500 in Asian or Amerindian populations to 1/2,000 in populations of African ancestry (Vanderas 1987; Croen et al. 1998; Mossey and Little 2002). The etiology is complex, with both genetic and environmental components (Murray 1995; Wyszynski et al. 1996; Zeiger and Beaty 2002). The genetic component of nonsyndromic CL/P is demonstrated by the 40 60% concordance rate in monozygotic twins, compared to approximately 5% concordance in dyzygotic twins (Mitchell 2002). Moreover, several studies have demonstrated associations between CL/P and candidate genes such as IRF6, MSX1, TGF 3, MTHFR, and Gabrb3, although the patterns of association have been inconsistent across studies, suggesting considerable genetic heterogeneity (Marazita and Neiswanger 2002). Environmental risk factors such as alcohol, smoking, thalidomide, and even low socioeconomic status have been shown to increase the prevalence of CL/P (Murray 2002). In addition to specific genes and environmental exposures, generalized developmental instability may contribute to the risk of developing a cleft (Woolf and Gianas 1977; Livshits and Kobyliansky 1991). Phenotypically, such global developmental instability may manifest itself through differences in the frequency of dermatoglyphic pattern types (Rife 1979) and/or by the presence of elevated levels of fluctuating asymmetry (Naugler and Ludman 1996). A biological link between oral clefting and atypical pattern variation is supported by the fact that palatogenesis and dermatoglyphic development overlap during the first trimester (4th 9th week and 6th 24th week, respectively) (Babler 1991; Sperber 2002a, 2002b). Several previous studies have shown that dermatoglyphic pattern types differ between CL/P cases and unaffected unrelated controls (Azumi and Shiono 1966; Yamagata 1973; Woolf and Gianas 1976, 1977; De Bie et al. 1977; Vormittag et al. 1979; Deshmukh et al. 1979, 1981; Balgir 1984, 1993; Kanematsu et al. 1986; Kobyliansky et al. 1999). However, the relationship between CL/P and dermatoglyphics is complicated. Several studies have also reported no relationship between the dysmorphology and pattern frequencies (Silver 1966; Piatkowska and Sokolowski 1973; Neiswanger et al. 2002). Further, even when differences in pattern type frequencies are observed, the precise nature of these differences is highly inconsistent across studies. A summary of these results is provided in Table 1. Inconsistent dermatoglyphic findings across studies may be related to methodological differences, such as the use of different classification schemes or methods of analysis (Kanematsu et al. 1986; Jantz 1987), thus making the results difficult to compare (Mavalwala et al. 1991). Another possibility, however, is that considerable dermatoglyphic heterogeneity, like the genetic and epidemiological heterogeneity that accompanies CL/P, may be present between CL/P cases from different populations; that is, each group may manifest population-specific dermatoglyphic characteristics. To test this hypothesis, we compared the frequency of dermatoglyphic pattern types between CL/P groups and their unaffected relatives from China and the Philippines.

4 Dermatoglyphics and Cleft Lip / 259 Table 1. Comparison of Studies with Significant Differences in Pattern Frequency Between CL/P Cases and Control Subjects CL/P vs. Control Subjects Population Source Ulnar Loop Whorl Radial Loop Arch Japanese Azumi and Shiono (1966) X X Yamagata (1973) X Y Kanematsu et al. (1986) X X Indians Deshmukh et al. (1981) X, females Y, females X Balgir (1993) Y X, females Y Belgians De Bie et al. (1977) X, females Y, females Austrians Vormittag et al. (1979) Y Y* X Israelis Kobyliansky et al. (1999) X Y X X, Increase in frequency of pattern type. Y, Decrease in frequency of pattern type. *, Affected on the right side. Materials and Methods Two study samples were used: families from China and families from the Philippines, both of which were ascertained through affected individuals who presented for surgical correction of their clefts. For each study sample, dermatoglyphic prints were collected using standard inkless methods (Schaumann and Alter 1976) from individuals with nonsyndromic CL/P and their unaffected firstdegree relatives. Written informed consent was obtained from all participants. The Chinese study population was ascertained in Shanghai, China; for further details see Marazita et al. (1992) and Neiswanger et al. (2002). The study population from the Philippines was ascertained in the provinces of Negros Occidental and Cavite between 1999 and 2001; for further details see Murray et al. (1997). The Chinese and Filipino samples consist of both simplex and multiplex families. A summary of the data used in the current study is given in Table 2. Table 2. Study Populations Population Sex Status N Chinese Male CL/P 299 Relatives 46 Female CL/P 157 Relatives 118 Filipino Male CL/P 66 Relatives 33 Female CL/P 31 Relatives 57

5 260 / scott et al. The Chinese and Filipino populations are ancestrally related (Melton et al. 1995; Kim et al. 2000; Miranda et al. 2003). Filipinos are a genetic admixture resulting from the migration of various peoples from neighboring countries, including a contribution coming from China (Melton et al. 1995; Kim et al. 2000). These two population groups were targeted for this study primarily because there is a higher rate of CL/P in Asian populations than in European populations (about 1.5/1,000 live births compared to 1/1,000). Data evaluation and analyses were performed by the same research group for both populations. To examine the dermatoglyphic prints, three raters independently categorized the prints as ulnar loop, radial loop, arch, or whorl (Cummins and Midlo 1961). An additional category, called other, was created for prints that did not fit into any other designation. Any disagreements were re-evaluated. Individuals who did not have at least nine readable prints were dropped from the analysis. Within each population the frequencies of pattern types between affected CL/P cases and their unaffected relatives were compared using chi-square tests. To evaluate heterogeneity between the two populations, we used ANOVA tests (using the mean number of pattern types), with affection status, sex, and population as covariates. Furthermore, an ANOVA was used to evaluate population heterogeneity between just the CL/P cases from China and the Philippines; for this analysis, only sex and population were covariates. SAS (SAS Institute Inc. 1999) was used for all descriptive and general statistical analyses. Results were considered significant if p Results Table 3 shows the frequencies and percentages of pattern types for CL/P cases and unaffected relatives in each population. Pooling the sexes within each population resulted in several population-specific differences in frequency of pattern types. There was a significant increase in radial loops in individuals with CL/P in China compared to unaffected relatives ( p ). However, in the Philippines significantly more arches ( p 0.02) and more ulnar loops ( p 0.05) and less whorls ( p ) were found in the affected group. For sex-specific and affection-status-specific comparisons within each population, differences were found in the Chinese sample between unaffected males and females in the frequency of ulnar loops (43% vs. 49.7%, p 0.02) and whorls (53.3% vs. 48.6%, p 0.04). The frequency of whorls also differed significantly between affected males and females in the Philippines (35.6% vs. 28.4%, p 0.03). The ANOVA models demonstrate that the population designation (e.g., China or the Philippines) was significant for all pattern types (except arches) and affection status was significant in only the radial loop model (F 24.15, p ). Sex was not a significant parameter in any pattern type. The F values for the population parameter and the mean number of patterns per individual

6 Table 3. Frequency (%) of Dermatoglyphic Pattern Types in Each Population Population Subject N Pattern Type Ulnar Loop Whorl Radial Loop Other Arch Chinese (Shanghai) Cases 4,464 2,035 (45.6%) 2,192 (49.1%) 97 (2.2%) a (3.1%) Males 2,930 1,319 (45.0%) 1,444 (49.3%) 67 (2.3%) b (3.4%) Females 1, (47.7%) 748 (48.8%) 30 (1.9%) a 0 40 (2.6%) Unaffected 1, (47.7%) 817 (49.8%) (2.4%) Males (43.0%) 245 (53.3%) (3.7%) Females 1, (49.7%) 572 (48.6%) (2.0%) Filipino (Negro Occidental and Cavite) Cases (58.7%) c 315 (33.9%) b 33 (3.7%) 3 (0.3%) 34 (3.4%) c Males (57.5%) 230 (35.6%) 21 (3.2%) 2 (0.3%) 21 (3.0%) Females (62.9%) b 85 (28.4%) a 12 (4.0%) 1 (0.3%) 13 (4.3%) c Unaffected (55.2%) 364 (40.6%) 24 (2.8%) 5 (0.6%) 16 (1.9%) Males (56.1%) 125 (37.9%) 12 (3.7%) 2 (0.6%) 6 (1.8%) Females (53.7%) 239 (41.9%) 12 (2.1%) 3 (0.5%) 10 (1.8%) p values reflect the frequency in cases versus their unaffected relatives. a. p b. p c. p 0.05 Dermatoglyphics and Cleft Lip / 261

7 262 / scott et al. Table 4. ANOVA F Values for Population Parameter and Corresponding Mean Patterns per Individual in Each Population Pattern F Value for Population Pattern (Adjusted for Cleft Status) China Philippines Ulnar loop a Whorl a Radial loop a Other a Arch a. p for both China and the Philippines are given in Table 4. When only the CL/P cases were considered, the population designation was highly significant for all pattern types except for the arch pattern. The F values for the population parameter from the ANOVA of CL/P cases only and corresponding means for patterns in each population are given in Table 5. Discussion Our results comparing pattern frequencies between CL/P cases and their unaffected relatives from the Philippines and China demonstrate that the relationship between CL/P and dermatoglyphic pattern types is variable across these populations. Furthermore, two forms of heterogeneity can be identified: differences in the association of specific pattern types and CL/P within each population and overall differences in the frequencies of pattern types between populations. Regarding the within-population heterogeneity, Table 3 shows that the significant associations between pattern types and CL/P were not the same in both Table 5. ANOVA for CL/P Cases Only: F Values for Population Parameter and Corresponding Mean Pattern Types per Individual in Each Population Pattern Pattern F Value for Population China Philippines Ulnar loop a Whorl a Radial loop 4.90 c Other b Arch a. p b. p c. p 0.05.

8 Dermatoglyphics and Cleft Lip / 263 populations. Within the Chinese population, CL/P cases possessed significantly more radial loops compared to their unaffected relatives, yet this relationship was not noted in the Filipino population. Conversely, the Filipino CL/P cases had significantly more ulnar loop patterns than their unaffected relatives, but the Chinese CL/P cases showed no such difference. Several other differences were also noted (see Table 3). These results support the notion that a population-specific heterogeneity exists in the relationship between CL/P and fingerprint pattern types. In addition, our results, compared to the results for other populations given in Table 1, show that the Filipino group exhibits increases in both ulnar loops and arches and decreases in whorls similar to the Israeli population (Kobyliansky et al. 1999) and the Indian population (Deshmukh et al. 1981). Only the Indian population (Balgir 1993) demonstrated any resemblance to the Chinese cases, with an increase in radial loops; however, in the current study the increase was demonstrated in both females and males. It must be noted that any comparison of the current results with Table 1 does not take into account methodological and analytical differences between studies. Furthermore, these studies are comparing CL/P cases to control subjects, not to unaffected relatives. Regarding the between-population heterogeneity, the ANOVA models demonstrate that the pattern frequencies differed across China and the Philippines; in our analyses the population variable was consistently significant (see Table 4). Such heterogeneity across populations also exists among the CL/P cases, because significant differences were noted for ulnar loop, whorl, and other patterns (see Table 5). Dermatoglyphic pattern differences across populations (also known as population heterogeneity) were expected, because population differences have been noted by several investigators. For example, several studies have noted a west to east trend of increasing whorl patterns (Jantz 1987; Plato et al. 1978). Comparing the results here to the data in Table 1 also supports this, although such a comparison is hindered by the methodological differences. Interestingly, this heterogeneity has not been reported previously in CL/P cases from different populations, but it clearly demonstrates the effect that local environment and genes may have on determining the full phenotype in CL/P. Many family-based studies of CL/P have demonstrated significant genetic associations in some populations, whereas other studies have found no association (Marazita and Neiswanger 2002). For example, the transforming growth factor alpha locus (TGFA) has been found to be associated with CL/P in U.S. whites, in Australian whites, in West Bengal, India, and in Japanese (and others); yet no associations were found in Filipinos, U.S. Hispanics, Danish whites, Shanghai Chinese, and others (Marazita and Neiswanger 2002). It has been suggested that the differences in association represent the action of different genes in different environments and populations. Because CL/P is known to be a genetically heterogeneous entity, related phenotypic traits, such as dermatoglyphics, may be similarly heterogeneous. Our results support this hypothesis and, in addition, in terms of dermatoglyphics, support the idea that the heterogeneity stems from both differences in the association of pattern types and CL/P within populations

9 264 / scott et al. and population-specific differences in pattern distributions resulting in overall heterogeneity across populations. The facts that methodological inconsistencies were reduced, because our research group analyzed the data from each population, and that the population genetic variation was reduced through the use of two ancestrally related populations (Melton et al. 1995; Kim et al. 2000; Miranda et al. 2003) lend support to the finding that the associations between specific pattern types and CL/P were not the same in both populations. This is the first study to demonstrate population-specific associations between CL/P and particular dermatoglyphic patterns. Such findings may help to explain previously reported discrepancies in the literature (see Table 1). The mechanisms underlying the observed dermatoglyphic heterogeneity are as yet unclear. However, it may represent underlying populationbased differences in disease-causing alleles and/or developmental instability. Acknowledgments We would like to thank Terry Reed for advice about categorizing prints and Margaret E. Cooper for suggestions regarding statistical analysis. This research was supported by the National Institutes of Health and the National Institute of Dental and Craniofacial Research through grants DE-09886, DE-08559, and P50-DE Received 12 February 2004; revision received 15 December Literature Cited Azumi, J., and H. Shiono Dermatoglyphic diagnosis of patients with cleft lip/ palate. Nihonijishinpo 2900: Babler, W. J Embryonic development of epidermal ridges and their configurations. In Dermatoglyphics: Science in Transition, J. Mavalwala, ed. New York: Wiley-Liss, Balgir, R. S Congenital oral clefts and dermatoglyphics. Isr. J. Med. Sci. 20: Balgir, R. S Dermatoglyphics in cleft lip and cleft palate anomalies. Ind. Pediatr. Mar. 30: Croen, L., G. Shaw, C. Wasserman et al Racial and ethic variations in the presence of orofacial clefts in California, Am. J. Med. Genet. 79: Cummins, H., and W. C. Midlo Fingerprints, Palms, and Soles: An Introduction to Dermatoglyphics. New York: Dover. De Bie, S., M. Hayashi, M. T. Matton et al Dermatoglyphic analysis of primary and secondary cleft palate patients. Cleft Palate J. 14: Deshmukh, R. N., M. S. Grewal, and S. S. Sidhu Dermatoglyphics in cleft lip and cleft palate anomaly: Familial and teratogenic groups. Ind. J. Med. Res. 70: Deshmukh, R. N., M. S. Grewal, and S. S. Sidhu Cleft lip with or without cleft palate and isolated cleft palate as 2 etiological entities: Dermatoglyphic evidence. Ind. J. Med. Res. 73: Jantz, R. L Anthropological dermatoglyphic research. Annu. Rev. Anthropol. 16: Kanematsu, N., Y. Yoshida, N. Kishi et al Study on abnormalities in the appearance of finger and palm prints in children with cleft lip, alveolus, and palate. J. Maxillofac. Surg. 14: Kim, W., D. J. Shin, S. Harihara et al Y chromosomal DNA variation in East Asian populations and its potential for inferring the peopling of Korea. J. Hum. Genet. 45:76 83.

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