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Genetic Distances and Founder Population of Sardinia

This article explores the genetic map of Sardinia and its unique genetic frequencies, isolation, consanguinity, and stable population. It also discusses the impact of historical events on the island's genetic makeup.

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Genetic Distances and Founder Population of Sardinia

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

  2. Cagliari

  3. Gene and diseases in the founder population of Sardinia

  4. Sardinia and the geneticmap of Europe According to Cavalli-Sforza et al. 1994 Different colours indicate genetic distances • Genes • Uniformly distributed • Frequencies unique for Sardinia • RH-; MNS-M; DIA2, HLA B18 • Cavalli-Sforza et al. (1994) • Isolation • Insularity and geographical position • Physical geography • Low population density • 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 • Consanguinity • Kinship • 1880-1884 = 12.26% • 1945 = 8.21% • Today = very rare • Moroni et al (1972) • Stable population • About 300,000 inhabitants from 3rd 800 b.C. Phoenicians and • century b.C. to 17th century Carthaginians • No real colonization in terms of 238 b.C. Romans • agent of demographic development456 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) • 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) • 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) • 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) • Stable population • Struggle for survival i.e. not to become extinct • Famine and malnutrition • Endemic illness (Malaria and other major infections) 24,000 sq. Km popul. 1.654.470 Lat. 39°-41° N Long.8°-10° E

  5. GENETIC DISTANCE AMONG POPULATIONS DAN SVE LAP NOR FINLANDIA DUT 1.40 IRI SCO FMG GER 1.14 AUS SWI 0.88 CZE MAR PUG 0.62 TOS FRE HUN CAL 0.36 UMB BAS PIE 0.10 CAM SPA -0.16 SIC EMI POR -0.42 LIG VEN LOM -0.68 LAZ SARDEGNA GRE -0.94 -1.20 0.64 1.42 0.38 0.12 0.90 1.16 -0.40 -0.14 -1.70 -1.44 -1.18 -1.96 -0.92 -0.66

  6. TUR CRE ROM ITA MOR SPA ALG TUN GB NOR US WHITE FRA CZE SARD GRE BULG Neighbor-joining tree of 16 European and North-African populations using DRB1-DQA1-DQB1 haplotype frequencies (Courtesy of F. Cucca) 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.

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

  8. Multi-dimensional scaling analysis carried out on the DRB1-DQA1-DQB1 haplotype frequencies 1.5 SEN 1 GRE 0.6 BULG SARD KOGI MEX-AM CRE Second dimension ROM POLY 0.2 ITA TUN BRA BLACK MOR TUR FRA FIN USA WHITE ALG KAY UK CZE SPA SAHA SWE CHI - 0.2 NOR USA BLACK HONG KONG JAP - 0.6 S AFR - 1 - 1.5 - 1 - 0.5 0 0.5 1 1.5 2 2.5 3 First dimension (Courtesy of F. Cucca)

  9. DRB1* DQA1 DQB1* haplotypes in 5 ethnic groups 25 20 20 Chinese 15 15 10 10 5 5 25 25 Blacks 20 20 15 15 10 10 5 5 25 25 Latin American 20 20 15 15 10 10 haplotypefrequency (%) 5 5 25 25 Caucasians 20 20 15 15 1501-0102-0602 0301-0501-0201 10 10 5 5 25 Sardinians 20 15 30% of Sardinians 10 5 0 0101-0101-0501 0102-0101-0501 0103-0101-0501 0301-0501-0201 0302-0401-0402 0401-0301-0301 0401-0301-0302 0402-0301-0301 0402-0301-0302 0403-0301-0302 0403-0301-0304 0403-0301-0305 0404-0301-0301 0404-0301-0302 0404-0301-0401 0405-0301-0201 0405-0301-0302 0405-0301-0401 0405-0501-0301 0406-0301-0302 0407-0301-0301 0407-0301-0302 0407-0301-0304 0408-0301-0301 0408-0301-0302 0409-0301-0401 0701-0201-0201 0701-0201-0303 0701-0301-0201 0801-0301-0302 0801-0401-0402 0802-0401-0402 0803-0103-0601 0803-0601-0301 0804-0401-0402 0804-0501-0301 0901-0301-0201 0901-0301-0303 1001-0101-0501 1101-0102-0602 1101-0501-0301 1102-0501-0301 1103-0501-0301 1104-0501-0301 1201-0101-0501 1201-0501-0301 1301-0103-0502 1301-0103-0603 1302-0102-0501 1302-0102-0604 1301-0102-0605 1303-0201-0201 1303-0501-0301 1305-0201-0201 1401-0101-0501 1401-0101-0503 1402-0501-0301 1403-0501-0301 1501-0102-0501 1501-0102-0602 1502-0101-0501 1502-0103-0601 1503-0101-0501 1503-0102-0602 1601-0102-0501 1601-0102-0502 1601-0102-0603 1602-0102-0502 1602-0501-0301 Lampis, Cucca et al. 2001

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

  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 countries 1-2:100,000 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 Jews 1:9,000 Sardinians 1:14,400 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. Other autoimmune diseases Celiac disease (CD)* in background population PopulationNumber Prev. (95% C.I. ) Ref. North Sardinia1,607 1.06%(0.6-1.6)Meloni et al. 1999 Schoolchildren Italy - Marche 3,351 0.33% (0.1-0.5) Catassi et al. 1994Schoolchildren 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

  18. Other autoimmune diseases CD* among T1D patients PopulationNumber 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 4983.2% (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 3832.6% (1.3-4.7) Sategna-Guidetti et al. 1994 T1D patients 8207.0% (5.4-9.0) De Vitis et al. 1996 * biopsy proven

  19. Other autoimmune diseases Myasthenia gravis (MG) in background adult populations PopulationNumber Prev*. Incid*. Ref. North Sardinia 270.000 11.10.8Aiello et al.1997 Whole Sardinia 1.5mil4.5 0.25 Giagheddu et al. 1995 Denmark 2.8mil7.8 0.5 Christensen et al. 1993 Whole Norway 4.5mil 90.24Storm-Mathisen et al. 1984 Italian adults BO 815.0004.9D’Alessandro et al. 1991 FE 381.118 9.7 * x100.000

  20. Other autoimmune diseases Thyroid autoantibodies (TA) in background population PopulationNumber Prev. (95% C.I. ) Ref. Sardinian 8,484 3.7%(3.3-4.1)Mariotti et al. 2000Schoolchildren Italian 419 2.4% (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 PopulationNumber 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 Sardinian399 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 patients111 27.9% (19.6-36.3)Fernandez-Castaner et al, 1999

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

  23. 70 93 280 75 96 165 140 55 60 70 100 85 40 90 120 25 40 60 110 80 26 50 80 50 40 120 65 30 35 30 60 13 150 10 17 53 90 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 PopulationNumber MS (Prev) (95% C.I. ) Reference Sardinians270,000 0.16 %(0.14-0.17)Granieri et al. 2000 (NW,all ages) Italians (all ages)0.05 % Granieri et al. 1997 Sardinian T1D424 0.47%(0.05-1.69)Songini et al. (unpubl) adults (15-50 yrs) Sardinian T1D650 0.77%(0.25-1.79)Chessa et al. (unpubl) schoolchildren PopulationNumber 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 pop6,2550.37%(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 PopulationNumber MS (Prev) (95% C.I. ) Reference Sardinians270,000 0.16 %(0.14-0.17)Granieri et al. 2000 (NW,all ages) Italians (all ages)0.05 % Granieri et al. 1997 Sardinian T1D424 0.47%(0.05-1.69)Songini et al. (unpubl) adults (15-50 yrs) Sardinian T1D650 0.77%(0.25-1.79)Chessa et al. (unpubl) schoolchildren PopulationNumber 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 pop6,2550.37%(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) *p<0.01 † unaffected with T1D n/a non applicable Dorman JS, Songini M et al. Diabetes Care,november 2003

  29. 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); Mediterranean sea Tuscany 15% A SASSARI Corse (F) 20% Gallura 20% NUORO Barbagia 50% 2 CAGLIARI 1 4 3 7 9 22 6 5 8 11 10 13 12 15 14 16 17 18 19 20 21 B MS prevalence gradient Gallurese-speaking communes 23

  30. Figure 5. MS prevalence gradient (total population) <130 140-150 >150 Figure 6. MS prevalence gradient (0-15 years population) <190 190-200 >200

  31. Nuoro Sassari Ferrara 6 4 rate per 100,000 2 0 1965-74 1975-84 1985-93 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 12 12 10 10 8 8 Mean population (x 1000) MS incidence rate (100,000) 6 6 4 4 2 2 1912- 1942- 1947- 1952- 1957- 1962- 1967- 1972- 1977- 16 46 51 56 61 66 71 76 81 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. DRB1* DQA1 DQB1* haplotypes in 5 ethnic groups 25 20 20 Chinese 15 15 10 10 5 5 25 25 Blacks 20 20 15 15 10 10 5 5 25 25 Latin American 20 20 15 15 10 10 haplotypefrequency (%) 5 5 25 25 Protetctive T1DM MS Caucasians 20 20 15 15 10 10 5 5 MS and T1DM MS 25 20 15 Sardinians 10 5 0 1501-0102-0602 0301-0501-0201 0101-0101-0501 0102-0101-0501 0103-0101-0501 0302-0401-0402 0401-0301-0301 0401-0301-0302 0402-0301-0301 0402-0301-0302 0403-0301-0302 0403-0301-0304 0403-0301-0305 0404-0301-0301 0404-0301-0302 0404-0301-0401 0405-0301-0201 0405-0301-0302 0405-0301-0401 0406-0301-0302 0407-0301-0301 0407-0301-0302 0407-0301-0304 0408-0301-0301 0408-0301-0302 0701-0201-0201 0701-0201-0303 0701-0301-0201 0801-0301-0302 0801-0401-0402 0802-0401-0402 0803-0103-0601 0803-0601-0301 0804-0401-0402 0804-0501-0301 0901-0301-0201 0901-0301-0303 1001-0101-0501 1101-0102-0602 1101-0501-0301 1102-0501-0301 1103-0501-0301 1104-0501-0301 1201-0101-0501 1201-0501-0301 1301-0103-0502 1301-0103-0603 1302-0102-0501 1302-0102-0604 1301-0102-0605 1303-0201-0201 1303-0501-0301 1305-0201-0201 1401-0101-0501 1401-0101-0503 1402-0501-0301 1403-0501-0301 1501-0102-0501 1502-0101-0501 1502-0103-0601 1503-0101-0501 1503-0102-0602 1601-0102-0501 1601-0102-0502 1601-0102-0603 1602-0102-0502 1602-0501-0301 0409-0301-0401 0405-0501-0301 Lampis,R et al. 2001

  34. 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 theimmunological 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. What we are doing now... (2) • 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!

  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. Bottazzo VicePresident: M.Songini C. Putzu, A. Casu R. Cavallo R.A.S. (Regione Autonoma della Sardegna) European Union Italian Ministry of Healh, ADCT National Institute of Health GPs&Pediatricians from Sardinia….and many more!

  44. My Diabetes staff thanks you

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