Niigata, JapanNiigata, Japan

The biggest city in the coast of Japan sea

Famous for snow, fish and delicious foods

Global Oral

Health

Collaborating with WHO

Global Oral

Health

Collaborating with WHO

Epidemiological

Study

Epidemiological

Study

Niigata UniversityPreventiveDentistry

Clinical work

Clinical work

Community Oral HealthCommunity Oral Health

Relationship between oral disease Relationship between oral disease and systemic conditionand systemic condition

Akihiro YOSHIHARAAkihiro YOSHIHARA

Graduate School of Medical & Dental Sciences, Graduate School of Medical & Dental Sciences,

Niigata UniversityNiigata University

Aging speed of Japan is faster than Aging speed of Japan is faster than any other countryany other country

The population of dependent The population of dependent elderly is 280,000 and will be elderly is 280,000 and will be

520,000 in 2025520,000 in 2025

The rate of 65yrs old in population get 7% →14%

U.S.

England

Japan

Sweden

69 years

82 years

46 years

24 years

Subjects for the presentationSubjects for the presentation

Yokogoshi study(n=1310 ）School of Medicine, Niigata University, Niigata University Health and Welfare

Kochi study(n=331 ）Kyoto University,Tokyo Women’s Medical University

Niigata longitudinal cohort study (n=4542 ）National Institute of Public Health, National Institute of Health and Nutrition, National Institute of Infectious Diseases, et al

Methods

・ Personal interview (smoking and alcohol drinking habits, utilization of dental services, etc.)

・ Biochemical measurements on blood and urine, Micronutrients, Height and weight (Body mass index), Physical fitness, Bone mineral density, Blood pressure, Electrocardiogram, etc

Assessments:

Measurements:

・ Food intake status including dietary habit

・ Oral health conditions (dental caries, perio, oral mucosa, etc.)

・ Medical conditions (Heart disease, Blood disease, Liver disease, Kidney disease, Diabetes mellitus, etc.)

FcRIIIb

QOL ADL

070101

7, 25

3, 25, 26, 4115

23

24

10

9, 13, 29, 43

8

4, 19, 33, 37, 39 14

8

27, 43

6

5

16, 28, 36

IgG

18

8

20

11

36

Rep 21

52

22

12

35

DM intervention study30

34

48

47

42

Diabetes Mellitus

（HbA1C）

Heart Diseases

Obesity

Systemic

Diseases

FIM

ImmunityBMI

SmokingDrinking

Exercise

Life style

Outcome of Niigata Elderly StudyCause-effect

Relationship

Saliva

CoronalRoot PeriodontalOral

Tonsil

Pneumonia

Bone

NutritionCalorie intake

Serum albumin

Vitamins

Face Scale

AgilityEquilibriumMuscle strength

Physical

Fitness

Sleep

Vision・

Masticatory

Occlusal

Eichner Index

Tooth loss

DALE

Bacteria

Bacteriacaries diseasescaries

Serum calcium

Dementia

Hearing

density

function

condition

Drugs

Serum Zn

40

functionRenal

Rep 21

49

46

21, 31,

32, 45

38

51

50

Dietary intake and Nutrition

NutritionDiet

Oral condition

Disease, General

condition

Development

Host Resistance

Oral Biofilm

Bone metabolism

The subjects aged 74 (n=57)

A precise weighing methos, during 3 days

NitritionEnergy, Protein, Lipid,

Carbohydrates, Minerals, Vitamins,

Fatty acids, Dietary Fibere

Food groupCereals, Nuts and starches, Sugars and sweetners, Fats and oils, Bean,

Fruits, Vegetables, Fungi, Seaweed, Fish ･ sellfish, Meat, Egg,

Milk etc

0-19 20+ 0-19 20+

（ g/day ） **p<0.05

*

200

0

100

300

400

Intake of vegetables and sea foods by number of teeth present

(No. of teeth)Vegetables Fish, shellfish & their products

Yoshihara A, et al. Gerodontology, 22: 211-218, 2005.

0-19

20+

(mcg/1000Kcal)

*p<0.05

V-B6

**p<0.01

V-D V-B1(mg/1000Kcal) (mg/1000Kcal) (mg/1000Kcal) (mg/1000Kcal)

10

5

4

0

*

*

**

**

**3

21

67

8

9

Vitamin levels by number of teeth

Pantothenic acidNiacin

Yoshihara A, et al. Gerodontology, 22: 211-218, 2005.

≦4g/dl (N=34) >4g/dl (N=232)

Num

ber

of r

oot c

arie

s ev

ents

3

2

1

0

4

No. of root caries events based on serum albumin at baseline

p<0.031

A. Yoshihara, et al.: J. Dent. Res., 86: 1115-1119, 2007.

>4g/dl (N=264) ≦ 4g/dl (N=40)

Num

ber

of p

erio

eve

nts 16

12

8

0

20

No. of perio events based on serum albumin at baseline

p<0.007

4

Iwasaki M, et al.: J Clin Periodontol 35(4):291-296, 2008 .

The hypothetical model of the relationship between nutrient factors and the number of present teeth

Chewing Ability ↓

Nutritional intake↓

Vegetables, Seafood

Macro factors ↓

Vitamin factors ↓ Mineral factors↓

Present teeth ↓

Oral diseases

Periodontaldisease

Rootcaries

Calorie intake

Nutrition

Mastcatory function

Occlusalcondition

Tooth loss

Nutrients

Serum albmin

Chronic Kidney Disease

Kidney disease is recognized as a global health problem

Chronic renal failure is associated with marked disturbances of bone structure and metabolism.

Older adults display an increased risk of chronic renal insufficiency.

Osteoporosis can develop in patients with chronic kidney disease.

Tooth loss is frequent in the elderly population.

Glomerular filtration rate (GFR) is the clinically recommended way to measure the level of kidney function and determine the stage of CKD

eGFR (mL/min/1.73m2)= 194×(sCr)-1.094×(age)-0.287

(×0.739 if female)

※Serum Creatinine (sCr) values are measured by an enzymatic method

※Adapted for 18 or older

Estimate equation for Japanese (Japanese Society of Nephrology)

eGFR 90 60 30 15

5 stages of CKD

STAGE 1 STAGE 2 STAGE 3 STAGE 4 STAGE 5

Kideny Damage with Normal or↑ Kidney Function

Kidney Damage with Mild↓ Kidney Function

Moderate ↓Kidney Function

Severe ↓Kidney Function

KidneyFailure

Prevalence of chronic kidney disease (CKD) in Japan according to age group

Emai E et al. 2007

Systemic health(Diabetes, Chronic kidney disease)

Oral health(Periodontal disease)

？

Subjects and criteriaSubjects and criteria55-75 yrs 55-75 yrs Oral examinationOral examination

The number of remaining teethThe number of remaining teeth

Clinical attachment level (CAL)Clinical attachment level (CAL) Probing pocket depth (PD) Probing pocket depth (PD) Bleeding on probing(BOP)Bleeding on probing(BOP)

Renal function markerRenal function marker Creatinine clearance for 24 hoursCreatinine clearance for 24 hours

Serum cystatin CSerum cystatin C

Glomerular filtration rate Glomerular filtration rate (GFR)(GFR)

Personal interviewsPersonal interviews Smoking habits, BMISmoking habits, BMI

【 【 Predictor variables Predictor variables 】】

PISA (periodontal inflamed surface area) reflects the surface area of bleeding pocket epithelium in square millimeters. Nesse et al 2003.

Biochemical markers of bone turnover have been discovered over the past 30 years. Many studies have reported the efficacy of serum and urinary markers of bone turnover to evaluate bone metabolism.

<Bone formation markers>*Serum bone-specific alkaline phosphatase (S-BAP)*Serum osteocalcin (S-OC)<Bone resorption markers>*Urinary deoxypyridinoline (U-DPD)*Urinary or serum cross-linked N-telopeptide of type I collagen (U or S-NTX)

The correlation between selected The correlation between selected variables and serum cystatin C levelvariables and serum cystatin C level

Variables

Serum cystatin C (mg/dL)

Low (≤ 0.91mg/dL) High (>0.91mg/dL)

Past or current smokers(%) 5.4 5.4

BMI (kg/m2) 22.6±3.2 23.8±3.7***

Serum osteocalcin (ng/d) 9.4±3.3 9.9±3.7

Serum NTX (nmol BCE/L) 19.5±4.9 21.3±6.0**

Mean clinical attachment level

2.9±0.8 3.1±0.9*

Number of remaining teeth

23.8±6.1 21.2±7.7***

* p<0.05, **p<0.01, ***p<0.001 Yoshihara et al. Gerodontology, 29: e363-7, 2012

Mean number of remaining teeth Mean number of remaining teeth for each quartile of serum cystatin for each quartile of serum cystatin

CCp < 0.0001

p for trend < 0.0001 Serum cystatin CYoshihara et al. Gerodontology, 31: 111-116, 2014

Bone turnover markers and periodontal Bone turnover markers and periodontal diseasedisease

0

5

10

15

20

25

30

35

1st 2nd 3rd0

5

10

15

20

25

30

35

1st 2nd 3rd

0

5

10

15

20

25

30

35

1st 2nd 3rd

p=0.012

S-OC S-BAP

U-DPD U-NTX

% 6＋

mm

CA

L

% 6＋

mm

CA

L

0

5

10

15

20

25

30

35

1st 2nd 3rd

p=0.047

% 6＋

mm

CA

L

p value for trend=0.005 p value for trend=0.112

p value for trend=0.001 p value for trend=0.010

% 6＋

mm

CA

L

Yoshihara et al. J Perio Res 46:491-496, 2011.

The correlation between selected The correlation between selected variables and bone turnover markersvariables and bone turnover markers

Variables Mean (SD) r p value r p value r p value r p value

Mean number ofremaining teeth

18.0 (8.3) 0.15 0.078 0.03 0.769 0.12 0.178 -0.04 0.677

Mean CAL (mm) 3.5 (1.0) -0.26 0.002 -0.14 0.116 -0.22 0.010 -0.14 0.112

4+ mm CAL (%) 42.0 (30.5) -0.24 0.006 -0.10 0.267 -0.18 0.037 -0.10 0.238

6+ mm CAL (%) 9.8 (13.3) -0.32 <0.001 -0.15 0.081 -0.31 <0.001 -0.20 0.021

PD (mm) 2.2 (0.5) -0.05 0.557 -0.02 0.817 <0.01 0.999 -0.02 0.792

BOP(+) (%) 9.5 (11.4) 0.08 0.372 -0.04 0.682 0.17 0.050 0.08 0.359

S-OC (ng/ml) S-BAP (U/l)U-DPD

(nM/mM*Cr)U-NTX

(mM*BCE/mM*Cr)

Yoshihara et al. J Perio Res 46:491-496, 2011.

Bone turnover markers and Bone turnover markers and renal function markerrenal function marker

Variables Mean (SD) r p value r p value r p value r p value

Renal function marker

Creatinine clearance for 24hours (l/day)

77.9 (21.3) -0.22 0.011 -0.02 0.775 -0.04 0.621 <0.01 0.971

S-OC (ng/ml) S-BAP (U/l) U-DPD (nM/mM*Cr)U-NTX

(mM*BCE/mM*Cr)

Yoshihara et al. J Perio Res 46:491-496, 2011.

【 Results 】Table. The association between periodontal inflammation and worsened kidney function

Crude relative risk (95% CI) = 2.31 (1.19 - 4.47)

Adjusted relative risk (95% CI)† = 2.23 (1.04 - 4.75)

†Simultaneously taking into account baseline kidney condition, gender, proteinuria, hyperglycemia, hypertension, obesity, and smoking status.

※CI, confidence interval

Improvement or nochange in kidney function

Worsenedkidney function

Total

Others(Referent group)

88.7%n = 211

11.3%n = 27

238

Highest quartileof PISA

77.2%n = 61

22.8%n = 18

79

Total 272 45 317

Kidney function after 2 years

Period

onta

lst

atus

Iwasaki et al. Am J Kidny Dis 59:202-209, 2012.

Periodontal disease

Bone formation

Bone turnover

Low renal function

Bone resorption

Osteocalcin

S-OC

U-DPD

Tooth loss

Periodontal disease, Obesity and Beta-3 adrenergic receptor

Lifestyle diseases are becoming more common in Japan

A disease associated with the way a person or group of people lives.

Lifestyle diseases include •Atherosclerosis

•Heart disease, and stroke

•Obesity and type 2 diabetes

•And diseases associated with smoking and alcohol and drug abuse.

Gene polymorphisms

Systemic diseasesAtherosclerotic

vascular diseasesAspiration pneumonia

CancerAdverse pregnancy outcomes

OsteoporosisObesity

Diabetes

Periodontitis

Genetic factors were involved in 30-Genetic factors were involved in 30-50% of periodontal disease.50% of periodontal disease.

Many of the genes involved have not Many of the genes involved have not been identified.been identified.

GeneGene polymorphisms related to obesity polymorphisms related to obesity and diabetes have been found.and diabetes have been found.

One of which is beta-3 adrenergic One of which is beta-3 adrenergic receptor, which promotes lipolysis in receptor, which promotes lipolysis in human adipose tissue.human adipose tissue.

We hypothesized that bea-3 adrenergic We hypothesized that bea-3 adrenergic receptor polymorphism might be a new receptor polymorphism might be a new genetic factor for periodontal disease.genetic factor for periodontal disease.

In Japan, very obese individuals are rare, but the probability of diabetes occurring in obese people is higher than in Westerners.

WHO defines obesity as a

BMI of 30 or higher

For Japanese

BMI of 25 or higher

Beta-3 adrenergic receptor

It is located mainly in adipose tissue and is involved in the regulation of lipolysis.

A/A, A/G, G/G G:Risk allele　　　　　　　　　　　　　　　　　　　　　　

　　　　　　 　　　　　　 TrpTrp

atcatc gccgcc ttgg gg actact 　　　　 A typeA type ↓↓ 　　　　　　　 　　　　　　　　 　 atcatc gccgcc ccgggg actact 　　　　 G type G type →→ ObesityObesity 　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　

　　　　　　　　　　

　　　　　　 　　　　　　 ArgArg 　　

　　

It is necessary to consider the It is necessary to consider the possibility of gene-environmental possibility of gene-environmental interactions.interactions.

The utility of focusing on individual The utility of focusing on individual genes is limited and that an individual’s genes is limited and that an individual’s susceptibility to disease might be susceptibility to disease might be modified by environmental factors.modified by environmental factors.

Subjects and criteriaSubjects and criteria

55-74 yrs: N=339 women (non-smoker) 55-74 yrs: N=339 women (non-smoker) Oral examinationOral examination

The number of remaining teethThe number of remaining teeth Clinical attachment level Clinical attachment level

Biochemical parametersBiochemical parameters Total cholesterol, HbA1C, Triglyceride Total cholesterol, HbA1C, Triglyceride HDL_cholesterol HDL_cholesterol

Gene polymorphrismGene polymorphrism Beta-3 adrenergic receptor

BMIBMI

BMI

PRR

PRR adjusted by age (y), HbA1C (%) and number of remaining teeth (offset variable)* <0.05, † <0.01, ‡ <0.001

‡

‡

*

‡ ‡ ‡

‡

≥6 mm CAL

≥4 mm CAL

†*†

* † ‡

*

PRRs of beta-3 adrenergic receptor genotype for number of sites with ≥6 mm CAL, and ≥4 mm CAL as classified by BMI.

BMI

PRR

PRR adjusted by age (y), HbA1C (%) and number of remaining teeth (offset variable)* <0.05, † <0.01, ‡ <0.001

†

†

†

‡

≥6 mm PD

≥4 mm PD*

‡

PRRs of beta-3 adrenergic receptor genotype for number of sites with ≥6 mm PD, and ≥4 mm PD as classified by BMI.

BMI and periodontal disease had connection, but it confined in an obese people (Socransky 2005).

While beta-3 adrenergic receptor polymorphism was not related to weight gain in originally nonobase subjects, related to weight gain in obese subjects (Masuo 2005).

TNFα mediates endotoxin-induced injury in periodontal tissue (Gemmell 1997), especially is correlated with BMI in obese subjects.

According to these findings, it might reasonable that we observed significantly greater PRR of beta3 adrenergic receptor polymorphism to periodontal disease in obese subjects.

There might be ethnic differences in genetic polymorphisms and susceptibility to lifestyle diseases and periodontal disease

•Genetic polymorphisms related to obesity show a higher frequency in Japanese.

•In the onset and progression of periodontal disease, Japanese appear to show greater effects on obesity.

The objectives of our collaboration study are

A) to clarify the differences in nutrition, diet intake, incidences of genetic polymorphisms related to life style disease such as obesity, diabetes, CKD and periodontal disease among ethnic groups

B) to clarify the effects of differences in genetic polymorphisms among ethnic groups on oral health condition, including periodontal disease, by adult subjects aged 40 or higher from Japan and the other countries