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E-Mail karger@karger.com
Pittsburgh, PA 15261 (USA)
www.karger.com/cre
E-Mail jrs51@pitt.edu
Introduction While it is currently unknown whether gene-by-sex
interactions are important for dental caries, recent find-
Dental caries is the process of enamel or dentin demin- ings from genetic studies have suggested that this may be
eralization caused by acid produced by cariogenic oral the case. Sex chromosomes have been historically regard-
bacteria. This process is opposed by the natural function ed as important for sexual dimorphism [Mank, 2009],
of saliva to remineralize dental tissue by supplying calci- and in a family based study, Vieira et al. identified a locus
um and phosphate ions that incorporate into the crystal- on the X-chromosome showing suggestive linkage to
line structure of tooth enamel [Lukacs and Largaespada, dental caries (p = 5E-5) [Vieira et al., 2008]. Similarly, a
2006; ten Cate et al., 2008]. Caries progression occurs as recent genome-wide association scan (GWAS) of dental
a result of an imbalance in the processes of demineraliza- caries by Zeng et al. implicated two highly homologous
tion and re-mineralization, eventually leading to cavita- genes on opposite arms of the X-chromosome, BCOR
tions [Featherstone, 2008]. Many factors can affect the (p= 4E-7) and BCORL1 (p = 5E-6) [Zeng et al., 2013]. The
processes of demineralization and remineralization in- same genetic variant in BCORL1 was also reported in a
cluding bacterial flora, dietary and oral hygiene behav- GWAS of novel caries phenotypes in the same sample
iors, saliva composition, flow rate, and pH buffering ca- (p = 3E-6) [Shaffer et al., 2013a]. Mutations in BCOR
pacity, positional and morphological features of the teeth, cause oculofaciocardiodental (OFCD) syndrome, a disor-
fluoride exposures, and socioeconomic factors including der presenting craniofacial and dental anomalies includ-
access to oral health care [Martinez-Mier and Zandona, ing cleft palate, radiculomegaly, delayed dentition, oligo-
2013]. Host genetics may influence many of these factors dontia, persistent primary teeth, and defective tooth
leading to inter-individual variation in susceptibility to enamel [Gorlin et al., 1996; Ng et al., 2004]. BCORL1
caries. Indeed, previous studies have shown that dental shows high sequence similarity to BCOR, although its
caries is highly heritable, with 2065% of variation attrib- function is unknown. Additionally, notable candidate
utable to genetics [Boraas et al., 1988; Bretz et al., 2005a; genes reside on the X-chromosome, such as AMELX,
Bretz et al., 2006; Bretz et al., 2005b; Shaffer et al., 2012a; which codes amelogenin, the major protein component
Shaffer et al., 2012b; Shaffer et al., 2013b; Shaffer et al., of the enamel matrix. Other genes on the X-chromosome,
2012c; Shuler, 2001; Wang et al., 2010]. The current con- such as MST4 and FGF13, may also influence susceptibil-
sensus is that the genetics of dental caries may be truly ity to dental caries [Kuchler et al., 2014]. While X-inacti-
complex, affected not only by many genetic variants, but vation in females is traditionally thought to balance the
also by important interactions between genetic and non- gene dosage between diploid females and haploid males
genetic factors that may change over the life course. for genes on the X-chromosome, recent studies have
In conjunction with the environmental and genetic shown that 15% of genes on the X-chromosome escape
risk factors listed above, sex also affects susceptibility to inactivation to some degree, and another 10% show vary-
caries, with epidemiological surveys usually showing fe- ing patterns of inactivation [Carrel and Willard, 2005].
males at higher risk and having greater numbers of af- Thus, X-linked genes may be involved in gene-by-sex in-
fected tooth surfaces compared to males [Lukacs and Lar- teractions via dosage effects.
gaespada, 2006; Martinez-Mier and Zandona, 2013]. The While some genes related to sex differences, such as
causes of sex differences in dental caries experience are dental caries experience, may reside on the X-chromo-
not fully understood, although possible explanations in- some, the majority of gene-by-sex interactions likely in-
clude earlier tooth eruption (and thus longer exposure to volve autosomal loci [Wijchers et al., 2010]. Differential
cariogenic processes) in females, as well as sex differences patterns of autosomal gene expression for males and fe-
in dietary and oral hygiene behaviors, utilization of oral males may occur for a number of reasons, including the
health care, hormones/physiology, and characteristics of response to estrogen or other sex hormones. Though
saliva [Lukacs and Largaespada, 2006; Martinez-Mier others have speculated a possible role for gene-by-sex in-
and Zandona, 2013]. The differential actions of genes in teractions on dental caries [Ferraro and Vieira, 2010;
men and women have also been proposed [Ferraro and Vieira et al., 2008], no direct evidence for gene-by-sex
Vieira, 2010; Vieira et al., 2008]. Genetic variants related interactions has yet been reported. In the present study
to tooth eruption, dietary preferences, physiology, saliva, we have used a family based approach to explore this
or other unknown caries risk factors may have different question. Specifically, we have extended our previously
effects in men versus women; such genetic effects are published models of dental caries heritability [Shaffer et
called gene-by-sex interactions. al., 2012c; Wang et al., 2010] to include the contribution
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Heritability (h2)
0.6
0.5
0.4
0.3
0.2
Fig. 1. Heritability estimates in males and 0.1
females, combined and separately, for den- 0
tal caries indices in the primary (dfs) and dfs PF dfs SM dfs DMFS PF DMFS SM DMFS
permanent (DMFS) dentitions, and in pit
Primary Permanent
and fissure (PF) and smooth (SM) tooth
surfaces.
reported by [Wang et al., 2010] and [Shaffer et al., 2012c] by fur- Table 2. Demographic characteristics and summary statistics of
ther partitioning the genetic variance, G2 , into separate sex-specif- dental caries phenotypes
ic genetic variances, GM2 and 2 , and by including a new param-
GF
eter, the male-female genetic correlation, G, to describe the cova- Summary statistics
riance between opposite-sex relative pairs. Models were adjusted
for sex and age. See Appendix for model details. Sample size 2,663
The extended model allowed us to calculate sex-specific herita- Number of kinships 740
bilities (i.e., the proportion of phenotypic variance due to genetics Size of kinships, mean (range) 4.72 (120)
in males and females) simultaneously. Moreover, the extended Self-reported whites, % 89.64
model provided a framework for testing two lines of evidence for Females, % 55.61
gene-by-sex interactions: (1) whether the magnitude of the genet- Age in years, mean SD (range) 19.8315.29 (193)
ic variance differs between males and females (i.e., test GM2 2 ),
GF Primary dentition (n = 1,058)
and (2) whether the malefemale genetic correlation differs from dfs, mean SD (range) 3.937.32 (053)
100% (i.e., test G 1.0). A significant difference in the magnitude PF dfs, mean SD (range) 1.853.09 (016)
of the sex-specific genetic variances indicates that genes cumula- SM dfs, mean SD (range) 2.244.82 (037)
tively have a larger role in caries experience in one sex compared Permanent dentition (n = 1,937)
to the other. A value for genetic correlation that is significantly less DMFS, mean SD (range) 14.3418.76 (0122)
than 1.0 roughly indicates that different genes may be important PF DMFS, mean SD (range) 6.336.24 (024)
for males than for females, and vice versa. Both of these statistical SM DMFS, mean SD (range) 8.1813.82 (098)
tests can provide evidence for the role of gene-by-sex interactions.
Trait 2
GM 2
GF G p values
2 = 2
GM GF G = 1.0
six caries phenotypes, males showed greater heritability ly different between males and females (p > 0.05 for all).
than females and greater than both sexes combined. For However, for DMFS and SM DMFS indices, the estimates
primary dentition phenotypes, the combined heritability of genetic correlation were both significantly less than 1.0
estimates were partway between those of the sexes, where- (p = 0.004 and 0.038, respectively), and for the PF DMFS
as for the permanent dentition phenotypes, the combined index, the estimate of genetic correlation showed a simi-
heritabilities were lower than for either of the sexes. Note lar trend (i.e., G = 0.50), although it was not quite statis-
that heritability is defined as the proportion of phenotype tically significant (p = 0.09). These results suggest that the
variability attributable to genetic causes. In other words, magnitudes of the genetic effects are similar between
these values are ratios, and therefore dependent not only males and females, but that different genes or suites of
on the magnitude of the genetic contribution, but also on genes may be involved in the different sexes. These results
the magnitude of the total phenotype variance (which are also consistent with the observation that the sex-spe-
also includes the environmental contribution). Thus, cific heritability estimates are both greater than the com-
strictly speaking, heritability estimates cannot be directly bined heritability estimate (fig.1); the combined estimate
compared between the sexes to test for gene-by-sex inter- reflects only the subset of genes contributing to caries ex-
actions. perience in both sexes, and is expected to be compara-
However, both sex-specific genetic variances and tively lower if different genes are involved.
malefemale genetic correlations can be used to test for
gene-by-sex interactions. Table3 shows the estimates of
these parameters. For caries phenotypes in the primary Discussion
dentition, genetic variances were significantly greater in
males than in females (p = 0.002 to 0.028), but the genet- In this study we presented the first direct evidence that
ic correlations were not different than 1.0 (p > 0.05 for gene-by-sex interactions may contribute to dental caries
all). The greater genetic variance in males suggests that in experience. We observed that in the primary dentition,
the primary dentition the magnitude of the genetic effect the size of the role that genes play differed between males
(i.e., the cumulative role of genes on caries susceptibility) and females, whereas in the permanent dentition, differ-
differs between the sexes. However, the fact that genetic ent sets of genes may be involved. For both sexes, and
correlations were not different than 1.0 suggests that the across both dentitions, dental caries experience was
same set of genes may be involved in both sexes. This is moderately to highly heritable. Altogether, these results
consistent with the sex-specific and combined heritabil- suggest that gene-by-sex interactions may be partly re-
ity estimates (fig.1). For caries phenotypes in the perma- sponsible for the observed sexual dimorphism in caries
nent dentition, the genetic variances were not significant- experience. Furthermore, these results suggest that fu-
125.161.70.201 - 6/2/2017 6:15:29 PM
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