View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UnissResearch Original Articles Analysis of 12,517 inhabitants of a Sardinian geographic isolate reveals that predispositions to thrombocytopenia and thrombocytosis are inherited traits Ginevra Biino, 1,2 Carlo L. Balduini, 3 Laura Casula, 1 Piergiorgio Cavallo, 3 Simona Vaccargiu, 1,,2 Debora Parracciani, 4 Donatella Serra, 2 Laura Portas, 1 Federico Murgia, 1 and Mario Pirastu 1,2 1Institute of Population Genetics, National Council of Research, Sassari, Italy; 2Shardna Life Sciences, Cagliari, Italy; 3Department of Internal Medicine, IRCCS Foundation Policlinico S. Matteo, University of Pavia, Italy, and 4Genetic Park of Ogliastra, Perdasdefogu, Ogliastra, Italy ABSTRACT GB and CLB contributed equally to this manuscript. Background Thrombocytopenia is a common finding in several diseases but almost nothing is known about Acknowledgments: the authors the prevalence of thrombocytopenia in the general population. We examined the prevalence of would like to thank the thrombocytopenia and determinants of platelet count in a healthy population with a wide age population of Ogliastra for their range. collaboration and the municipal administrations for economic Design and Methods and logistic support. We performed a cross-sectional study on 12,517 inhabitants of ten villages (80% of residents) in a secluded area of Sardinia (Ogliastra). Participants underwent a complete blood count eval - Funding: this work was uation and a structured questionnaire, used to collect epidemiological data. supported by a grant from the Italian Ministry of Education, Results University and Research (MIUR) n°: 5571/DSPAR/2002. We observed a platelet count lower than 150 ¥10 9/L in 3.2% (2.8%-3.6%) of females and 4.8% (4.3%-5.4%) of males, with a value of 3.9% (3.6%-4.3%) in the entire population. 9 9 Manuscript received on July 2, Thrombocytopenia was mild (platelet count: 100 ¥10 /L -150 ¥10 /L), asymptomatic and not 2010. Revised version arrived associated with other cytopenias or overt disorders in most cases. Its standardized prevalence on August 31, 2010. was quite different in different villages, with values ranging from 1.5% to 6.8%, and was neg - Manuscript accepted atively correlated with the prevalence of a mild form of thrombocytosis, which ranged from on September 6, 2010. 0.9% to 4.5%. Analysis of platelet counts across classes of age revealed that platelet number decreased progressively with aging. As a consequence, thrombocytopenia was nearly absent in Correspondence: young people and its prevalence increased regularly during lifetime. The opposite occurred for Ginevra Biino, thrombocytosis. Institute of Molecular Genetics, CNR, Via Abbiategrasso 207, Conclusions 27100 Pavia, Italy. Given the high genetic differentiation among Ogliastra villages with “high” and “low” platelet E-mail: [email protected] counts and the substantial heritability of this quantitative trait (54%), we concluded that the propensity to present mild and transient thrombocytosis in youth and to acquire mild throm - The online version of this article bocytopenia during aging are new genetic traits. has a Supplementary Appendix. Key words: thrombocytopenia, thrombocytosis, genetic trait, Sardinia, geografic isolate. Citation: Biino G, Balduini CL, Casula L, Cavallo P, Vaccargiu S, Parracciani D, Serra D, Portas L, Murgia F, and Pirastu M. Analysis of 12,517 inhabitants of a Sardinian geographic isolate reveals that predispositions to thrombocytopenia and thrombocytosis are inherited traits. Haematologica 2010;96(01):96-101. doi:10.3324/haematol.2010.029934 ©2011 Ferrata Storti Foundation. This is an open-access paper. 96 haematologica | 2011; 96(1) Novel genetic traits underlying platelet counts Introduction respondents were invited to give fasting blood samples and under - go an interview, after signing informed consent. It is well known that thrombocytopenia is a common Trained personnel administered a structured questionnaire col - finding in several illnesses and clinical conditions. For lecting information on socio-demographic factors, lifestyle, drug instance, it has been shown that 46% of critically ill medical consumption as well as medical and family history of many and surgical patients have a platelet count lower than pathologies, including cancer, liver disorders, bleeding and throm - 150 ¥10 9/L, 1 and that the prevalence of thrombocytopenia is botic events. Questions about present and past illnesses were all 20% in patients with systemic lupus erythematosus, 2 37% asked following the same fixed schemes, for example, for liver in human immunodeficiency virus-positive drug users, 3 disease: “Have you ever had any liver disease (e.g., hepatitis, cir - 18% in patients with chronic active hepatitis B, and 13% in rhosis)? If yes, (since) when (year or age). Any relapse (number)? those with chronic hepatitis C. 4 Number and degree of affected relatives”. The disorders were clas - In contrast, almost nothing is known about the preva - sified according to the International Classification of Diseases, 9 th lence of thrombocytopenia in the general population, revision, Clinical Modification (ICD-9 CM 13 ). Hematologic vari - although there is a general consensus that a low platelet ables, including platelet, white blood cell and red blood cell counts, count is recognized with increasing frequency in apparently mean corpuscular volume and hemoglobin concentration, were healthy subjects, especially due to the measurement of determined by a Coulter LH Hematology analyzer (Beckman- platelet numbers as part of routine blood testing. 5,6 In some Coulter, Brea, CA, USA). Thrombocytopenia was defined as a of these cases, further clinical investigation reveals that platelet count less than 150 ¥10 9/L, thrombocytosis as a platelet thrombocytopenia is secondary to an occult disease, while count more than 400 ¥10 9/L, anemia as a hemoglobin concentration in others it is found that the low platelet count is inherited. less than 14.0 g/dL in men and 12.3 g/dL in women and leukopenia When all known disorders are ruled out, subjects are usually as a white blood cell count less than 4 ¥10 9/L. classified as affected by immune thrombocytopenia, since For each participant we collected genealogical information dat - no positive criteria have been identified for this disease and ing back to 17 th century and stored them in a relational database its diagnosis remains one of exclusion. 7 along with clinical and epidemiological data. To construct pedi - This study takes advantage of the availability of a data - grees we used a utility implemented in the PedNavigator soft - base including clinical, laboratory and genetic data of 12,517 ware, 14 which allows the reconstruction of different types of subjects, resulting from a large population-based survey genealogies starting from a list of individuals and setting the performed in the Ogliastra region, Sardinia. This area is desired number of generations. Available data allowed us to organ - characterized by genetic, demographic and environmental ize the 12,517 enrolled people into 538 pedigrees (on average 4.6 features which are typical of founder populations and thus generations deep) with an average family size of 37.7 individuals. ideal for studying genetic and non-genetic risk factors of Sixty-four pedigrees had more than one member with a platelet common diseases because of the reduced background vari - count lower than 150 ¥10 9/L. All of them were evaluated and clas - ability. 8,9 We addressed the issues of the prevalence of sified into four groups according to the degree of relationship of thrombocytopenia and determinants of platelet count in a affected members: (i) at least three first- or second-degree throm - healthy population with a wide age range. Although our bocytopenic relatives (high probability of a genetic disorder); (ii) study analyzed a specific, small geographic area, the results two first- or second-degree affected relatives (medium probability); we obtained shed new light on some determinants of (iii) at least two third-degree affected relatives (low probability); platelet count that could also operate in other populations. (iiii) no first- to third-degree affected relatives (no probability). The study adhered to the tenets of the Declaration of Helsinki and was approved by the review board of the institution that fund - Design and Methods ed the research (Italian Ministry of Education, University and Research n°: 5571/DSPAR/2002). Study design and data collection We analyzed data from 12,517 inhabitants of the Ogliastra region, in central eastern Sardinia, Italy (Figure 1). This mountain - ous area is sparsely populated with a total of 60,000 inhabitants (34 inhabitants/km 2) clustered in 23 villages. Ogliastra represents a genetic isolate since it has been geographically and socially seclud - ed for thousands of years due to the morphology of its territory. Mitochondrial analysis traced the original population back to the Neolithic era. 10 Furthermore, several Ogliastra villages grew slowly in isolation and had little or no admixture with the others, giving rise to high endogamy (ranging from 70% to 90%) and inbreeding. As a consequence of founder effects and genetic drift, a great deal of genetic differentiation among subpopulation isolates within Ogliastra was observed. 11 Genetic diversity measures showed that these villages rank among the most genetically homogenous European populations. 12 The data set comes from