Predictors of thalassaemia carriers in Trinidad and Tobago

OBJECTIVE: To determine possible predictors of thalassaemia carriers among prospective blood donors in Trinidad and Tobago. DESIGN AND METHODS: 460 prospective blood donors were screened for microcytosis (MCV<83fL) by performing a complete blood count (CBC) using a Sysmex XE-2100. The 86 samples with microcytosis further had a blood film analysis, iron studies, haemoglobin electrophoresis, haemoglonin F and A2 quantification, and DNA analysis for thalassaemia mutations. Statistical analysis was done using SPSS to determine predictors of thalassaemia trait. The variables tested were ethnicity, haemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin volume (MCHC), red blood cell (RBC), RBC distribution width (RDW-SD and RDW-CV). We looked at different mathematical formulae to predict thalassaemia trait ie the Mentzer Index, Shine and Lal Index, Green and King Index, Srivastava Index, RDW Index and the red cell indices tested were RDW-CV, RDW-SD and RCC. RESULTS: 86 (18.7%) subjects had microcytosis. 44(51.2%) of these had DNA results. 31(70.5%) had thalassaemia trait: 25(80.6%) with genotype –α/αα, 4(12.9%) α-/α-(all α3.7), one IVS I-5 G/C and one IVSII-666 T/C. The MCV, RDW-SD and RDW-CV were useful in predicting thalassaemia trait. RDW-SD identified 30 (96.8%) of the 31 carriers, the Green and King formula identified 27 (87.1%), and Ricerca index identified all 31 (100%). CONCLUSION: MCV, RDW-SD, Green and King formula and Ricerca index may be useful predictors of thalassaemia trait in Trinidad and Tobago.

Evidence for genetic hitchhiking effect associated with insecticide resistance in Aedes aegypti

Information on genetic variation within and between populations is critical for understanding the evolutionary history of mosquito populations and disease epidemiology. Previous studies with Drosophila suggest that genetic variation of selectively neutral loci in a large fraction of genome may be constrained by fixation of advantageous mutations associated with hitchhiking effect. This study examined restriction fragment length polymorphisms of four natural Aedes aegypti mosquito populations from Trinidad and Tobago, at 16 loci. These populations have been subjected to organophosphate (OP) insecticide treatments for more than two decades, while dichlor-diphenyltrichlor (DDT) was the insecticide of choice prior to this period. We predicted that genes closely linked to the OP target loci would exhibit reduced genetic variation as a result of the hitchhiking effect associated with intensive OP insecticide selection. We also predicted that genetic variability of the genes conferring resistance to DDT and loci near the target site would be similar to other unlinkded loci. As predicted, reduced genetic variation was found for loci in the general chromosomal region of a putative OP target site, and these loci generally exhibited larger F (ST) values than other random loci. In contrast, the gene conferring resistance to DDT and its linked loci show polymorphisms and genetic differentiation similar to other random loci. The reduced genetic variability and apparent gene deletion in some regions of chromosome 1 likely to reflect the hitchhiking effect associated with OP insecticide selection(AU)

Population genetics of four hypervariable loci

Populations of white Caucasians, Afro-Caribbeans and Asians residing within the UK have been analysed at 4 different hypervariable loci. A computerised system was used to store and to analysed the data. Simulation experiments were carried out in order to determine whether there was any evidence for population stratification, which would lead to non-independence of allelic distributions. (AU)

Fetal hemoglobin levels and beta s globin haplotypes in an Indian population with sickle cell disease

To further explore the cause for variation in hemoglobin F (HbF) levels in sickle cell disease, the á globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126SS, 141AS, 17Sá§, 7Aá§, and 12AA) Indians from the state of Orissa. The ás globin gene was found to be linked almost exclusively to a ás haplotype (+++-++-), which is also common in Saudi Arabian patients from the Eastern province (referred to as the Asian ás haplotype). By contrast, the majority of áA and ᧠thalassemia globin genes are linked to hoplotypes common in all European and Asian populations (+-----[+/-];--++-++). Family studies showed that there is a genetic factor elevating HbF levels dominantly in homozygotes (SS). This factor appears to be related to the Asian ás globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary presistance of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.(AU)

Interaction of the OOO globin gene haplotype and sickle haemoglobin

We have studied the interaction of the OOO/OO gene arrangements with various á globin genotypes (AA, AS, AC, SS and SC). Whereas this interaction has no detectable clinical or haematological effects in subjects with AA, SS or SC genotypes it is associated with a significantly increased level of Hb S or Hb C in heterozygotes for these variants. These findings indicate that the additional O globin gene in the OOO gene arrangement is functional (Summary)

The interaction of alpha-thalassemia and homozygous sickle-cell disease

Patients with homozygous sickle-cell disease may be homozygous for alpha-thalassemia 2 (O-/O-), may be heterozygous for alpha-thalessemia 2 (O-/OO), or may have a normal alpha-globin-gene complement (OO/OO). We compared the clinical and hematologic features of 44 patients who had sickle-cell disease and homozygous alpha-thalassemia 2 with those of controls with the two hematologic conditions. The patients with homozygous alpha-thalassemia 2 had significantly higher red-cell counts and levels of hemoglobin and hemoglobin Aý, as well as significantly lower hemoglobin F, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, reticulocyte counts, irreversibly-sickled-cell counts, and serum total billirubin levels, than those with a normal alpha-globin-gene complement. Heterozygotes (O-/OO) had intermediate values. In the group with homozygous alpha-thalassemia 2, fewer patients had episodes of acute chest syndrome and chronic leg ulceration and more patients had splenomegaly, as compared with patients in the other two subgroups. These data confirmed previous suggestions that alpha-thalassemia inhibits in vivo sickling in homozygous sickle-cell disease and may be an important genetic determinant of its hematologic severity.

The genetics and molecular basis of alpha thalassaemia in association with Hb S in Jamaican Negroes

We have studied seven Jamaican Negro families in whom the genes for O thalassaemia and the sickle cell mutation (ás) were independently segretated. Using a combination of techniques we identified two O thalassaemia phenotypes which resemble the reserve (O thalassaemia 1) and mild (O thalassaemia 2) determinants previously described in Orientals. This study has enabled us to clearly correlate the phenotype of O thalassaemia with the genotype in this population. Furthermore, since in each family O thalassaemia was present in association with the gene for the sickle cell mutation we have determined the proportion of Hb S in the peripheral blood of individuals with the OO/OO, -O/-O genotype who are also heterozygous for the ás mutation. Genetic analysis in these families shows that in each case subjects with the O thalassaemia 1 phenotype are homozygous for the O thalassaemia 2 defect (-O/-O). We have found no instances of the genotype --/OO in this population which may explain the rarity of the severe O thalassaemia 2 homozygotes from this population shows that the (-O/) haplotype results from a deletion of one of the linked pair of O globin and that this had probably arisen by an unequal crossover between non-homologous O genes (AU)

Comparison of haematological features of the ᧠and á+ thalassaemia traits in Jamaican negroes

Haematological characteristics have been compared in 29 subjects with heterozygous ᧠thalassaemia and in 33 subjects with heterozygous á+ thalassaemia, identified by the type of sickle-cell-á thalassaemia among close relatives, in a Jamaican Negro population. Total haemoglobin, MCV and MCH were significantly lower in the ᧠type but the level of Hb A2 was not significantly different. Individual values for MCV, MCH and Hb A2 in the 225+ type occasionally overlapped those in the normal population casting doubt on the adequacy of these criteria in identifying all cases of heterozygous á+ thalassaemia. The haematological differences are those which would be expected on theoretical grounds. The inability to confidently differentiate the two types of heterozygous á thalassaemia has implications for genetic counselling. The inability to distinguish heterozygous á+ thalassaemia from normals on any single haematological index suggests that surveys depending on estimations of Hb A2 or on MCV alone may have underestimated the prevalence of the á+ thalassaemia gene. (AU)

Linkage relationships between beta- and delta-structural loci and African forms of beta thalassaemia

Five families are described in which there have been matings between individuals doubly heterozygous for beta thalassaemia and the delta-chain variant haemoglobin A2' to normal persons. In all there were 24 informative offspring. There were no crossovers between the beta-thalassaemia and delta-chain loci; in three of the families the genes were linked in cis and in two families the genes were found in trans.Together with previously reported families there have now been 58 opportunities for crossing over between the beta-thalassaemia and delta-chain loci and there have been two possible and one highly probable crossovers. Of the total of 9 families reported to date 4 have had the genes for beta thalassaemia and Hb A2' in cis and 5 in trans. These findings are contrasted with the findings in families where a beta-chain structural variant and Hb A2' have been observed together and these genes have always been found in trans and never in cis. The reasons for linkage disequilibrium of this type are discussed. It is concluded tentatively that the distance between the delta-structural and beta-thalassaemia loci is greater than that between the delta-structural and beta-structural loci. To date this conclusion can only be applied to the beta+ -thalassaemia and beta-thalassaemia genes as found in the African population, since this is the only population with a high incidence of delta-chain mutants which allow linkage analysis of this type to be carried out. (AU)

Globin synthesis in the Jamaican Negro with beta-thalassemia

Globin synthesis was studied in three Jamaican Negro families with 18 heterozygotes and 5 homozygotes for beta-thalassemia. Synthesis of the beta chain of Hb A in the peripheral blood of heterozygotes was equal to that of the alpha-chain in 10 patients and was decreased in the remainder. In one patient with Hb C beta-thalassemia the beta/alpha ratio was normal. These findings were similar to those in American Negroes, but differed from those in Caucasian with beta-thalassemia trait, in each of whom the beta/alpha ratio was decreased. Globin synthesis was balanced in the bone marrows of Negro and Caucasian heterozygotes. Despite the milder clinical disease in Negro homozygotes as compared to Caucasian patients, the beta/alpha ratios were similar in both groups. The presence of alpha-thalassemia combined with beta-thalassemia in Negro heterozygotes is not a likely explanation for the high incidence of balanced globin synthesis ratios. The expression of relative beta to alpha chain synthesis in Negro heterozygotes appears to be modified by a factor which is not linked to the delta-chain locus. The nature of this factor is not known at present.(Summary)

Leg ulceration in sickle cell anaemia

In Jamaica, leg ulcers are a major manifestation of sickle cell disease. The chronicity of the lesions is such that education and consequent work potential are seriously affected. Although these lesions rarely cause mortality, they are a major determinant of the morbidity of the disease. (AU)

Hemoglobin O Arab in four negro families and its interaction with hemoglobin S and hemoglobin C

Hemoglobin O Arab (O2á2 121 Glu leads to Lys) was found in 25 members of four apparently unrelated Negro families in the West Indian island of Jamaica. In each family the propositus had Hb SO disease. Two cases had been mistakenly diagnosed as Hb SC disease. Two persons heterozygous for both Hb C and Hb O Arab were found in these families, and Hb O Arab á thalassemia in one other relative. The clinical course and symptomatology of Hb SO disease is comparable to that in Hb SD(O2á2 121 Glu leads to GluNH2) disease and more severe than Hb SC disease. In vitro mixtures of Hb O Arab and Hb S change from a liquid to a gel phase at total hemoglobin concentrations weaker than those required to gel pure Hb S, whereas mixtures of Hb C require a stronger total hemoglobin concentration before gelling will occur. Oxygen dissociation studies on red cells containing Hb SO show a homozygous sickle-cell anemia and outside the range for subjects with sickle-cell Hb C disease.(AU)