140 CHAPTER 5 Genetics and Orthodontics is necessarily or absolutely predetermined or on a are, to some degree, simplistic categorizations. If taken particular immutable track, although it may be pre- literally, the assigned classiﬁcation would lead the reader disposed to remain on the same track if the inﬂuence to make presumptions about the interaction of genetic is monogenic. and environmental (nongenetic) factors, as well as the5. The response to a particular environmental factor number of factors involved to a certain extent, and the (e.g., treatment) does not necessarily depend on the extent to which the factors are involved in individuals. prior interaction of genetic and environmental factors, but rather on the response of the individual to the Monogenic Traits new environmental factor (e.g., treatment). The outcome of treatment will be a function of the inter- Traits that develop because of the inﬂuence of a single action of proteins from genetic factors that are gene locus are monogenic. These types of traits also tend expressed (or not) and the other environmental to be described as discrete or qualitative (dichotomous factors present at that time, against the backdrop of or yes/no) in occurrence. However, if they are present, the developmental maturity of the individual.9–12 It is these traits still may be variable and quantiﬁable in some important to understand the cause of the problem. cases. All human beings normally have 22 homologous Much of the literature in orthodontics about genetics pairs of chromosomes called autosomes that are num- has discussed the contribution of genetic factors to bered by size and other characteristics. In addition, one growth and malocclusion. The most important practi- pair of sex chromosomes may be homologous (X, X) in cal question regarding orthodontics and genetics is females or only partly homologous (X, Y) in males. whether different individuals respond to some degree Genes at the same locus on a pair of homologous chro- to a changed environment (treatment) in different mosomes are alleles. When both members of a pair of ways according to the inﬂuence of their particular alleles are identical, the individual is homozygous for genetic factors. that locus. When the two alleles at a speciﬁc locus are different, the individual is heterozygous for that locus. Autosomal Dominant Traits and Penetrance. If having only one particular allele of the two alleles on aBASIC DEFINITIONS homologous pair of autosomes (heterozygosity) is sufﬁ-Before proceeding, a few basic deﬁnitions are required. cient to lead to the production of the trait, the effect isThe genome contains the entire genetic content of a set autosomal dominant. If production of the trait does notof chromosomes present within a cell or an organism. occur with only one particular allele of the two allelesGenes represent the smallest physical and functional on an autosome but does occur when both alleles are theunits of inheritance that reside in speciﬁc sites (called loci same (homozygosity), then the effect is autosomal reces-for plural or a locus for a single location) in the genome. sive. Although the trait (phenotype) actually is dominantA gene can be deﬁned as the entire DNA sequence nec- or recessive and not the gene itself, the terms dominantessary for the synthesis of a functional polypeptide gene and recessive gene are used commonly to describe(production of a protein via a messenger or mRNA inter- these types of inherited traits in families. The nature ofmediate) or RNA (transfer, or tRNA, and ribosomal, or these traits is studied by constructing family trees calledrRNA) molecule.13 Genotype generally refers to the set pedigrees in which males are denoted by squares andof genes that an individual carries and, in particular, females by circles, noting who in the family has the traitusually refers to the particular pair of alleles (alternative and who does not.forms of a particular gene) that a person has at a given If the mode of inheritance for a particular trait isregion of the genome. In contrast, phenotypes are observ- homogeneous, then the study of multiple families willable properties, measurable features, and physical char- yield the following criteria for autosomal dominantacteristics of an individual,14 as determined by the inheritance: (1) the trait occurs in successive generations;individual’s genotype and the environment in which the that is, it shows vertical inheritance (Figure 5-1); (2) onindividual develops over a period of time. For further the average, 50% of the offspring of each parent whoinformation, the reader is referred to the reviews by has the trait also will have the trait; (3) if an individualMossey,2,15 Abass and Hartsﬁeld,16 and Lidral et al.17 has the gene that results in the trait, each child has a 50% chance of inheriting the gene that leads to the expression of the trait; (4) males and females are equallyTYPES OF GENETIC EFFECTS likely to have the trait; and (5) parents who do not haveAND MODES OF INHERITANCE the trait have offspring who do not have the trait.A trait is a particular aspect or characteristic of the phe- Exceptions to this include the trait showing nonpen-notype. When considering genetic inﬂuences on traits, it etrance in a particular offspring. When a person with ais convenient to think of three types: monogenic, poly- given genotype fails to demonstrate the trait character-genic, and multifactorial. Although deﬁning these types istic for the genotype, the trait is said to show nonpen-can be helpful in understanding genetic inﬂuences, they etrance in that individual and incomplete penetrance in
CHAPTER 5 Genetics and Orthodontics 141 Mendellian (monogenic) traits Gene Environmental factors Modifying gene(s) Protein Protein(s)FIGURE 5-1 Three-generation pedigree of a family with an auto-somal dominant trait with the younger generations below the older Phenotypegenerations. Square symbols are male and round symbols are FIGURE 5-2 Mendelian (monogenic) traits or diseases resultfemale. Affected members are denoted by ﬁlling in their individual because a single gene polymorphism or mutation usually results insymbol. a recognizable phenotype. Environmental factors and other genes may modify the clinical expression of the disease or other type of trait but are not of crucial importance for its development.16any group of individuals who have the genotype. Thetrait is present or not (nonpenetrant) in an individual. Ifsome of the individuals do not manifest the trait in a for type I collagen. The minimum phenotypic expressionsample of individuals with the trait-associated genotype, of the gene observed in a family then might be only athen the trait is said to have a penetrance of whatever blue color to the sclera, which could go unnoticed by thepercentage of the trait-associated genotype that the clinician. In this case, highly variable gene expressiongroup actually manifests. This is a situation most com- may fade into nonpenetrance.18monly seen with dominant traits. Other exceptions are The craniosynostosis syndromes, along with their(1) a new mutation occurred in the sperm or egg that effect on craniofacial growth and development associ-formed the offspring and (2) germinal mosaicism ated with premature closure of one or more cranialoccurred, in which case one of the parents is mosaic in sutures, often result in maxillary hypoplasia and a Classthe germ cell line and the sperm or eggs are of two III malocclusion. Most of these are autosomal dominanttypes—one cell line with and one cell line without the traits associated with single gene mutations that providemutation. Chance determines which sperm cell line will a good example of how, even with the strong inﬂuencebe passed on. The other obvious exception is nonpater- of a single gene, the phenotype can vary considerably.nity. Although this is not strictly a genetic problem, the Although at one time it was presumed that a particularillegitimacy rate in the U.S. population is high enough to mutation in a particular gene would always result in amake this a possible explanation for a couple without speciﬁc syndrome, several identical mutations in thethe trait to have a child with a completely penetrant ﬁbroblast growth factor receptor 2 (FGFR2) gene havedominant trait. been found in patients diagnosed with the three overlap-Variable Expressivity. Although in each individual the ping yet different clinical entities of Crouzon, Pfeiffer,trait is present or not when discussing penetrance, if the and Jackson-Weiss syndromes.19,20trait is present, it may vary in its severity or expression. Further evidence for the variable expressivity in auto-Thus, not all individuals with the trait may have it to the somal dominant phenotypes associated with a singlesame extent and they may express varying degrees of gene mutation presumably resulted from the interactioneffect or severity. Variable expressivity also may apply to of different proteins from modifying genes and environ-the pleiotropic effect of a particular genotype; that is, the mental factors (Figure 5-2) occurring when individualsexpression of the same gene may result in seemingly with, for example, the classic phenotypes of two over-disparate traits in an individual. The association of two lapping but clinically distinct syndromes (Pfeiffer andor more traits together more often than what would be Apert), as well as seven other individuals with a facialexpected by chance deﬁnes a syndrome. Although the resemblance to yet another syndrome (Crouzon),term genetic syndrome often is used, not all syndromes occurred in the same family.21necessarily have a strong genetic basis. Even with an autosomal dominant condition that For example, at least four clinical types of osteogen- typically manifests, the phenotype may be so variableesis imperfecta involving type I collagen abnormalities that, as a second example, an individual may appear toprovide an illustration of variable gene expression: (1) be clinically normal yet have the same gene mutationmultiple fractures, (2) blue sclera, (3) dentinogenesis associated with Crouzon syndrome as his three childrenimperfecta, and (4) hearing loss. Variation occurs among and two of his grandchildren. In this case, only throughthe different clinical types of osteogenesis imperfecta: cephalometry was a minimal expression of features sug-Affected persons in a single family may show a variable gestive of Crouzon syndrome evident.22 These examplescombination and severity of the classic signs and symp- give a clear message: Even a generally extreme phenotypetoms, illustrating the considerable variation in gene associated with an autosomal dominant mutation isexpression even within a family, with presumably the variable. Simply discovering the gene mutation likelysame genetic abnormality in one of the genes that code will indicate a future effect on craniofacial growth and
142 CHAPTER 5 Genetics and Orthodonticsdevelopment but will not necessarily predict the preciseeffect.Autosomal Recessive Traits. The concept of a genecarrier is used with autosomal recessive traits. The carrieris heterozygous for a recessive gene that has only subtle,if any, expression of that single gene. Parents of a childwith the autosomal recessive trait are typically heterozy- FIGURE 5-3 Three-generation pedigree of a family with an auto-gous (carriers) and most often are diagnosed as normal. somal recessive trait. The symbols for presumed carriers (heterozy-Sometimes, however, the carrier status can be detected, gotes) of the autosomal recessive gene are ﬁlled in halfway. Somegreatly improving the precision of genetic counseling, other family members also may be carriers but cannot be deter-before a child being born with the recessive trait. In mined strictly from the pedigree.autosomal recessive traits, the following three gene pairsare found: AA—homozygous, not showing the trait orbeing a carrier for the trait; Aa—heterozygous, notshowing the trait but being a carrier of the trait; andaa—homozygous, showing the trait. The rarer the recessive gene, the more likely it is thatnormal parents who have an affected child will be bloodrelatives—that is, a consanguineous mating. Still, we alllikely carry a number of recessive genes, so it is possible FIGURE 5-4 Three-generation pedigree of a family with anfor unrelated couples to have a child with an autosomal X-linked recessive trait. The symbols for presumed female carriersrecessive trait. A study on inbreeding in Japan by Schull (heterozygotes) of the X-linked recessive gene have a dot in theand Neel that was cited by Niswander23 found that mal- middle of the circle. Some other female family members also mayocclusion occurred 6% to 23% more often (depending be carriers but cannot be determined strictly from the pedigree.on the sample and the sex) in children of ﬁrst cousinscompared with children of nonrelated parents, indicatingthe potential for the effect of recessive genes when chromosome, recessive genes on the one male X chromo-homozygous. some express themselves phenotypically as if they were Given that both parents who produce a child with an dominant genes. However, X-linked recessive genes mustautosomal recessive trait are presumed to be heterozy- be present at the same (homologous) locus in females togotes, only one of the four possible gene combinations express themselves fully. Consequently, full expression offrom the parents will result in the homozygous genotype rare X-linked recessive phenotypes is almost completelyassociated with the autosomal recessive trait. Hence, the restricted to males, although occasionally it is seen inrecurrence risk for an affected child in this case is 25%. females (Figure 5-4). However, females who are hetero-Note that transmission of the phenotype in a pedigree is zygous for the gene associated with the X-linked reces-horizontal (typically present only in siblings) and not sive phenotype may show some expression of thevertical, as with a dominant trait (Figure 5-3). phenotype because most of the genes on one of the XX-Linked Traits and Lyonization. Most of the genes on chromosomes in the female normally will be inactivatedthe X and Y chromosomes are not homologous and are by a process called lyonization.unequally distributed to males and females. This inequal- The lyonization process starts early in developmentity is because males have one X and one Y chromosome, when each cell in the female inactivates almost all of thefemales have two X chromosomes, and the genes active genes on one of her two X chromosomes. The homolo-on the Y chromosome are concerned primarily with the gous X chromosome in each succeeding cell also willdevelopment of the male reproductive system. For these inactivate the same X chromosomes of the pair. Eachreasons, males are hemizygous for X-linked genes, female carrying a gene associated with an X-linked reces-meaning that they have only half (or one each) of the sive phenotype has a variable number of cells in whichX-linked genes. Because females have two X chromo- the X chromosome, where the X-linked recessive associ-somes, they may be homozygous or heterozygous for ated phenotype gene is located, is inactivated. UnderX-linked genes, just as with autosomal genes. these circumstances, the inactivated chromosome does Interesting genetic combinations are made possible by not inﬂuence the phenotype. The remaining cells havingthe male hemizygous condition, which is the result of the the X chromosome, where the X-linked recessive associ-male normally having only one X chromosome. Although ated phenotype gene is on the “active” X chromosome,the Y chromosome has some loci that correspond to loci inﬂuence the phenotype.on the X chromosome, most of the loci on the one X Human Monogenic (Mendelian) Traits Online Data-chromosome in the male do not have homologous loci base. The traits in peas that Mendel described in hison the Y or any other chromosome. Because a normally inheritance studies happened to be monogenic; thus,functioning homologous allele is not present on another monogenic traits sometimes are called mendelian traits.
CHAPTER 5 Genetics and Orthodontics 143A numbered database/catalog of human genes and malocclusion and also concluded that the overall inheri-genetic disorders associated with mendelian inheritance tance pattern best ﬁt an autosomal dominant model.is available. Online Mendelian Inheritance in Man Cruz et al.28 had a similar outcome when the majority(OMIM), McKusick-Nathans Institute for Genetic Med- of their Brazilian pedigrees suggested autosomal domi-icine, Johns Hopkins University [Baltimore, MD] and nant inheritance with incomplete penetrance. They con-National Center for Biotechnology Information, National cluded that there was a major gene and a multifactorialLibrary of Medicine [Bethesda]) may be searched at component that inﬂuenced the expression of mandibularwww.ncbi.nlm.nih.gov/sites/entrez?db=omim. prognathism.Mandibular Prognathism. Searching on the term mal- The genetic factors likely are heterogeneous, withocclusion in OMIM reveals more than 40 entries for a monogenic inﬂuences in some families and multifactorialvariety of syndromes known to include malocclusion as inﬂuences in others.23 This contributes to the variety ofone of their features. Although these are not all the anatomic changes in the cranial base, maxilla, and man-monogenic syndromes or traits that may include maloc- dible that may be associated with “mandibular progna-clusion as a feature, the best-known example of familial thism” or a Class III malocclusion.29,30 The prevalence of“mandibular prognathism” is referred to as the Haps- Class III malocclusion varies among races and can showburg jaw. The reference is OMIM *176700; the asterisk different anatomic characteristics between races.31 Con-indicates that in the opinion of the database/catalog sidering this heterogeneity and possible epistasis (theauthors, mendelian inheritance is certain. interaction between or among gene products on their Although mandibular prognathism has been said to expression), it is not surprising that genetic linkagebe a polygenic24 or multifactorial trait (i.e, inﬂuenced studies to date have indicated the possible location ofby the interaction of many genes with environmental genetic loci inﬂuencing this trait in several chromosomalfactors), in the majority of cases, there are families in locations.32,33which the trait (and possibly some other associated ﬁnd-ings) appears to have autosomal dominant inheritance, Complex (Polygenic/Multifactorial) Traitssuch as in the European noble families. Analysis of apedigree comprising 13 European noble families with The predominant role of genetics in the clinic has been409 members in 23 generations determined that the the study of chromosomal and monogenic phenotypesmandibular prognathism trait was inherited in an auto- that are associated clearly with speciﬁc changes (muta-somal dominant manner, with a penetrance of 0.95 (i.e, tions) in the genome of the individual. However, new95% of the time that someone was believed to have the knowledge and techniques are allowing the study ofgene for the mandibular prognathism trait in their pedi- phenotypes that “run in families” but do not adhere togree, the trait itself also was expressed). Although the patterns of mendelian inheritance. These are referred topenetrance is high, considerable variation exists in the as complex or common diseases, as well as phenotypesclinical expression of the trait.25 or traits, reﬂecting their complex etiological interaction Also noted was that some of the members of the between genes from more than one locus and environ-European noble families had, in addition to varying mental factors (Figure 5-5). Another consideration isdegrees of mandibular prognathism, other facial charac- their greater incidence compared with monogenic phe-teristics such as a thickened lower lip, prominent nose, notypes. Understanding the concept of genetic heteroge-ﬂat malar areas, and mildly everted lower eyelids (which neity is critical to understanding the genetic inﬂuencesmay be associated with a hypoplasia of the infraorbital on common phenotypes. 34 For example, although ortho-rims), as also were reported in three generations of a dontists often ﬁrst classify a malocclusion as Angle Classfamily by Thompson and Winter.26 In that family, one I, II, or III, orthodontists also know that a number ofmember had oxycephaly because of multiple suture syn- different subtypes of occlusion have varying genetic andostosis, which also was suspected in Charles V, a severely environmental inﬂuences.affected member of the Hapsburg family. Apparent max- Traits inﬂuenced by polygenic factors are also heredi-illary hypoplasia, as well as malar ﬂattening and down- tary and typically exert inﬂuence over rather commonward eversion of the lower eyelids, may indicate that characteristics. This inﬂuence takes place through manyalthough the trait is referred to as mandibular progna- gene loci collectively asserting their inﬂuence on the trait.thism, the overall clinical effect may be at least in part Historically, each gene involved was thought to have adue to hypoplasia of the maxilla. Even in the most rec- minimal effect by itself, with the effect of all genesognizable family trait, there may be those who would involved additive. The associated phenotype is rarelybe expected to have the trait and do not. Furthermore, discrete and is most commonly continuous or quantita-variability in the severity of the trait and associated ﬁnd- tive. Because these traits show a quantitative distributionings suggest more than an isolated effect on sagittal of their phenotypes in a population, they do not showmandibular/maxillary growth. mendelian inheritance patterns. El-Gheriani et al.27 performed segregation analysis Although the use of the term polygenic has inferredon 37 Libyan families of patients who had a Class III the effect of multiple genes on the phenotype,
144 CHAPTER 5 Genetics and Orthodontics Complex (polygenic) traits Gene 1 Gene 2 Gene 3 Gene 4 Environmental EF EF EF Factors (EF) Protein 1 Protein 2 Protein 3 Protein 4 EF EF EF Phenotype FIGURE 5-5 Unlike Mendelian traits, environmental factors and multiple genes are critical to the development of complex (polygenic) traits. These types of physical traits are continuous rather than discrete (although diseases of this type can still be present or not). Such traits are referred to as quantitative traits or multifactorial because they are caused by some number of genes in combination with environmental factors.16environmental factors can play a variable and generallygreater role than in monogenic traits. A change in phe- Trait manifestationnotype depends on the result of the genetic and envi- thresholdronmental factors present at a given time. Thus, one Number of peoplemay expect that compared with monogenic traits, poly-genic traits will be more amenable to change (or agreater change) following environmental (treatment)modiﬁcation. Another aspect to consider is the fourth dimensionof development—time. Although an environmental mod-iﬁcation may alter the development of the phenotype ata particular moment, gross structural morphology,already present, may not change readily unless the envi-ronmental modiﬁcation is sufﬁcient to alter preexisting 0 Total liability for a multifactorial traitstructure.12 Examples of polygenic traits include height FIGURE 5-6 The liability to have a multifactorial trait is inﬂuencedand intelligence quotient, both of which are continuous by multiple genes and environmental factors that are distributedtraits greatly inﬂuenced by genetic factors. However, throughout a population. However, if some of the populationheight and intelligence quotient also can be affected members do not have the trait and some do, then there is a thresh- old on which a member of the population who has a particulargreatly by environmental factors, particularly if they are susceptibility to the trait will manifest it. If the genetic liability,deleterious. environmental liability, or both increase, then the liability distribu- As polygenic traits are inﬂuenced by environmental tion curve shifts to the right, increasing the number of persons whoand multiple genetic factors, they also have been referred are affected.to as multifactorial, meaning they are inﬂuenced by theinteraction of multiple genes and environmental factors.However, a distinction from polygenic traits has been major gene effect. Nonsyndromic cleft lip-palate, neuralmade for some multifactorial traits that are discrete tube defects such as spina biﬁda and anencephaly, and(dichotomous). Although polygenic and multifactorial congenital hip dislocation are examples of multifactorialtraits are described as resulting from the interaction of traits.17multiple genes and environmental factors, the discrete As mentioned, “mandibular prognathism” has beenmultifactorial traits occur when a liability threshold is said to be a polygenic or multifactorial trait that also hasexceeded (Figure 5-6). Typically, numerous genes are been found to ﬁt the criteria of a mendelian trait (auto-believed to be involved. Occasionally, though, only a few somal dominant with incomplete penetrance and vari-genes have a major inﬂuence on the trait. Their effect on able expressivity) in some studies. Even in this group ofthe phenotype is therefore a net effect, not a simple addi- heterogeneous subtypes, the sagittal length of the man-tive one. This leads to a phenotypic expression pattern dible, maxilla, or both may be continuous polygenicin a family that approaches that of a discrete mendelian traits if measured quantitatively and related to eachtrait and therefore cannot be classed readily as a quan- other. However, the alternative is that they are a multi-titative trait. The effect of a gene inﬂuencing the complex factorial or mendelian discrete trait if the relation of thetrait may not be to the extent of a gene associated with sagittal length of one jaw relative to the other is deemeda monogenic trait but may be referred to as having a sufﬁcient (at the threshold) to state that the mandible is
CHAPTER 5 Genetics and Orthodontics 145farther anterior relative to the maxilla. Thus, a mandibu- environmental factors common to both siblings. That is,lar prognathism may be skeletally deﬁned mandibular given genetically inﬂuenced facial types and growth pat-protrusion, maxillary retrusion, or a combination of the terns, siblings are likely to respond to environmentaltwo. Analysis of the phenotype and its outcome may factors (e.g, reduced masticatory stress, chronic mouthdepend on the method and endpoint(s) used in the study. breathing) in similar fashions. Malocclusions appear to be acquired, but the fundamental genetic control of cra- niofacial form often diverts siblings into comparableNATURE VERSUS NURTURE physiologic responses leading to development of similarConsideration of which factors inﬂuence, determine, or malocclusions.”even drive growth and development often has involveda discussion, if not debate, of nature versus nurture, as Heritability and Its Estimationthough it could only be one or the other. However,growth and development are not the result of genetic and Although the gene-mediated developmental processesenvironmental (nongenetic or epigenetic) factors working bring about basic embryonic development,41–43 variationin total absence or independence of others. Full siblings from individual to individual is not necessarily the resultshare on average half of their genes, and it is apparent of genetic variation.9 Traits are familial (“run” in fami-that siblings can have similar occlusions. However, this lies), if for whatever reason(s) members of the sameis in some part environmental (e.g., inﬂuenced by dietary family have them. It has been said that parents give notand respiratory factors in common) and in some part only their genes to their children but also their environ-genetic factors that inﬂuence development.35–37 Indeed, ment.44 Traits are heritable only if the familial similarityCorrucini38 points out that the rapid increase in maloc- arises from shared genes. For a quantitative trait, heri-clusion comparing industrialized (urban) to nonindustri- tability (in the narrow sense) is the proportion of thealized (rural) samples of several disparate populations total phenotypic variance in a sample that is contributedemphasizes the importance of environmental factors. by additive genetic variance. However, the estimated Not to be lost in this discussion is the understanding ratio of genetic to environmental variation does not takethat how the individual responds to environmental into account gene–gene (epistatic through their proteinchanges is inﬂuenced by genetic factors. Moss,8 in a products and their effect on gene expression) or gene–revisitation of the functional matrix hypothesis and environment interaction, as well as other aspects ofresolving synthesis of the relative roles of genomic and variation.epigenetic (environmental) processes and mechanisms Genetic variation is also not a measure of the relativethat cause and control craniofacial growth and develop- contribution of genes and environment to phenotype orment, concluded that both are necessary. Neither genetic of which part of the phenotype can be attributed tonor epigenetic (environmental) factors alone are sufﬁ- genetic factors and which to environmental factors.9 Forcient, and only their integrated (interactive) activities example, one cannot meaningfully say that 3 inches ofprovide the necessary and sufﬁcient causes of growth and the radiographic length of a patient’s mandible is due todevelopment. Moss further considered genetic factors as genetic factors, whereas 2 inches is due to environmentalintrinsic and prior causes and what he termed “epigen- factors. To paraphrase Strachan and Read,44 heritabilityetic” (environmental) causes as extrinsic and proximate. of a continuous trait actually means heritability of theMost likely for the majority of individuals, the ability to variations of a continuous trait. The question, “To whatrespond to a variety of environmental modiﬁcations extent is a continuous trait (like length of the mandible)overlaps considerably. Also expected would be that, if genetic?” is a meaningless question. The meaningful,pressured sufﬁciently, some would respond to a given albeit difﬁcult to answer, question is, “How much ofenvironmental modiﬁcation differently or to a different the differences in a continuous trait (like length of thedegree than others. mandible) between persons in a particular place at a The genetic background of the individual can inﬂu- particular time is caused by their genetic differences, andence the response to environmental factors, particularly how much by their different environments and lifethose that are more likely to delineate different individ- histories?”ual responses. This is supported by the ﬁnding that the A trait with a heritability estimate of 1 is expresseddifferences in shape of the mandibular condyles was theoretically without any environmental inﬂuence,“slightly greater” among four different inbred strains of whereas a trait with a heritability of 0.5 would have halfmice on a hard diet than on a soft diet for 6 weeks. 39 its variability (from individual to individual) inﬂuencedWhen the environment changed sufﬁciently, the response by environmental factors and half by genotypic factors.was different among animals with different genotypes Values greater than 1 may occur because the methodol-that was not evident before the environmental change. ogy for estimating heritability in human beings operatesTo quote King et al.40 in regard to human beings, under several simplifying assumptions that may be inc-“We propose that the substantive measures of intersib orrect. One must remember some important aspectssimilarity for occlusal traits reﬂect similar responses to of heritability when reviewing them. First, heritability
146 CHAPTER 5 Genetics and Orthodonticsestimates refer to a speciﬁc sample and do not necessarily BOX 5-1 Heritability (h2)pertain to the situation of a given individual, even fromwithin the sample. Thus, they do not allow one to tell Aspects of (additive) heritability in the narrow sense, estimating theto what degree a particular trait was determined by effect of an indeﬁnitely large number of genes that all contribute equally to the phenotype. It cannot take into account allele–allelegenetic or environmental factors in a single individual. interactions at a gene locus (termed dominance) and gene–geneIn addition, heritability estimates are descriptive of vari- interactions involving two or more loci (termed epistasis).ances within a sample at a given time; they are not • Refers to a speciﬁc sample and does not necessarily pertain topredictive.45 the situation of a given individual, even from within the sample Although the mode of inheritance (e.g., autosomal • Is descriptive of variances within a sample at a given time anddominant or polygenic) of a trait is a ﬁxed property in is not necessarily predictivea given individual, heritability is not.44 Heritability esti- • Can change with agemates can change with age, as in a longitudinal analysis • A different environment can alter the phenotypic expression thatof 30 sets of siblings who had not undergone orthodontic the genes would have promoted under other conditionstreatment who showed a signiﬁcant increase overall in • A high heritability does not necessarily prevent a trait from beingmedian heritability estimates between the ages of 4 and substantially inﬂuenced by subsequent changes in environmen- tal conditions in that sample14 years for 29 craniofacial skeletal variables, includingincreases for total anterior face height, upper anteriorface height, total posterior face height, and upper poste-rior face height. Still, despite the general increasing trend Craniofacial Skeletal and Dentoalveolarin heritability estimates for the craniofacial skeletal vari- Occlusal Heritability Studiesables, a decrease was noted for lower posterior faceheight. The median estimates of heritability for cranio- Consideration of the genetic aspect of occlusal variationsfacial skeletal variables increased from 0.6 at age 4 years and malocclusion has been a major focus of interest toto 0.9 at age 14 and 20 years. This is in contrast to the orthodontists. The different studies directed toward heri-heritability estimates of arch and occlusal variables that tability of occlusion have varied in method. In additiondecreased from 0.5 at age 4 years to 0.2 and 0.1 at ages to environmental covariance, a limitation of many of14 and 20, respectively.46 This study also examined the these studies is that they were based just on twins orsuggestion that vertical craniofacial variables were inﬂu- siblings who did not receive orthodontic treatment. Pos-enced more by genetic factors than horizontal cranio- sibly, twin pairs and sibships containing one or morefacial variables,1,47–49 ﬁnding no signiﬁcant difference treated patients (with moderate to severe malocclusion)between the vertical and horizontal variable heritability were excluded from most studies. Therefore, estimatesestimates for ages 4, 14, or 20 years. of genetic and environmental contributions may have The heritability of a trait cannot necessarily be been affected by lack of accounting for a common envi-extrapolated from one sample and set of environmental ronmental effect36 and ascertainment bias.40conditions to another.9 An adverse environment can The cause of most skeletal- and dentoalveolar-alter the phenotypic expression that the genes would based malocclusions is essentially multifactorial in thehave promoted under more favorable conditions, an sense that many diverse causes converge to produceextreme example of which is the delayed growth seen the observed outcome.40 Numerous studies have exam-from the effects of famine associated with war.50 There- ined how genetic variation contributes to either orfore, a high heritability in and of itself does not prevent both occlusal and skeletal variation among familya trait from being inﬂuenced substantially by subsequent members.1,6,40,46,49,53–71 Many reviews of the genetics ofchanges in environmental conditions in that sample malocclusion actually focus on the cephalometric com-(Box 5-1).5,9 ponent of craniofacial form, not on the occlusal compo- Methods to estimate heritability are based on correla- nent. In most studies (particularly those that try totions of measurements of the trait between various kinds account for bias from the effect of shared environmentalof pairs of individuals in families, including monozygotic factors, unequal means, and unequal variances in mono-twins, dizygotic twins, parent-child, and sib-sib (sib- zygotic and dizygotic twin samples),10 variations in ceph-pair).51 However, environmental sources of covariance alometric skeletal dimensions are associated in general(the effect of those being studied being similar because with a moderate to high degree of genetic variation,they are in a similar environment) may be signiﬁcant and whereas in general, variation of occlusal relationshipscontribute to an inﬂated heritability estimate.52 Conﬁrm- has little or no association with genetic variation.5ing a certain degree of genetic inﬂuence on a trait for a Although the heritability estimates are low, most ofparticular sample in a particular environment at a par- the studies that looked at occlusal traits found thatticular time is a preliminary step to further speciﬁc genetic variation has more to do with phenotypic varia-genetic linkage studies (using DNA markers) to deter- tion for arch width and arch length than for overjet,mine areas of the genome that appear to be associated overbite, and molar relationship. Still, arch size andwith the characteristics of a given trait.45 shape are associated more with environmental variation
CHAPTER 5 Genetics and Orthodontics 147than with genetic variation.56 Because many occlusal by evolutionary ﬁtness pressure.74 The most likely expla-variables reﬂect the combined variations of tooth posi- nation for the increased malocclusion seen in “civiliza-tion and basal and alveolar bone development, these tion” is changed environment, such as food and airwayvariables (e.g., overjet, overbite, and molar relationship) effects.38cannot be less variable than the supporting structures.They will vary because of their own variation in position Use of Family Data to Predict Growthand those of the basilar structures.46 The example of reported heritability estimates for Siblings have been noted as often showing similar typesanterior and posterior face height and the observed effect of malocclusion. Examination of parents and older sib-of perennial allergic rhinitis and mouth breathing are lings has been suggested as a way to gain informationinteresting. Some (although not all) studies suggest that regarding the treatment need for a child, including earlya greater heritability exists for total anterior face height treatment of malocclusion.23,24,69,75 Niswander23 notedand lower anterior face height than for upper anterior that the frequency of malocclusion is decreased amongface height and posterior face height. This implies that siblings of index cases with normal occlusion, whereasthe greater estimate of heritability for the total anterior the siblings of index cases with malocclusion tend toface height is due to the greater estimate of lower ante- have the same type of malocclusion more often. Harrisrior face height than upper face height. Possibly a lower and colleagues63 have shown that the craniofacial skel-heritability for the upper anterior face height reﬂects the etal patterns of children with Class II malocclusions areeffect of the airway, and a lower heritability for posterior heritable and that a high resemblance to the skeletal pat-face height reﬂects dietary effects. terns occurs in their siblings with normal occlusion. How are those ﬁndings reconcilable with an increase From this it was concluded that the genetic basis for thisin total anterior face height and lower anterior face resemblance is probably polygenic, and family skeletalheight, in particular, being associated with perennial patterns were used as predictors for the treatment prog-allergic rhinitis and mouth breathing? One hypothesis is nosis of the child with a Class II malocclusion, althoughthat the lower anterior face height may have a greater it was acknowledged that the current morphology of theheritability than the upper anterior face height in some patient is the primary source of information about futuregroups of individuals unless increased nasal obstruction growth.75resulting in mouth breathing becomes a predominating Each child receives half of his or her genes from eachfactor in group members.72 Remembering that heritabil- parent, but not likely the same combination of genes asity is a descriptive statistic for a particular sample under a sibling unless the children are monozygotic twins.whatever environmental conditions existed is essential. When looking at parents with a differing skeletal mor- Malocclusion is less frequent and less severe in popu- phology, knowing which of the genes in what combina-lations not industrialized (urbanized) and that tend to be tion from each parent is present in the child is difﬁcultisolated. Typically an increase in malocclusion occurs until the child’s phenotype matures under the continuingas these populations are “civilized” or become more inﬂuence of environmental factors. As Hunter76 pointedurbanized. This has been attributed to the interbreeding out, with polygenic traits the highest phenotypic correla-of populations with, to some degree, different physical tion that can be expected based on genes in commoncharacteristics, presumably resulting in a synergistic dis- by inheritance from one parent to a child, or betweenharmony of tooth and jaw relationships. This idea was siblings, is 0.5. Because the child’s phenotype is likelysupported by the crossbreeding experiments of Stockard to be inﬂuenced by the interaction of genes from bothand Anderson73 in inbred strains of dogs, increasing the parents, the “mid-parent” value may increase the cor-incidence of malocclusion, typically caused by a mis- relation with their children to 0.7 because of the regres-match of the jaws. However, the anomalies they pro- sion to the mean of parental dimensions in theirduced have been attributed to the inﬂuence of a major children.gene or genes that have been bred to be part of speciﬁc Squaring the correlation between the two variablesbreeds. Considering the polygenic nature of most cranio- derives the amount of variation predicted for one vari-facial traits, it seems improbable that racial crossbreed- able in correlation with another variable. Therefore, ating in human beings could resemble the condition of best, using mid-parent values, only 49% of the variabil-these experiments and thereby result in a synergistic ity of any facial dimension in a child can be predictedincrease of oral-facial malrelations.6,23,74 by consideration of the average of the same dimension A study of disparate ethnic groups that have interbred in the parents. Only 25% of the variability of any facialin Hawaii found that children of racial crosses are at dimension in a child can be predicted, at best, by con-no increased risk of malocclusion beyond what would sidering the same dimension in a sibling or one parent.have been expected from the usual parental inﬂuence. Because varying effects of environmental factors interactIn addition, the increase in malocclusion in populations with the multiple genetic factors, the usual correlationthat have moved recently into an industrialized lifestyle for facial dimensions between parents and their childrenis too quick to be the result of genetic change caused is about 30%, yielding even less predictive power.76
148 CHAPTER 5 Genetics and Orthodontics In most patients, the mode of inheritance for the cra- mesial-distal size of the permanent maxillary incisor andniofacial skeleton is polygenic (complex). However, in canine crowns tends to be large in cases with supernu-some families (e.g., with a relatively prognathic mandible merary teeth.85 Relatives who do not have hypodontiacompared with the maxilla), the mode of inheritance is still may manifest teeth that are small. This suggests anot polygenic. Future research may investigate the genetic polygenic inﬂuence on the size and patterning of thefactors that do not ﬁt a polygenic mode that may be dentition, with a multifactorial threshold for actualpresent in some families. Identiﬁcation of those factors hypodontia in some families.will increase the ability to predict the likelihood of a The presence of a single primary and permanentparticular resulting morphology. maxillary incisor at ﬁrst may appear to be a product Unfortunately, orthodontists do not have sufﬁcient of fusion. However, if the single tooth is in the midlineinformation to make accurate predictions about the and symmetric with normal crown and root shapedevelopment of occlusion simply by studying the fre- and size, then it can be an isolated ﬁnding or can bequency of its occurrence in parents or even siblings. part of the solitary median maxillary central incisorAdmittedly, family patterns of resemblance are frequently syndrome. This heterogeneous condition may includeobvious, and family tendencies are ignored at the clini- other midline developmental abnormalities of the braincian’s peril. Nonetheless, predictions must be made cau- and other structures that can be due to mutation intiously because genetic and environmental factors and the sonic hedgehog (SHH) gene, SIX3 gene, or genetictheir interaction are unknown and difﬁcult to evaluate abnormality.86 Although rare, the development of onlyand predict with precision. one maxillary central incisor is an indication for review of the family medical history and evaluation for other anomalies.TOOTH SIZE, HYPODONTIA, AND Analysis of the variation in dental age as determinedDENTAL ROOT DEVELOPMENT by root development was explained best by additiveAdditive genetic variation for mesial-distal and buccal- genetic inﬂuences (43%) and by environmental factorslingual crown dimensions of the permanent 28 teeth common to both twins (50%). Environmental factors(excluding third molars) ranged from 56% to 92% of unique or speciﬁc to only one twin accounted for thephenotypic variation, with most over 80%.77 Estimates remainder. The importance of the common environmen-of heritability for a number of variables measuring tal factor was thought to be due to twins sharing theoverall crown size of the primary second molars and same prenatal, natal, and immediate postnatal condi-permanent ﬁrst molars were moderate to high. Yet less tions that are important for tooth formation.87genetic variation was associated with distances between Incisor mesial distal crown dimensions were found tothe cusps on each tooth, implying that phenotypic varia- be small as a part of the extreme form of the Class II,tion for overall crown size was associated more with Division 2 malocclusion in which the mandibular inci-genetic variation than was the morphology of the occlu- sors are concealed in habitual occlusion, along withsal surfaces.78 strong vertical development of the posterior mandible, Hypodontia may occur without a family history of forward rotation, and skeletofacial hypodivergence.88hypodontia, although it is often familial. Hypodontia Following a review of published family pedigrees involv-also may occur as part of a syndrome, especially in one ing Class II, Division 2 malocclusion, Peck and col-of the many types of ectodermal dysplasia, although it leagues88 noted the probability of autosomal dominantusually occurs alone (isolated). Note that “isolated” in inheritance with incomplete penetrance, although poly-this use means not a part of a syndrome, although it still genic inheritance was also a possibility.may be familial. Genetic factors are believed to play a One of the most common, if not the most common,major role in most of these cases with autosomal domi- pattern of hypodontia (excluding the third molars)nant, autosomal recessive, X-linked, and multifactorial involves the maxillary lateral incisors. This can be aninheritance reported.79 Still, only a couple of genes autosomal dominant trait with incomplete penetrance(MSX1 and PAX9) involved in dentition patterning so and variable expressivity as evidenced by the phenotypefar have been found to be involved in some families with sometimes “skipping” generations and sometimes beingnonsyndromic autosomal dominant hypodontia, as well a peg-shaped lateral instead of agenesis and sometimesas the LTBP3 gene, which may also involve short stature involving one or the other or both sides.89 A polygenicand increased bone density in autosomal recessive mode of inheritance also has been proposed.90 Unidenti-hypodontia,80–82 although there are other chromosomal ﬁed currently, the gene mutation that primarily inﬂu-locations that nonsyndromic hypodontia has been ences this phenotype has been suggested, in themapped to and candidate genes, including 10q11.2 and homozygous state, to inﬂuence agenesis of the succeda-KROX-26.79,83,84 neous teeth or all or almost all of the permanent denti- A general trend in patients with hypodontia is to have tion.91,92 In addition, an associated increased agenesis ofthe mesial-distal size crowns of the teeth present to be premolars occurs,93 as well as with palatally displacedrelatively small (especially if more teeth are missing). The canines.94
CHAPTER 5 Genetics and Orthodontics 149 Maxillary canine impaction or displacement is labial/ occurrence of this phenomenon in approximately one-buccal to the arch in 15% of the cases of maxillary quarter of cases facilitated the investigation and discov-canine impaction and often is associated with dental ery of the PTHR1 gene being involved.104,105 Advancementscrowding. The canine impacted or displaced palatally in this area could not only help to deﬁne patients whooccurs in 85% of the cases and typically is not associated are likely to develop or have PFE, but also potentiallywith dental crowding.95 Palatally displaced canines fre- result in the molecular manipulation of selective toothquently, but not always, are found in dentitions with eruption rates to enhance treatment protocols on anvarious anomalies. These include small, peg-shaped or individual basis.106missing maxillary lateral incisors, hypodontia involvingother teeth, dentition spacing, and dentitions with ENVIRONMENTAL AND GENETICdelayed development.96 Because of varying degrees of INFLUENCES ON BILATERAL SYMMETRYgenetic inﬂuence on these anomalies, there has beensome discussion about palatally displaced canines them- Van Valen107 described three types of asymmetry: direc-selves also being inﬂuenced by genetic factors to some tional, antisymmetry, and ﬂuctuating asymmetry. Direc-degree. In addition, the occurrence of palatally displaced tional asymmetry occurs when development of one sidecanines does occur in a higher percentage within families is different from that of the other during normal develop-than in the general population.97 ment. The human lung, having three lobes on the right A greater likelihood exists of a palatally displaced side and two lobes on the left side, is an example ofcanine on the same side of a missing or small maxillary directional asymmetry. Because this may be predictedlateral incisor, emphasizing a local environmental effect.98 before development occurs, it is under signiﬁcant geneticAlso, in some cases, a canine is displaced palatally inﬂuence. Antisymmetry occurs when one side is largerwithout an apparent anomaly of the maxillary lateral than the other, but which side is larger varies in normalincisors, and in some cases, lateral incisors are missing development and cannot be predicted before develop-without palatal displacement of a canine. Adding to the ment. Antisymmetry is much less common than direc-complexity is the heterogeneity found in studies of cases tional asymmetry. The ﬁrst two types of asymmetry areof bucally displaced canines99 and palatally displaced considered developmentally normal. Like directionalcanines.96 Although the canine eruption theory of guid- asymmetry, antisymmetry has a signiﬁcant genetic com-ance by the lateral incisor root cannot explain all ponent that is not fully understood.108instances of palatally displaced canines, it does seem to Unlike structures that have normal directional asym-play some role in some cases.100 metry, facial and dental structures lateral to the midline With apparent genetic and environmental factors are essentially mirror images of each other, with the sameplaying some variable role in these cases, the cause genetic inﬂuences affecting both sides. The conditionsappears to be multifactorial.101 The phenotype is the are theoretically identical for the trait on both sides ofresult of some genetic inﬂuences (directly or indirectly or the body because they are developing simultaneously andboth, for example, although a primary effect on develop- therefore should develop identically.ment of some or all of the rest of the dentition) interact- One does not ﬁnd one group of genes for the perma-ing with environmental factors. Some of these cases may nent maxillary right ﬁrst molar and another group ofbe examples of how primary genetic inﬂuences (which genes for the permanent maxillary left ﬁrst molar. Thestill interact with other genes and environmental factors) third type of asymmetry, ﬂuctuating, occurs when a dif-affect a phenotypic expression that is a variation in a ference exists between right and left sides, with whichlocal environment, such as the physical structure of the side is larger being random. This reﬂects the inability oflateral incisor in relation to the developing canine. Can- the individual to develop identical, bilaterally homolo-didate genes that are proposed possibly to inﬂuence the gous structures.56occurrence of palatally displaced canines and hypodon- Fluctuating asymmetry has been observed in thetia in developmental ﬁelds include MSX1 and PAX9.102 primary and permanent dentitions,109,110 as well as in the Investigations so far indicate that a number of hetero- craniofacies.56 The greater amount of ﬂuctuating asym-geneous genetic factors may be involved in hypodontia. metry for the distance between cusps on each tooth thanIncreased understanding of the various morphogenetic for the overall crown size of primary second molars andsignaling pathways regulating tooth development should permanent ﬁrst molars indicates that the occlusal mor-allow for induction of tooth development in areas of phology of these teeth is inﬂuenced more by environmen-tooth agenesis.103 In addition to hypodontia and its tal factors than the overall crown size.78primary or secondary relationship to maxillary canine The ﬁdelity of developmental symmetry as measurederuption, there are emerging data regarding the inﬂuence by ﬂuctuating asymmetry is an indirect measure of envi-of genetics on dental eruption. Presently this is most clear ronmental stress so that differences between bilateralin cases of primary failure of eruption (PFE), in which structures are due predominantly to environmentalall teeth distal to the most mesial involved tooth do not factors.111 An individual’s level of ﬂuctuating asymmetryerupt or respond to orthodontic force. The familial is an indicator of how well the genome can produce the
150 CHAPTER 5 Genetics and Orthodonticsideal phenotype under certain circumstances. However, reduced crestal bone heights.116 Individuals with bruxism,not everyone’s genome can do as well producing the chronic nailbiting, and anterior open bites with concomi-ideal phenotype under certain circumstances. Therefore, tant tongue thrust also may show an increased extent ofMoller and Pomiankowski112 propose that ﬂuctuating EARR before orthodontic treatment.117asymmetry may be used as an indication of an individ- EARR is also increased as a pathologic consequenceual’s “ability to cope with its environment.” Sprowls of orthodontic mechanical loading in some patients.118,119et al.113 reported a previously unreported association The amount of orthodontic movement is positively asso-between decreased developmental stability (evident in ciated with the resulting extent of EARR.120–122 Orth-increased ﬂuctuating asymmetry), arch form discrepan- odontic tooth movement, or “biomechanics,” has beencies, and anterior maxillary dental crowding. Although found to account for approximately one-tenth to one-heritability (h2) estimations that include environmental third of the total variation in EARR.123–125 Owman-Mollcovariance for dental position, rotation, and angulation and coworkers126 showed that individual variation over-collectively suggest that the predominant source of shadowed the force magnitude and the force type inocclusal variation is environmental, they suggested that deﬁning the susceptibility to histologic root resorptiona variable component of occlusal variation may be the associated with orthodontic force. Individual variationsindividual’s relative ability to develop right and left were considerable regarding both extension and depthmirror images, which has experimentally been associated of histological root resorption within individuals, andwith gene–gene interaction that (h2) does not measure. these were not correlated to the magnitude of tooth movement achieved.127 There is considerable individual variation in EARRINVESTIGATING THE GENETIC associated with orthodontic treatment, indicating anBASIS FOR VARIABLE RESPONSE individual predisposition and multifactorial (complex)TO TREATMENT etiology.128–133 Heritability estimates have shown thatIncreased understanding of the various morphogenetic approximately half of EARR variation concurrent withsignaling pathways regulating development of the cra- orthodontia, and almost two-thirds of maxillary centralniofacies should allow for the manipulation of the pro- incisor EARR speciﬁcally, can be attributed to geneticliferation, patterning, and differentiation of tissue to variation.133,134 A retrospective twin study on EARRtreat skeletal discrepancies that contribute to malocclu- found evidence for both genetic and environmentalsion.103 An important aspect of this is increased compre- factors inﬂuencing EARR.135 In addition, studies in ahension of how epigenetic (including environmental or panel of different inbred mice supported a genetictreatment) factors affect expression of genes that inﬂu- component involving multiple genes in histologic rootence postnatal growth.114 Because the relative inﬂuence resorption.136,137of genetic factors on development of an occlusion does While there is a relationship between orthodonticnot necessarily determine the response to treatment, and force and root resorption, it is against the backdropthe ability to predict abnormal growth is usually of of previously undeﬁned individual susceptibility. Becauselimited speciﬁcity in reference to an individual when mechanical forces and other environmental factors dolooking at family members, the future of genetics in not adequately explain the variation seen among indi-orthodontics primarily will involve analyzing the genetic vidual expressions of EARR, interest has increased onbasis for variable response to treatment. In other words, genetic factors inﬂuencing the susceptibility to EARR.are there genetic factors that inﬂuence the response to The reaction to orthodontic force, including rate of toothtreatment? If so, what are they? Can they be identiﬁed movement, can differ depending on the individual’sbefore treatment to assist in devising the most effective genetic background.133,134,138,139and efﬁcacious treatment, including the avoidance of Variation in the interleukin-1β gene (IL-1B) inunwanted responses?115 orthodontically treated individuals accounts for 15% of the variation in EARR. Persons in the orthodontically treated sample who were homozygous for IL-1B +3953GENETIC FACTORS AND EXTERNAL (previously designated as +3954) SNP rs1143634 alleleAPICAL ROOT RESORPTION “1” were estimated to be 5.6 times (95% conﬁdenceAnalysis of the genetic basis for variable response to interval, 1.89–21.20) more likely to experience EARR oftreatment has been applied to the speciﬁc adverse 2 mm or more than were those who were heterozygousoutcome sometimes associated with orthodontic treat- or homozygous for allele “2” (p = .004).140 Investigatorsment called external apical root resorption (EARR). The in Brazil followed essentially the same protocol exceptdegree and severity of EARR associated with orthodon- for using periapical instead of lateral cephalometrictic treatment are multifactorial, involving host and envi- radiographs for pretreatment and posttreatment mea-ronmental factors. An association of EARR exists, in surements and also found this genetic marker to bethose who have not received orthodontic treatment, with signiﬁcantly associated with EARR concurrent withmissing teeth, increased periodontal probing depths, and orthodontic treatment141 (Table 5-1 and Figure 5-7).
CHAPTER 5 Genetics and Orthodontics 151 TAB L E 5- 1 External Apical Root Resorption response to orthodontic force that may be mediated at of Maxillary Central Incisors least in part by IL-1β and IL-1RA cytokines. This sup- of 2 mm or Greater Compared ports the hypothesis that bone modeling mediated, at by IL-1B +3953 (+3954) SNP least in part, by IL-1β as an individual response to ortho- rs1143634 Genotype dontic force can be a factor in EARR. A large number of other genes and their proteins that affect bone physiol- 1,1 1,2 2,2 ogy could also be involved in the rate of tooth move- Indiana ment, as well as EARR.138 Affected 12 (71%) 20 (38%) 0 Further testing of another candidate gene using non- Unaffected 5 (29%) 32 (62%) 4 (100%) parametric sibling pair linkage analysis with the DNA Brazil microsatellite marker D18S64 (tightly linked to the gene Affected 11 (65%) 7 (37%) 5 (20%) Unaffected 6 (35%) 12 (63%) 20 (80%) TNFRSF11A) identiﬁed evidence of linkage (LOD = 2.5; Combined p = .02) of EARR affecting the maxillary central incisor.143 Affected 23 (68%) 27 (38%) 5 (17%) This indicates that the TNFRSF11A locus, or another Unaffected 11 (32%) 44 (62%) 24 (83%) tightly linked gene, is associated with EARR. The TNFRSF11A gene codes for the protein RANK, part of Number affected or unaffected for each genotype and percentage of total the osteoclast activation pathway.144 Future estimation for that genotype in each cell. The protocols for the independent investiga- tions in Indiana and Brazil were essentially the same, except the Indiana of susceptibility to EARR likely will require the analysis measurements were from lateral cephalometric radiographs and the Brazil- of several genes as mentioned previously, root morphol- ian measurements were made from periapical radiographs.140,141 ogy, skeletodental values, and the treatment method to be used, or essentially the amount of tooth movement planned for treatment.134,145 Unaffected Affected EARR Ն 2 mm 100 PAIN PERCEPTION ANDPercentage of individuals 80 TEMPOROMANDIBULAR DYSFUNCTION 60 Temporomandibular dysfunction (TMD) can be broadly classiﬁed as somatic and neuropathic, although the indi- 40 vidual etiologies within each category are heterogeneous and probably often complex. Genetic factors may play 20 a role in TMD by inﬂuencing variation in individual pain perception, sex and ethnicity, production of proinﬂam- 0 (P Ͻ 0.0001) matory cytokines, the breakdown of extracellular matrix, (1,1) n ϭ 34 (1,2) n ϭ 71 (2,2) n ϭ 29 by other proteins from genes expressed in the TMJ, and IL-1B ϩ3953 (ϩ3954) SNP rs1143634 as a part of some genetic syndromes.146 Although rela- FIGURE 5-7 Percentage of orthodontic patients with 2 mm or tionships between genetic variants and disease can be more of external apical root resorption (EARR) by IL-1B +3953 investigated using family aggregation studies where clus- (previously designated as +3954) SNP rs1143634 genotype combin- ters of disease within genetically related family members ing the data from Table 5-1.140,141 are analyzed, to date, family-aggregation studies have failed to identify a genetic inﬂuence on TMD.147 These types of studies may have been “underpow- Note that in keeping with EARR concurrent with ered,” meaning that they did not have a sufﬁcient number orthodontic treatment being a multifactorial/complex of subjects to be effective in this type of analysis. Interest- trait, although this genetic marker is associated with the ingly in 2003, Zubietta et al.148 reported that a common trait occurring most of the time, there are patients who variant of the gene that codes for the enzyme catechol- have the DNA marker that usually accompanies EARR O-methyl-transferase (COMT) was associated in humans who do not have EARR and there are some patients with with diminished activity of pain regulatory mechanisms EARR who do not have the marker, so the “predictive” in the central nervous system. Instead of genetic family- value of this single marker is limited by itself, without aggregation (twin) studies, Slade et al.147 pursued genetic information about other DNA (gene) markers and other association studies, using traditional epidemiologic study variables that may be involved. designs in which risk of disease was contrasted among Interestingly, Iwasaki et al.142 found individual differ- subgroups (TMD affected versus unaffected) based on ences in a ratio of IL-1β to IL-1RA (receptor antagonist) common allelic (DNA) variants (markers). cytokines in crevicular ﬂuid that correlated with indi- Their 3-year prospective study of 202 healthy women vidual differences in canine retraction using identical (18 to 34 years old) who did not have TMD when exam- force. Although the relation to genetic markers was not ined at baseline (none of whom were in orthodontic undertaken, this study indicates a variable individual treatment at the time, although 99 had a history
152 CHAPTER 5 Genetics and Orthodonticsof orthodontic treatment) found that TMD onset was The main use of this human SNP map will be to deter-2.3-fold greater for subjects who had only high pain mine the contributions of genes to diseases (or nondis-sensitivity (HPS) and/or average pain sensitivity (APS) ease phenotypes) that have a complex, multifactorialhaplotypes based on COMT genetic variation, compared basis. Likewise, the development of the Mouse Genomewith subjects who had one or two low pain sensitivity Project will increase the number of known DNA markers(LPS) haplotypes. that may be used in the study of putative relevant genetic What about the women who had a history of orth- factors and genetic–environmental interactions, whichodontic treatment? Of 174 available for analysis, there then may be tested for in the human population. Althoughwere 15 (8.6%) new cases of TMD. The risk of TMD the scale of such studies could be daunting and there arewas 3-fold greater among subjects who reported a history still problems to solve, their potential for studying howof orthodontic treatment compared with those who did natural variation leads to each one of our qualities isnot, although the associated relative risk was not statisti- signiﬁcant. They may be the best opportunity yet tocally signiﬁcant (95% conﬁdence interval, 0.89–10.35). understand the roles of nature and nurture (includingHowever, although in the subjects who had COMT pain- treatment), rather than nature versus nurture, inresistant haplotypes, there was no difference in having a development.72,149history of orthodontics; in the subjects with pain-sensitive Heritability estimates can indicate how much of thehaplotypes, there were signiﬁcantly (p = .04) more indi- phenotypic variation is associated with genetic variation,viduals with a history of orthodontia who developed a consideration in the feasibility of a search for identify-TMD than there were those who developed TMD and ing the genetic factors. The search for DNA markershad no history of orthodontia.147 linked with certain phenotypes may indicate areas of the It was noted that statistically signiﬁcant elevation in genome that have a gene or genes that inﬂuence therisk is not sufﬁcient evidence that an attribute (in this phenotype. The DNA marker does not necessarily deﬁnecase, orthodontic treatment) is causal, although it does precisely what gene in the area is contributing or whatbring up the question of whether patients with pain- allele of that gene may be more inﬂuential than others.sensitive haplotypes experience relatively greater discom- Nonetheless, the search for markers linked with certainfort or pain when undergoing procedures used during phenotypes can indicate areas of the genome that containﬁxed orthodontic treatment. It should also be noted that inﬂuential genes that previously were not known or evenin this study the experience of orthodontic treatment was suspected to have an inﬂuence on the phenotype. Onceassessed merely by asking subjects a single question, a particular gene (or genes) in an area of the genome isand there was no attempt to clarify whether ﬁxed orth- identiﬁed, it becomes a candidate gene for speciﬁc analy-odontic treatment, duration of the treatment, or other sis of its structure to pinpoint the relevant allele(s).treatment such as surgery was involved. The study of the effect of particular genetic factors on Any etiologic role of orthodontic treatment in this development also may be done using a candidate genestudy would require that the putative causal effect of chosen because of its function, or the function of anorthodontic treatment was one that persisted after com- associated protein, instead of using DNA markers to seepletion of treatment yet did not cause the person to what genes may be linked with a phenotype. This wasdevelop TMD at the time of recruitment. This raises the the approach in a study of the association of the Pro-possibility that there was yet another environmental 561Thr (P56IT) variant in the growth hormone receptorinteraction that occurred in the time between completion gene (GHR), which is considered to be an importantof orthodontic treatment and enrollment in the study. factor in craniofacial and skeletal growth. Of a normalStill, it is an intriguing outcome, and one that needs to Japanese sample of 50 men and 50 women, those whobe further investigated. did not have the GHR P56IT allele had a signiﬁcantly greater mandibular ramus length (condylion-gonion) than did those with the GHR P56IT allele. The averageHUMAN GENOME PROJECT mandibular ramus height in those with the GHR P56ITAND BEYOND allele was 4.65 mm shorter than the average for thoseThe Human Genome Project resulted in not only a single without the GHR P56IT allele. This signiﬁcant correla-human genome sequence composed of overlapping parts tion between the GHR P56IT allele and shorter man-from many human beings but also a catalog of some 1.4 dibular ramus height was conﬁrmed in an additional 80million sites of variation in the human genome sequence. women.150This increased number of variations (or polymorphisms) Interestingly, the association was with the mandibularmay be used as markers to perform genetic (including ramus height but not mandibular body length, maxillarygenetic–environment interaction) analysis in an outbred length, or anterior cranial base length. This suggests apopulation such as human beings. The human genome site-, area-, or region-speciﬁc effect. The study concludedvaries from one individual to the next most often in that the GHR P56IT allele may be associated with man-terms of single-base changes of the DNA, called single dibular height growth and can be a genetic marker fornucleotide polymorphisms (SNPs, pronounced “snips”). it. Still, whether the effect is directly on the mandible or
CHAPTER 5 Genetics and Orthodontics 153some other nearby tissue or on another matrix is not although there may be considerable overlap. The capac-clear. To see what effect different diets would have on ity of an individual to respond to a change in environ-individuals with and without the GHR P56IT allele ment inﬂuenced by genetic factors is of more importancewould be interesting as a means of looking at genetic clinically than the relative inﬂuence genetic variation hasand environmental factor interaction. Undoubtedly on phenotypic variation before treatment. In the future,many other genes that may inﬂuence craniofacial struc- orthodontists’ ability to treat patients better will dependture, including ramus height, could be identiﬁed, and on investigations into how environmental factors affecttheir variation could be studied along with different gene expression that inﬂuences malocclusion. 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