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Marco Songini, Director Diabetes Unit - Azienda Ospedaliera “G.Brotzu” Cagliari – Sardinia, Italy The Center for Immunology.

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Presentation on theme: "Marco Songini, Director Diabetes Unit - Azienda Ospedaliera “G.Brotzu” Cagliari – Sardinia, Italy The Center for Immunology."— Presentation transcript:

1 Marco Songini, Director Diabetes Unit - Azienda Ospedaliera “G.Brotzu” www.aob.it, marcosongini@aob.it Cagliari – Sardinia, Italy The Center for Immunology and Transplantation University of Florida, Gainesville, July 5th, 2005 type 1 diabetes and related ADs in Sardinia

2 Cagliari

3 Gene and diseases in the founder population of Sardinia

4 Isolation Insularity and geographical position Physical geography Low population density Language Romance (the most archaic neo-latin language spoken so far) Early Latinization Isolated location Resistance to innovation Any lexical innovation mostly regards some Southern and Northern areas Paulis (1995) Stable population About 300,000 inhabitants from 3rd About 300,000 inhabitants from 3rd 800 b.C. Phoenicians and century b.C. to 17th century century b.C. to 17th century Carthaginians No real colonization in terms of 238 b.C. Romans agent of demographic development 456 A.D. Vandals No large-scale admixture between 534 A.D. Eastern Roman populations from costal to internal empire (Byzantium) regions 1258 A.D. Pisans The invaders were not inclined 1323 A.D. Catalan-Aragoneses towards permanent inhabitation of 1479 A.D. Spanish the island 1720 A.D. Italians – Piedmont Little genetic flow from invaders (Savoys) Genes Uniformly distributed Frequencies unique for Sardinia RH-  ; MNS-M  ; DIA2 , HLA B18  Cavalli-Sforza et al. (1994) Consanguinity Kinship 1880-1884 = 12.26% 1945 = 8.21% Today = very rare Moroni et al (1972) Stable population Struggle for survival i.e. not to become extinct Famine and malnutrition Endemic illness (Malaria and other major infections) Sardinia and the genetic map of Europe According to Cavalli-Sforza et al. 1994 Different colours indicate genetic distances 24,000 sq. Km popul. 1.654.470 Lat. 39°-41° N Long.8°-10° E Life expectancy The oldest man in the world lives currently in Sardinia at birth 1year 1930-32 54.9 60.5 1960-62 69.4 71.8 1970-72 72.9 73.9 1989-93 73.9 73.6 (National Institute of Statistics) Genetic drift Paleolitic: 700-1800 inhabitants (14.000 b.C.; about 750 generations ago) Small number of founders Same ancestral gene pool Skewing effect of selection Considerable drift Matrimonial mobility (average distances of birth place of the spouses) 1850 = 13.3 Km 1911-1949 = 20 Km 1950-1965 = 39.9 Km Nowadays > 40 < 50 Km Gatti (1990)

5 -1.20 -0.94 -0.68 -0.42 -0.16 0.10 0.36 0.62 0.88 1.14 1.40 -1.96-1.70-1.44-1.18-0.92-0.66-0.40-0.14 0.120.380.640.901.161.42 SARDEGNA GRE LAZ LOM BAS CAL PUG LAP FINLANDIA DAN SVE NOR SCO FMG IRI DUT GER AUS SWI CZE FRE HUN MAR TOS CAM SIC UMB PIE SPA POR LIG VEN EMI GENETIC DISTANCE AMONG POPULATIONS

6 Neighbor-joining tree of 16 European and North-African populations using DRB1-DQA1- DQB1 haplotype frequencies FRA CZE US WHITE NOR CRE GB SPA ITAMOR TUN GRE BULG ROM SARD ALG TUR ALG, Algerians; BULG, Bulgarians; CRE, Cretan; CZE, Czech; FRA, French; GB, Britons; GRE, Greeks; ITA, Italians; MOR, Moroccan; NOR, Norwegians; ROM, Romanians; SARD, Sardinians; SPA, Spanish; TUN, Tunic: TUR, Turks; US-WHITE, American Whites. (Courtesy of F. Cucca)

7 Neighbor-joining tree of 7 Sardinian sub-populations and continental Italians using DRB1-DQA1-DQB1 haplotype frequencies LANUSEICAGLIARI CARBONIA ORISTANO SORGONO SASSARI TEMPIO ITALY 1 Cagliari 2 Carbonia 3 Lanusei 4 Oristano 5 Sassari 6 Sorgono 7 Tempio (Courtesy of F. Cucca)

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9 0101-0101-05010102-0101-05010103-0101-05010301-0501-02010302-0401-04020401-0301-03010401-0301-03020402-0301-03010402-0301-03020403-0301-03020403-0301-03040403-0301-03050404-0301-03010404-0301-03020404-0301-04010405-0301-02010405-0301-03020405-0301-04010405-0501-03010406-0301-03020407-0301-03010407-0301-03020407-0301-03040408-0301-03010408-0301-03020409-0301-04010701-0201-02010701-0201-03030701-0301-02010801-0301-03020801-0401-04020802-0401-04020803-0103-06010803-0601-03010804-0401-04020804-0501-03010901-0301-02010901-0301-03031001-0101-05011101-0102-06021101-0501-03011102-0501-03011103-0501-03011104-0501-03011201-0101-05011201-0501-03011301-0103-05021301-0103-06031302-0102-05011302-0102-06041301-0102-06051303-0201-02011303-0501-03011305-0201-02011401-0101-05011401-0101-05031402-0501-03011403-0501-03011501-0102-05011501-0102-06021502-0101-05011502-0103-06011503-0101-05011503-0102-06021601-0102-05011601-0102-05021601-0102-06031602-0102-05021602-0501-0301 0 5 10 15 20 25 Sardinians 5 10 15 20 25 5 10 15 20 25 Caucasians 5 10 15 20 25 5 10 15 20 25 haplotype frequency (%) Latin American 5 10 15 20 25 5 10 15 20 25 Blacks 5 10 15 20 5 10 15 20 25 Chinese DRB1* DQA1 DQB1* haplotypes in 5 ethnic groups 1501-0102-0602 Lampis, Cucca et al. 2001 0301-0501-0201 30% of Sardinians

10 Genetic clusters for T1D in Sardinians Cappello et al. 1996 Vona et al. 1997 Genetic tree of the Sardinian and Italian populations for HLA Genetic tree for the 21 linguistic domains in Sardinia for 12 polymorphisms

11 Genetic diseases G6PD deficiency (favism). Prevalence (%) among males Silvetti et al. 1969

12 Genetic diseases Beta thalassemia in Sardinia Epidemiology of beta-thalassemia (95% beta39=founder effect): 13% beta-thalassemia carrier rate 1:70 couple is at risk for 1:250 newborns would be affected but they are reduced to 1:4,000 thanks to prenatal diagnosis Rosatelli et al. 1992; Cao et al. 1996

13 Genetic diseases Wilson’s Disease Incidence: Sardinia 1-2:10,000 Other countries1-2:100,000 Heterozygous in Sardinia: 3.4% Heterozygous in other countries: 1.1% Loudianos et al 1999

14 Genetic diseases Wilson’s Disease mutations in Sardinian population (founder effect) Loudianos et al. 1999

15 Other diabetes-related autoimmune diseases in Sardinia

16 Other autoimmune diseases APECED (APS1) Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Autosomal recessive disorder Incidence: Finns 1:25,000 Iranian Jews1:9,000 Sardinians1:14,400 Genetic: Mutation of AIRE ( autoimmune regulator ) gene: R139X (18/20 indipendent mutations found are R139X= founder effect) Heterozygous in Sardinia for R139X: 1.7% Rosatelli et al. 1998

17 Population Number Prev. (95% C.I. ) Ref. North Sardinia 1,607 1.06% (0.6-1.6) Meloni et al. 1999 Schoolchildren Italy - Marche 3,351 0.33% (0.1-0.5) Catassi et al. 1994 Schoolchildren Finnish sibs 550 1.1% (0.4-2.3) Saukkonen et al 2001 of T1D (mean age 12yrs) Finnish adults 1,070 0.8% (0.3-1.5) Kolho et al. 1998 * biopsy proven Other autoimmune diseases Celiac disease (CD)* in background population

18 Population Number Prev. (95% C.I. ) Ref. NorhtSardinian 650 4.1% (2.7-6.0) Frongia et al. (unpubl.) Schoolchildren T1D Italian 4,514 2.7% (2.2-3.1) Pocecco et al. 1989 Schoolchildren 498 3.2% (1.8-5.2) Barera et al. 1991 Sardinian adults 394 3.8% (2.1-6.2) Songini et al. 1998 T1D patients Italian adults 383 2.6% (1.3-4.7) Sategna-Guidetti et al. 1994 T1D patients 820 7.0% (5.4-9.0) De Vitis et al. 1996 * biopsy proven Other autoimmune diseases CD* among T1D patients

19 Population Number Prev*. Incid*. Ref. North Sardinia 270.000 11.1 0.8 Aiello et al.1997 Whole Sardinia 1.5mil 4.5 0.25 Giagheddu et al. 1995 Denmark 2.8mil 7.8 0.5 Christensen et al. 1993 Whole Norway 4.5mil 9 0.24 Storm-Mathisen et al. 1984 Italian adults BO 815.0004.9 D’Alessandro et al. 1991 FE 381.118 9.7 * x100.000 Other autoimmune diseases Myasthenia gravis (MG) in background adult populations

20 Other autoimmune diseases Thyroid autoantibodies (TA) in background population Population Number Prev. (95% C.I. ) Ref. Sardinian 8,484 3.7% (3.3-4.1) Mariotti et al. 2000 Schoolchildren Italian 4192.4% (1.1-4.3) Aghini et al. 1999 Schoolchildren 1424.3% (1.6-9.0) Fenzi et al. 1986 Sardinian mothers 2,500 11.8% (10.5-13.1) Olivieri et al. 2000 at delivery Mothers at 4,022 5.5% (4.8-6.2) Sakaihara et al. 2000 delivery (Japan, USA) 552 19.6% (18.1-21.1) Stagnaro et al.1990

21 Other autoimmune diseases Thyroid autoantibodies among T1D patients Population Number Prev. (95% C.I. ) Ref. T1D Sardinian 650 17.6% (14.6-20.5) Ricciardi et al. Schoolchildren (unpubl.) T1D Italy/Europe 212 16.5% (11.5-21.5) Lorini et al. 1996 Schoolchildren 495 22.0% (18.4-25.7) Holl et al. 1999 T1D Sardinian 399 28.3% (23.9-22.6) Songini et al. 1998 adults patients T1D European 258 19.8% (14.9-24.6) Mangendre et al. 2000 adults patients 111 27.9% (19.6-36.3) Fernandez-Castaner et al, 1999

22 The new concept of T1D as a cluster of autoimmune-related diseases: the example of MS and T1D in Sardinia Sardinia: Giants’ tomb

23 90 150 150 60 53 65 17 13 35 50 40 25 50 60 10 30 120 80 30 26 80 40 90 40 60 70 120 85 110 96 75 93 55 280 140 165 100 70 43 Prevalence of MS x 100.000 in Europe (MS pts= 2.5 mil ww) J Cl Nurology and Neurosurgery 104 (002) 182-91

24 Other autoimmune diseases Multiple Sclerosis (MS) and T1D Population Number MS ( Prev) (95% C.I. ) Reference Sardinians 270,000 0.16 % (0.14-0.17) Granieri et al. 2000 (NW,all ages ) Italians (all ages) 0.05 % Granieri et al. 1997 Sardinian T1D 424 0.47% (0.05-1.69) Songini et al. (unpubl) adults (15-50 yrs) Sardinian T1D 650 0.77% (0.25-1.79) Chessa et al. (unpubl) schoolchildren Population Number T1D ( Prev) (95% C.I. ) Reference Sardinian 1,053 2.40% (1.54-3.49) Marrosu et al. 2000 MS pts (9-65 yrs) Sardinian pop 6,2550.37% (0.22-0.52) Muntoni et al. 1988 (20-59yr)

25 Other autoimmune diseases Genetic association of MS with: In Northern Europeans: DRB1*1501-DQB1*0602 (DR2)* * Protective for T1D then T1D and MS occur together very rarely In Sardinians: DRB1*0301-DQB1*0201 (DR3)* DRB1*0405-DQB1*0301 (DR4)* * Also predisposing to T1D, DR2 is very rare then T1D and MS may coexist Marrosu et al. 2000

26 Multiple Sclerosis (MS) and T1D in Sardinia Population Number MS ( Prev) (95% C.I. ) Reference Sardinians 270,000 0.16 % (0.14-0.17) Granieri et al. 2000 (NW,all ages ) Italians (all ages) 0.05 % Granieri et al. 1997 Sardinian T1D 424 0.47% (0.05-1.69) Songini et al. (unpubl) adults (15-50 yrs) Sardinian T1D 650 0.77% (0.25-1.79) Chessa et al. (unpubl) schoolchildren Population Number T1D ( Prev) (95% C.I. ) Reference Sardinian 1,053 2.40% (1.54-3.49) Marrosu et al. 2000 MS pts (9-65 yrs) Sardinian pop 6,2550.37% (0.22-0.52) Muntoni et al. 1988 (20-59yr)

27 Genetic association of MS with T1D In Northern Europeans: DRB1*1501-DQB1*0602 (DR2)* * Protective for T1D then T1D and MS occur together very rarely In Sardinians: DRB1*0301-DQB1*0201 (DR3)* DRB1*0405-DQB1*0301 (DR4)* * Also predisposing to T1D, DR2 is very rare then T1D and MS may coexist Marrosu et al. 2000

28 MS with T1D: together at last (Allegheny County, US) Dorman JS, Songini M et al. Diabetes Care,november 2003 Characteristics T1DSiblings†Parents† Males (n=148) Females (n=149) Males (n=143) Females (n=187) Males (n=84) Females (n=140) Age (yrs)41.442.642.442.369.067.2 Duration T1D (yrs)35.235.4---- Observed MS prev.0%2.0%0%0.5%0% Expected MS prev.n/a0.1%n/a0.1%n/a Relative increased risk of MS n/a20fold*n/a5 foldn/a *p<0.01 † unaffected with T1D n/a non applicable

29 NUORO SASSARI 23 2 1 4 3 5 6 8 7 9 15 10 12 13 14 16 17 18 19 2120 22 Tuscany 15% Corse (F) 20% Barbagia 50% Gallura 20% Mediterranean sea MS prevalence gradient Gallurese-speaking communes A B 11 CAGLIARI The two Sardinian provinces under study: Sassari and Nuoro; the south- western to north-eastern gradient of MS prevalence in the province of Sassari (Pugliatti et al., 2002b), correspond to significant differences of genetic and linguistic domains (prevalence is expressed as number of cases per 100,000 population for each commune of the province: black communes >150, grey communes >130 and <150, blank communes < 130 MS cases). B. Polymorphisms of mitochondrial genes in Barbagia (central, “archaic” Sardinia), Gallura (norther Sardinia), Corse (insular France) and Tuscany (mainland Italy) (Morelli et al., 2000) and subdivision of the island in 23 linguistically and genetically domains (Cappello et al., 1996);

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31 0 2 4 6 1965-741975-841985-93 Sassari Ferrara rate per 100,000 Nuoro A Figure 4. A. Temporal trends of MS incidence rates in the province of Nuoro, Sassari and Ferrara, in the period 1965 to 1993.

32 Figure 1 2 4 6 8 10 12 1912- 16 1942- 46 1947- 51 1952- 56 1957- 61 1962- 66 1967- 71 1972- 76 1977- 81 Mean population (x 1000) MS incidence rate (100,000) 2 4 6 8 10 12 Five-years periods 1) Average annual incidence rates (per 100,000 per year, right Y axis) of MS in Macomer, Sardinia, from 1912 through 1981 (5-years periods). Left Y axis expresses the population growth (per 1,000). Adapted from reference [12].

33 0101-0101-05010102-0101-05010103-0101-0501 0301-0501-0201 0302-0401-04020401-0301-03010401-0301-03020402-0301-03010402-0301-03020403-0301-03020403-0301-03040403-0301-03050404-0301-03010404-0301-03020404-0301-04010405-0301-02010405-0301-03020405-0301-0401 0405-0501-0301 0406-0301-03020407-0301-03010407-0301-03020407-0301-03040408-0301-03010408-0301- 0302 0409-0301- 0401 0701-0201-02010701-0201-03030701-0301-02010801-0301-03020801-0401-04020802-0401-04020803-0103-06010803-0601-03010804-0401-04020804-0501-03010901-0301-02010901-0301-03031001-0101-05011101-0102-06021101-0501-03011102-0501-03011103-0501-03011104-0501-03011201-0101-05011201-0501-03011301-0103-05021301-0103-06031302-0102-05011302-0102-06041301-0102-06051303-0201-02011303-0501-03011305-0201-02011401-0101-05011401-0101-05031402-0501-03011403-0501-03011501-0102-0501 1501-0102-0602 1502-0101-05011502-0103-06011503-0101-05011503-0102-06021601-0102-05011601-0102-05021601-0102-06031602-0102-05021602-0501-0301 0 5 10 15 20 25 Sardinians 5 10 15 20 25 5 10 15 20 25 Caucasians 5 10 15 20 25 5 10 15 20 25 haplotype frequency (%) Latin American 5 10 15 20 25 5 10 15 20 25 Blacks 5 10 15 20 5 10 15 20 25 Chinese DRB1* DQA1 DQB1* haplotypes in 5 ethnic groups Lampis,R et al. 2001 MSMS and T1DM MS Protetctive T1DM

34 HLA alleleT1DM effectMS effect DRB1*1501 (DR2) – DQA1 0102- DQB1 0602 Dominant protection Predisposition in Caucasians DRB1* 0301(DR3) – DQA1 0501 - DQB1 0201- PredispositionPredisposition in Sardinians other loci outside the MHC region may be shared between MS and T1DM and contribute to the susceptibility to both the diseases.

35 The strong effect of having multiple MS affected relatives suggests that genetic variability in risk for diabetes is linked to genetic loading for MS, which is substantially increased in these individuals. These findings suggest that loci or genes predisposing to familial MS aggregation also contain an enrichment of diabetes predisposing genes.

36 Taken together, these data suggest: that common genes, either within the HLA region or outside it, influences susceptibility to both MS and T1DM that genetic structure of Sardinians might contain a particular combination of etiologic or a lack of protective genes for these diseases. Thus, Sardinians appears to be a very suitable population for studying what genes contribute to trigger and sustain autoimmunity in humans.

37 Conclusions…

38 To sum up (1) T1D has started to rise around the middle of the 20th century and keeps increasing ww in younger ages mainly in low risk countries (catch-up phenomenon) Whether it’s an earlier presentation or a true increase it’s not clear yet Sardinia is confirmed to be a hot spot for clinical T1D and islet-related autoimmunity, as for some other autoimmune- related diseases (CD, MS, not TD) An increasing T1D incidence in the Island has been found rising dramatically since the years 60’ as in other countries No defined geographical clustering for T1D was found across the island

39 To sum up (2) The combination of more than 1 islet-related autoantibody (rather than which) is the best predictor for the development of T1D in the Sardinian background population (SC) None of the classical ecological variables considered so far has shown any firm influence towards the etiopathogenesis of T1D in Sardinia; however other variables need to be further investigated Migrants data seems to support a different role of genetic vs environmental determinants There’s still a long way in front of us to possibly prevent type 1 diabetes…

40 What we are doing now with the help of so many (1) Trying to further improve the prediction of T1D in the general population by studying the immunological and genetic markers for T1D and other autoimmune diseases in Sardinian population and migrants and their relatives Investigating other putative environmental factors which can play a role towards the etiopathogenesis of T1D (e.g., chemicals, toxins, vaccinations, viral infections, etc.)

41 Broadening the original investigation for T1D on the prevalence of others autoimmune diseases and to study their associations Comparing data from Sardinia and other areas by new collaborative studies(RIDI,TRIGR,ENDIT, SARDINIAN DIABFIN) Sensitizing Sardinian Health Autorities & population towards primary prevention of T1D and autoimmune diseases …..and by this way... improving the current care of diabetes in Sardinia! What we are doing now... (2)

42 Acknoledgements Anthropology: G. Vona (Sardinia-Italy) Other autoimmune diseases: GF Bottazzo and coworkers (Rome-Italy) S. Mariotti and coworkers (Cagliari-Italy) T. Meloni and coworkers (Sardinia-Italy) M. Marrosu and coworkers (Sardinia-Italy) Epidemiology:The Sardinian Epidemiology Study Group Eurodiab TIGER Study Group IDA Study Group RIDI Study Group Z. Laron, I. Askenazi (Israel) L. Bernardinelli and C. Pascutto (Pavia-Italy) P. Contu, L. Minerba (Cagliari-Italy) Genetic: F. Cucca and coworkers (Sardinia-Italy) E.A.M. Gale and coworkers (UK) I. Loudianas (Sardinia-Italy)

43 Acknoledgements Echological studies: G.F. Bottazzo (Rome-Italy) M. Fadda (Sardinia-Italy) B. Elliot (New Zeland) P. Pozzilli (Rome-Italy) A. Contu, M. Carlini (Sardinia-Italy) Prediction Study:G.F. Bottazzo & M. Locatelli (Rome- Italy) S. Carta, M. Sorcini, A. Olivieri (Rome-Italy) GF Bottazzo, A. Loviselli and the Sardinian SchooIchildren Study Group (Sardinia-Italy) GF Bottazzo,R. Cirillo and the Sardinian Newborn Study Group (Sardinia-Italy) A. Dolei, G. Delitala (Sardinia-Italy) M.T. Tenconi, G. Devoti (Pavia-Italy) The League of Sardinian Migrant Associations ASRIS (Association for Study and Research of IDDM in Sardinia): M. Porceddu (secretary)Tina Carboni President: G.F. BottazzoVicePresident: M.Songini C. Putzu, A. Casu R. Cavallo R.A.S. (Regione Autonoma della Sardegna)European Union Italian Ministry of Healh, ADCTNational Institute of Health GPs&Pediatricians from Sardinia….and many more!

44 My Diabetes staff thanks you


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