Jan Lindhe. Clinical Periodontology

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PERIODONTITIS AS A RISK FOR SYSTEMIC DISEASE • 383

the "Periodontal Intervention and Vascular Events"

(

PAVE) pilot trial. This proposed multicenter study

hopes to ultimately design and conduct a large clinical

trial of periodontal therapy in patients at risk for

cardiovascular events.

Dentistry has come a long way since 1900 when

Willoughby Miller and William Hunter proclaimed

that

oral disease caused most systemic disease. A hun-

dred years later we are developing a scientifically-

based understanding of how in fact periodontitis may

be a risk for certain systemic diseases. As these more

recent observations are confirmed and clarified, den-

tistry will have a new responsibility in caring for

patients who may develop or who have periodontitis.

It is no longer just teeth that are at risk.

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CHAPTER 17

Genetics in Relation to

Periodontitis

BRUNo G. Loos AND UBELE VAN DER VELDEN

Introduction and definitions

Evidence for the role of genetics in

periodontitis

Human genes and polymorphisms

Genetics in relation to disease in general

A major disease gene associated with

periodontitis

Modifying disease genes in relation to

periodontitis

Cytokine gene polymorphisms FcyR

gene polymorphisms Conclusions and

future developments

INTRODUCTION AND

DEFINITIONS

Periodontitis is a multifactorial disease for which sev-

eral risk and susceptibility factors are proposed in the

naturalhistory of periodontitis (Page et al. 1997). Arisk

factor

for periodontitis is a factor (environmental, be-

havioral or biologic) confirmed by temporal sequence,

usually in longitudinal studies. The presence of a risk

factor directly increases the probability of a disease

occurring, and the absence of a risk factor reduces this

possibility (Norderyd 1998). Risk factors are part of

the causal chain, or expose the host to the causal chain.

Risk factors are by definition modifiable. Good exam-

ples of risk factors in relation to periodontitis are

plaque and smoking. In cross-sectional or case-control

studies

a risk indicator

may be observed, therefore

when such a factor is not (yet) identified in longitudi-

nal studies, the term

putative

risk factor is used.

In contrast to modifiable risk factors, non-modifi-

able determinants or background factors, like age,

gender and genotype (genetic make-up) are recog-

nized as

susceptibility factors. Putative

susceptibility

factors are determinants, only confirmed in cross-sec

tional or case-control studies.

In this chapter the terms

severity factor

and

putative

severity factor

will also be used. These terms are em-

ployed when factors are studied in patients only, and

no control subjects without periodontitis are included

in these investigations. For example, if a given geno-

type is more frequently observed in patients with

severe periodontitis than in patients with the moder-

ate form of the disease (cross-sectional study), one can

regard that genotype as a putative severity factor. If a

putative severity factor is confirmed in a longitudinal

patient population study, it becomes a severity factor.

Such a severity factor may or may not turn out to be a

susceptibility factor as well.

The area of research related to the role of genetic

factors in periodontitis frequently uses specific patient

populations. During the years, however, the nomen-

clature of the diagnosis of the various forms of perio-

dontitis has changed. In this chapter the diagnosis of

the form of periodontitis as mentioned in the original

research papers is used as much as possible. These

include early onset periodontitis (currently aggressive

periodontitis) subdivided into prepubertal periodon-

titis, juvenile periodontitis and rapidly progressive

periodontitis. The latter diagnosis is frequently a

synonym for post juvenile periodontitis and general-

ized juvenile periodontitis. Adult periodontitis is cur-

rently referred to as chronic periodontitis.

The definitions above are important in studies of

the etiology and pathogenesis of periodontitis, of

which genetics forms an important aspect.

388 • CHAPTER 17

EVIDENCE FOR THE ROLE OF

GENETICS IN PERIODONTITIS

Heritability of aggressive periodontitis (early

onset periodontitis)

It was recognized a long time ago that frequently

siblings of patients with juvenile periodontitis (JP)

also

suffer from periodontitis. This was mainly based

case reports of one or a few families ascertained on

the

basis of one subject (the proband) with JP In an

American study on

siblings of 39 probands with

localized (L) or generalized (G) JP, it was shown that

almost 50% of the siblings also suffered from JP

(

Boughman et al. 1992). In 11 families a co-occurrence

of LIP and GJP was present. As an epidemiological

survey in the US showed that the prevalence of JP

varies between 0.16 and 2.49% (Loe & Brown 1991),

the high prevalence of JP in these families suggests a

genetic background for the disease. The largest JP

family study included 227 probands with aggressive

periodontitis (Marazita et al. 1994). There were 26 GJP

individuals whose earlier records were consistent

with

LIP, i.e. demonstrating progression from the lo

calized

to a more generalized form.

Furthermore, there were 16 families with co-occur

rence of HP and GJP, confirming the findings of

Boughman et al. (1992). Out of the 227 probands, 104

had at least one first-degree relative clinically exam-

ined. Now it was possible to carry out a segregation

analysis on 100 families (four families each had two

probands). Segregation analysis is a formal method of

studying families with a disease to assess the likeli-

hood that the condition is inherited as a genetic trait.

The family members included 527 subjects: 60 with

LIP, 72 with GJP, 254 unaffected subjects and 141 sub

jects with an unknown periodontal condition. The

group of unaffected subjects included edentulous sub

jects, subjects with adult periodontitis and periodon-

tally healthy subjects. The majority of the families

were of African-American origin. The authors con-

cluded that the most likely mode of inheritance was

autosomal dominant in both African-American and

Caucasian kindreds, with 70% penetrance in African

Americans and 73% in Caucasians.

Heritability of chronic periodontitis (adult

periodontitis)

Very few investigations exist with regard to family

studies of probands with chronic (adult) periodontitis

younger subjects with minor periodontitis. Van der

Velden et al. (1993) studied the effect of sibling rela-

tionship on the periodontal condition in a group of

young Indonesians deprived of regular dental care.

The study population included 23 family units con-

sisting of three or more siblings. In all, 78 subjects aged

15-25 years were studied. The mean interproximal

amount of loss of attachment in this population was

0.29 mm. The individual mean ranged from 0 to 1.27

mm. In 33% of the subjects, 1 sites with a probing

depth of 5 mm or more in conjunction with 2 mm loss

of attachment were present. The results of the analysis

showed a significant siblingship effect for plaque,

calculus, loss of attachment, spirochetes on the tongue

and in the pocket,

gingivalis

on the gingiva and in

the saliva and

interim'dia

in the saliva. However, the

microbiological parameters which showed a signifi-

cant siblingship effect were not significantly corre-

lated with attachment loss (Van der Velden et al. 1993).

These findings suggest that also in less severe forms

of periodontitis there may be a genetic background for

the disease.

In order to study familial aspects of chronic (adult)

periodontitis in a Dutch population, 24 families were

selected at the Academic Center for Dentistry Amster

dam (Petit et al. 1994), each consisting of a proband

with chronic (adult) periodontitis, a spouse and 1-3

children. The mean age of the probands was 39 years,

with a range from 30 to 50 years. In total, 49 children

were investigated with an age range of 3 months to 15

years. The results showed that none of the children

under the age of 5 years was affected by periodontitis,

whereas in the group of 5-15 years, 21% had at least

one pocket 5 mm in conjunction with loss of attach-

ment. In the group of 10-15 years this was 45%. In

contrast, in an epidemiological study carried out in the

city of Amsterdam, it was shown that the prevalence

of pockets 5 mm in conjunction with loss of attach-

ment in 15-year-old adolescents is about 5% (Van der

Velden et al. 1989). Therefore, collectively, these results

suggest that periodontitis also aggregates in families.

The twin model

The twin model is probably the most powerful

method by which to study genetic aspects of peri-

odontal diseases. Monozygous (MZ) twins arise from

a single fertilized ovum and are therefore genetically

identical and of the same sex. Dizygous (DZ) twins

arise from the fertilization of two separate ova and

share, on average, one half of their descendent genes

in the same way as siblings do. In twin studies the

terms concordance and disconcordance are often

used. This means the degree of similarity or dissimi-

larity between twins in respect of one or more particu

lar characteristics. Any discordance in disease be-

tween MZ twins must be due to environmental fac-

tors. Any discordance between DZ twins could arise

from environmental and/or genetic variance. For a

condition that is predominantly environmental in ori

gin, the concordance rates of MZ and DZ twins would

be expected to be similar. However, if a disease has a

genetic background, concordance rates would be

greater in MZ twins compared to DZ twins. Even more

powerful is the addition of monozygous twins who

GENETICS IN RELATION TO PERIODONTITIS • 389

Fig. 17-1. Schematic drawing of 23 pairs of chromosomes (the diploid human genome). 22 pairs of autosomal chro

mosomes and 1 pair of sex chromosomes are present. In this case the genome of a male is shown (one X and one Y

chromosome). In the case of a female, two X chromosomes would have been present. G-banding generates a charac

teristic lateral series of bands in each member of the chromosome set. Adapted from Hart et al. (2000a).

were separated at birth and reared apart (MZA), since

in that case the effects of shared genes can be examined

without the confounding effects of a common family

environment.

The largest twin study included 4908 twin pairs of

which, on the basis of questionnaire data, 349 (116 MZ

and 233 DZ) pairs reported a history of periodontal

disease in one or both pair members (Corey et al.

1993). The mean age of the MZ twins was 33 years and

of the DZ twins 35 years. The concordance rates

ranged from 0.23 to 0.38 for MZ twins and 0.08 to 0.16

for DZ twins. Michalowicz and co-workers evaluated

the periodontal condition (attachment loss, pocket

depth, gingival index and plaque index) of 110 adult

twins with a mean age of 40 years ranging from 16 to

70 years (Michalowicz et al. 1991). This study included

63 MZ twin pairs reared together, 33 like-sexed DZ

twin pairs reared together and 14 MZA twin pairs.

Their results showed that the correlations of reared

together MZ twins are consistently greater than those

of DZ twins. Heritability estimates from the MZA

twins were 0.38 for attachment loss, 0.46 for plaque,

0.69 for pocket depth and 0.82 for the gingival index.

These values were, for the twins reared together, 0.48,

0.38, 0.51 and 0.40 respectively. These results indicate

that between 38 and 82% of the population variance

for these measures may be attributed to genetic fac-

tors. In a recent study on 117 adult pair twins (Micha

lowicz et al. 2000), the analysis included the evalu-

ation of the environmental factors like smoking and

utilization of dental services. The study included 64

MZ twin pairs (mean age 41 years) and 53 DZ pair

twins (mean age 42 years). The results showed that

chronic (adult) periodontitis was estimated to have

approximately 50% heritability, which was unaltered

following adjustments for behavioral variables in-

cluding smoking. In contrast, while MZ twins were

also more similar than DZ twins for gingivitis scores,

there was no evidence of heritability for gingivitis

after

behavioral covariates such as utilization of den

tal

care and smoking were incorporated in the analy

sis.

Another study on 169 adult twins with early peri-

odontitis (Michalowicz et al. 1999) looked at whether

host genetic factors influence the presence of A.

acti-

nomycetemcomitans, P. gingivalis, P. intermedia, E nuclea-

tum

and

corrodens.

The study included 21 MZ twins

and 17 DZ twins reared apart as well as 83 MZ twins

and 48 DZ twins reared together. The MZ twins

ranged in age from 16 to 80 years with a mean of 44

years, the DZ twins ranged in age from 22 to 67 years

with a mean of 48 years. The subject-based preva-

lences of the bacteria in the twin groups were: P.

gingivalis

11%, A.

actinomycetemcomitans

22%, P.

inter-

390 • CHAPTER

Fig. 17-2. Schematic representation of a gene. The gene consists of a promoter and a coding region. Within the cod

ing region, intermittent areas of non-coding DNA exist (intron). Exons contain triplets of nucleotides (codons) that

code for a specific amino acid. The number and length of exons and introns within the coding region is variable per

gene.

media

19%,

E. corroders

0.34% and F.

nucleatum

40%.

Interestingly, for all species examined the concordance

rates were not significantly different between MZ and

DZ twin groups. These findings were apparent de-

spite

similar smoking histories, self-reported oral hygiene

practices and antibiotic use. Furthermore, MZ

twins

reared together were no more similar than MZ

reared

apart twins with respect to any bacterial species

examined.

Therefore it can be concluded that the basis for

familial aggregation of periodontitis appears not bac-

terial/environmental/behavioural in nature; rather,

genetics seem to form the basis for the familial aggre-

gation of periodontitis.

HUMAN GENES AND

POLYMORPHISMS

Each normal human being has 23 pairs of

chromosomes

(the

diploid

human genome), 22 pairs of

autosomal

chromosomes and 1 pair of

sex

chromosomes (XX for

females and XY for males) (Fig. 17-1). From each pair,

one chromosome is inherited from the father and one

from the mother. Chromosomes show differences in

size and have characteristic lateral series of bands

(G-

banding); therefore each chromosome can be iden

tified

by its characteristic size and banding pattern.

Each

chromosome contains a single, very long

duplex

deoxyribonucleic acid (DNA). DNA consists of

chemically linked sequences of

nucleotides;

these are

the "building blocks" of the DNA and always contain

nitrogenous base. Four nitrogenous bases exist: ade-

nine (A), guanine (G), cytosine (C) and thymine (T).

The

bases are linked to a sugar (2-deoxyribose), where

phosphate group is also added. The

haploid

human

genome (i.e. one copy of 22 autosomal chromosomes

and one sex chromosome) consists of 3.3 x 10

nucleo-

tides (also written as 3.3 x 10

base pairs (bp)).

In the chromosomes, DNA is arranged in a double

helix model: two polynucleotide chains in the duplex

are associated together by hydrogen bonding between

the nitrogenous bases. These reactions are described

base pairing

and they are complementary: G pairs

only with C, and A pairs only with T. Therefore, if one

chain of DNA is sequenced, the complementary chain

of the duplex can be deduced.

DNA contains the genetic code and a given specific

sequence of nucleotides encodes for the sequence of

amino acids that constitutes the corresponding pro-

tein (Fig. 17-2). The genetic code is read in groups of

three nucleotides; each trinucleotide sequence (triplet)

is called

a codon.

Written in the conventional direction

from left to right, the nucleotide sequence of the DNA

strand that codes for a protein has a starting point and

an end point. In this way on the DNA strand, a gene

can be deciphered. A gene consists of two parts (Fig.

17-2): (1)

a coding region,

i.e. a reading frame starting

nucleotide position +1, containing a multitude of

triplets that codes for a sequence of amino acids to

form a protein; and

(2) a promoter

region, i.e. a se-

quence of nucleotides upstream (left) of the coding

region starting with nucleotide position -1 read from

right to left, that is not organized in a series of triplets

but contains stretches of nucleotides that are essential

for the regulation of the

transcription

of the coding

region. Within the coding region intermittent areas of

non-coding DNA exist; these regions are called

introns.

The true coding areas within the coding region are

called

exons

(Fig. 17-2). From the recent results of the

human genome project, it is estimated that about

000–40 000 human genes exist.

Variant forms of a gene that can occupy a specific

chromosal site

(locus)

are called

alleles.

For example,

hemoglobin is a complex molecule consisting of two

u,-

type and two R-type chains. The gene for the R chain

may have in some instances a mutation, causing sickle

cell anemia. In this case, the

rare

sickle allele, respon

sible for sickle cell anemia, is a variant of the

normal p

allele for the

gene. Two or more alleles for a given

locus may exist in nature throughout evolution, but

may develop any time.

A polymorphic

locus

one

whose alleles are such that the most common,

normal

variant (N-allele) among them occurs with < 99

frequency in the population. Thus, if a locus is for

example

bi-allelic,

the rarer allele (designated R-allele)

must occur with a frequency > 1% in the population.

This way, when different alleles of a given gene co-ex-

ist in the human population, we speak about

genetic

polymorphisms.

Polymorphisms arise as a result of mutation. All

organisms suffer from certain numbers of spontane-

GENETICS IN RELATION TO PERIODONTITIS •

391

ous mutations as the result of normal cellular opera-

tion or random interactions with the environment. An

alteration that changes only a single base pair is called

a point mutation. Not all such mutations are repaired

and they can therefore be inherited and transmitted

for generations. The most common class of point mu-

tations is the

transition,

comprising the substitution of

one nucleotide with another. The variation at the site

harboring such changes has recently been termed a

single nucleotide polymorphism" (SNP) (Schork et

al.

2000).

The SNP may have no effects or may have some

important biological effects. For example, if a transi-

tion has taken place within the coding region of a gene,

it may result in an amino acid substitution and there

fore an altered protein, perhaps with an altered func-

tion. Or, when such mutations have taken place in the

promoter region of the gene, it may or may not result

in altered gene regulation. The altered regulation due

to the mutation in the promoter region may give rise

to reduced or inhibited gene expression or, alterna-

tively, result in overexpression of the gene, perhaps

with biological consequences. SNPs occur the most

over any other type of polymorphism; the frequency

SNPs across the human genome is estimated at

every

0.3-1 kilobases (Kb) (Schork et al. 2000).

Other types of genetic polymorphisms result from

insertions

deletions

(Schork et al. 2000). The simple

form of this polymorphism is where a single nucleo-

tide pair may be deleted or may be inserted with the

same potential effects as described above for the tran

sition. The most common type of insertion/ deletion

polymorphism is the existence of variable numbers of

repeated bases or nucleotide patterns in a genetic

region. Repeated base patterns can consist of several

hundreds of basepairs, known as a variable number

of tandem repeats (VNTRs or

mini-satellites).

Also very

common are

micro-satellites,

which consist of two,

three or four nucleotides repeats, a variable number

of times; micro-satellites are also referred to as

simple

tandem repeats

(STRs). Such repeats are considered

highly polymorphic and often result in many alleles

or gene variants due to the existence of many different

repeat sizes within the population. The STRs may

occur every 3-10 Kb genome wide (Schork et al. 2000).

Genetic polymorphisms are highly useful in popu-

lation genetic studies. After genotyping of individuals

and assessing genotype frequencies among groups of

interest, one can also calculate the frequency of the

N-allele and the R-allele among the groups or popu-

lations under study. Each of the alleles and each of the

resulting genotypes have a particular frequency in the

population. It is important to realize that populations

with different genotype frequencies may have compa-

rable or equal allele frequencies. Furthermore, fre-

quencies of genotypes and alleles may differ between

a diseased group and a healthy group. Subsequently,

when a given allele is identified to be associated with

disease (as susceptibility and/or as severity factor),

functional studies can be started to investigate the

possible role of that gene in the etiology and patho-

genesis of the disease.

GENETICS IN RELATION TO

DISEASE IN GENERAL

Most human diseases have a complex pathogenesis.

For example, it is widely known that for heart dis-

eases, hypertension, cancer and Alzheimer's disease,

interactions between genetic and environmental fac-

tors determine disease expression. The genes that are

identified to be involved in complex multifactorial

diseases are called

modifying disease genes

(Hart

1996,

Hart et al. 2000b). They contrast with

major disease

392 • CHAPTER

genes,

which, when a given aberrant allelic form is

present, are responsible for disease expression accord

ing to Mendel's laws (Hart 1996, Hart et al. 2000b), for

example, the fatal inherited disease cystic fibrosis.

This disease is caused by a recessive mutation in the

cystic fibrosis transmembrane conductance regulator

(CFTR) gene. This gene encodes for a protein that

functions as a plasma membrane chloride channel in

epithelial tissues, in particular in lung epithelium. If a

person is

homozygous

for the rare disease allele (R-al-

lele), then he/she will develop cystic fibrosis. On the

other hand, individuals will not develop the disease

if they are homozygous for the normal (N) allele or

when they are

heterozygous,

i.e. they have both the

dominant

N-allele and the

recessive

R-allele.

To date, genetic studies in relation to periodontitis

have revealed only one major disease gene (see the

next section) that follows the principles of Mendel.

Most forms of periodontitis are likely to be associated

with multiple modifying genes, i.e. the disease is said

to be

polygenic.

Analogous to other complex diseases,

it is estimated that for periodontitis between 10 and 20

genes may be involved. However, it is important to

realize that the number and type of modifying disease

genes for the same disease may not be equal for dif-

ferent ethnic populations and may also be influenced

by environmental factors.

A MAJOR DISEASE GENE

ASSOCIATED WITH

PERIODONTITIS

Through an internal marriage event in a family of

Jordanian descent, Hart and co-workers have identi

fied and localized a gene on chromosome 11 that is

responsible for a severe form of prepubertal periodon

titis (Hart et al. 2000a). Starting with four affected

children from generation IV of two families, a disease

causing R-allele of the cathepsin C (CTS C) gene was

discovered (Fig. 17-3). Cathepsin C is a proteinase

which is found in neutrophils and lymphocytes as

well as epithelial cells. Affected children, but not their

brothers and sisters, were homozygous for an A to G

transition polymorphism at gene position +1040. This

resulted in a substitution of the amino acid tyrosine

by a cysteine. This polymorphism was shown to be

functional as there was a decreased cathepsin C activ

ity (Hart et al. 2000a).

Interestingly, other mutations in the CTS C gene

have been identified and have been linked to the

Papillon-Lefevre syndrome, a disease which is also

associated with a severe form of prepubertal perio-

dontitis (Hart et al. 1999, Toomes et al. 1999). There

fore, certain functional CTS C gene mutations need to

be considered causative for prepubertal periodontitis

and Papillon-Lefevre syndrome. However, the mecha

nism by which an altered function of cathepsin C

plays a role in the pathogenesis of the prepubertal

form of periodontitis is unknown.

MODIFYING DISEASE GENES IN

RELATION TO PERIODONTITIS

Periodontitis develops in a limited subset of humans

(

Chapter 2). About 10-15% of the population will de-

velop severe forms of destructive periodontal disease.

The disease is importantly influenced by the microor

ganisms in the subgingival lesion, by acquired sys-

temic diseases that reduce or hamper optimal host

resistance, and by environmental factors. Plaque and

smoking are such well-accepted risk factors. In addi

tion, modifying disease genes contribute to suscepti-

bility and severity of periodontitis. For these modify-

ing disease genes Mendelian principles do not apply

(Hart 1996, Hart et al. 2000b), because it is thought that

both carriers (heterozygotes) as well as homozygous

subjects for a given modifying disease gene, may not

necessary develop the disease if no other risk factors

are simultaneously present.

Currently very little is known about which genes

may be involved in periodontitis as modifying disease

genes. However, as the immune system is thought to

play a crucial role in the pathogenesis of periodontitis,

researchers have concentrated on the identification of

genetic polymorphisms in several aspects of the host

immunity. In particular, genetic variation in the genes

of immune mediators, such as cytokines, has been

used as a potential target for susceptibility factors in

relation to periodontitis.

The text below reviews progress in the search for

genetic polymorphisms that are associated with de-

structive periodontal disease.

CYTOKINE GENE

POLYMORPHISMS

There are several arguments why the genes encoding

for interleukin-1 (IL-1) and tumor necrosis factor-a

(

TNF-a) seem good candidates for genetic studies in

relation to periodontitis (Cox & Duff 1996, Kornman

et al. 1997, Verweij 1999, Craandijk et al. 2002):

1. There is evidence to suggest that IL-1 and TNF-a

play important roles in the pathogenesis of perio-

dontitis. IL-1a and IL-lp and TNF-a are potent

immunologic mediators with proinflammatory

properties. Moreover, IL-1 and TNF-a have the

capacity to increase bone resorption and can regu

late fibroblast cell proliferation, both from gingival

and periodontal ligament origin. IL-1 and TNF-a

levels are increased in the gingival crevicular fluid

in periodontitis and these cytokines are found in