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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
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