exudates and Elliptocytosis--Hereditary

Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations.. To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals.. We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants.. Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level.. We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

Topics: Adolescent; Adult; Aged; Anion Exchange Protein 1, Erythrocyte; Asian People; Blood Glucose; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Elliptocytosis, Hereditary; Ethnicity; Female; Gene Deletion; Genome-Wide Association Study; Glycated Hemoglobin; Humans; Malaysia; Male; Middle Aged; Polymorphism, Genetic; Singapore; Young Adult

Southeast Asian ovalocytosis (SAO) is a red blood cell abnormality common in malaria-endemic regions and caused by a 27 nt deletion of the band 3 protein gene. Since band 3 protein, also known as anion exchanger 1, is expressed in renal distal tubules, the incidence of SAO was examined in distal renal tubular acidosis (dRTA) in Malays in Kelantan, Malaysia. Twenty-two patients with dRTA and 50 healthy volunteers were examined for complication of SAO by both morphological and genetic analyses. SAO was identified in 18 of the 22 dRTA patients (81.8%), but only two of the 50 controls (4%). The incidence of SAO was significantly high in those with dRTA (p<0.001), indicating a dysfunctional role for band 3 protein/anion exchanger 1 in the development of dRTA.

Topics: Acidosis, Renal Tubular; Adult; Anion Exchange Protein 1, Erythrocyte; Child; Child, Preschool; Elliptocytosis, Hereditary; Erythrocytes; Female; Gene Deletion; Humans; Infant; Malaysia; Male; Middle Aged

We describe three mutations of the red-cell anion exchangerband 3 (AE1, SLC4A1) gene associated with distalrenal tubular acidosis (dRTA) in families from Malaysia and Papua NewGuinea: Gly(701)-->Asp (G701D), Ala(858)-->Asp(A858D) and deletion of Val(850) (DeltaV850). The mutationsA858D and DeltaV850 are novel; all three mutations seem to berestricted to South-East Asian populations. South-East Asianovalocytosis (SAO), resulting from the band 3 deletion of residues400-408, occurred in many of the families but did not itselfresult in dRTA. Compound heterozygotes of each of the dRTA mutationswith SAO all had dRTA, evidence of haemolytic anaemia and abnormal red-cell properties. The A858D mutation showed dominant inheritance and therecessive DeltaV850 and G701D mutations showed a pseudo-dominantphenotype when the transport-inactive SAO allele was also present. Red-cell and Xenopus oocyte expression studies showed that theDeltaV850 and A858D mutant proteins have greatly decreased aniontransport when present as compound heterozygotes (DeltaV850/A858D,DeltaV850/SAO or A858D/SAO). Red cells with A858D/SAO had only 3% ofthe SO(4)(2-) efflux of normal cells, thelowest anion transport activity so far reported for human red cells. The results suggest dRTA might arise by a different mechanism for eachmutation. We confirm that the G701D mutant protein has an absoluterequirement for glycophorin A for movement to the cell surface. Wesuggest that the dominant A858D mutant protein is possibly mis-targetedto an inappropriate plasma membrane domain in the renal tubular cell,and that the recessive DeltaV850 mutation might give dRTA because ofits decreased anion transport activity.

Topics: Acidosis, Renal Tubular; Adolescent; Adult; Anion Exchange Protein 1, Erythrocyte; Child; Child, Preschool; Chlorides; Elliptocytosis, Hereditary; Erythrocytes; Female; Humans; Ion Transport; Malaysia; Male; Mutation; New Guinea; Pedigree

The malaria parasite rates and densities were compared in 79 ovalocytic-normocytic pairs of Malayan Aborigines matched for age, sex, proximity of residence to each other, and use of bed nets when sleeping in their jungle settlement in central Peninsular Malaysia. Malaria infection was determined from thick and thin Giemsa-stained blood films collected monthly for a period of six months. Blood films from ovalocytic individuals were found to be positive for malaria less often than in persons with normal red blood cells (P less than 0.05). Malaria infections per 100 person-months at risk were 9.7 in the ovalocytic group compared with 15.19 in the normocytic group. Among individuals parasitemic at any time, heavy infections (greater than or equal to 10,000 parasites/mm3 of blood) with Plasmodium falciparum, P. vivax, and P. malariae were encountered only in normocytic subjects, which comprised approximately 12.5% of the malaria-positive individuals in this group. In an earlier survey of 629 settlers that identified subjects for the above study, the prevalence of ovalocytosis was found to increase significantly with age. The above field observations support the view that ovalocytic individuals might have a survival advantage in the face of malaria. Consideration of the ovalocytic factor is indicated in future evaluations of malaria control measures in areas where ovalocytosis is prevalent.. The malaria parasite rates and densities were compared in 79 ovalocytic-normocytic pairs of Malayan Aborigines matched for age, sex, proximity of residence to each other, and use of bednets when sleeping in their jungle settlement in central Peninsular Malaysia. Malaria infection was detected from thick and thin Giemsa-stained blood films collected monthly for a 6-month period. Blood films from ovalocytic individuals were found to be positive for malaria less often than in those individuals with normal red blood cells (p0.05). Malaria infections/100 person-months at risk were 9.7 in the ovalocytic group as compared with 15.19 in the other group. Among those parasitemic at any time, heavy infections (or= 10,000 parasites/cu.mm of blood) with Plasmodium falciparum, P. vivax, and P. malariae were seen only in normocytic subjects, approximately 12.5% of the malaria-positive persons in this group. In an earlier survey of 629 settlers who identified subjects for the above study, the prevalence of ovalocytosis was found to increase significantly with age. The above field observations support the view that ovalocytic individuals might have a survival advantage in the face of malaria. Consideration of the ovalocytic factor is indicated in future evaluations of malaria control measures in those areas where ovalocytosis is prevalent.

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Elliptocytosis, Hereditary; Female; Hemoglobins; Humans; Incidence; Infant; Malaria; Malaria, Falciparum; Malaria, Vivax; Malaysia; Male; Middle Aged; Native Hawaiian or Other Pacific Islander; Prevalence; Racial Groups; Regression Analysis

Topics: Adolescent; Adult; Child; Child, Preschool; Elliptocytosis, Hereditary; Female; Fertility; Genetics, Population; Humans; Infant; Malaria; Malaysia; Male

Topics: Adult; Anemia, Hemolytic, Congenital; Chromosome Aberrations; Chromosome Disorders; Elliptocytosis, Hereditary; Female; Fetal Blood; Humans; Infant, Newborn; Malaysia; Pregnancy

A high frequency of nonhemolytic hereditary ovalocytosis in Malayan aborigines is thought to result from reduced susceptibility of affected individuals to malaria. Indeed, Kidson et al. recently showed that ovalocytes from Melanesians in Papua New Guinea are resistant to infection in culture by the malarial parasite Plasmodium falciparum. In order to determine if protection against parasitic invasion in these ovalocytes might be the result of some altered membrane material property in these unusual cells, we measured their membrane and cellular deformability characteristics using an ektacytometer . Ovalocytic red cells were found to be much less deformable in comparison to normal discoid red cells. Similar measurements on isolated membrane preparations revealed a marked reduction in ovalocytic membrane deformability. To produce equal deformation of ovalocytic and normal membranes, ovalocytes required an 8-10-fold increase in applied shear stress, indicating that their membrane was capable of deforming under sufficient stress. To test the possibility that this increased membrane rigidity might confer resistance to parasitic invasion, we performed an in vitro invasion assay using Plasmodium falciparum merozoites and Malayan ovalocytes of varying deformability from seven different donors. The level of infection of the ovalocytes ranged from 1% to 35% of that in control cells, and the extent of inhibition appeared to be closely related to the reduction in membrane deformability. Moreover, we were able to induce similar resistance to parasitic invasion in nonovalocytic normal red cells by increasing their membrane rigidity with graded exposure to a protein crosslinking agent. Our findings suggest that resistance to parasite invasion of Malayan ovalocytes is the result of a genetic mutation that causes increased membrane rigidity.

Topics: Blood Viscosity; Elliptocytosis, Hereditary; Erythrocyte Membrane; Humans; Malaria; Malaysia; Osmolar Concentration

Hereditary ovalocytosis/elliptocytosis occurs in polymorphic frequencies among several Malaysian populations and also in Melanesia. Although the condition has been described as an autosomal dominant, Melanesian family studies suggest that it is inherited recessively. Based on 75 Orang Asli families, it is shown that the Malaysian form of elliptocytosis is most likely inherited as an autosomal dominant. It appears, therefore, that either the inference of recessive inheritance in Melanesians is incorrect or that the ovalocytosis/elliptocytosis phenotypes are due to distinct genetic entities in the two regions.

Topics: Asian People; Elliptocytosis, Hereditary; Genes, Dominant; Genetics, Population; Humans; Malaysia; Terminology as Topic

A survey of abnormal haemoglobins and hereditary ovalocytosis was carried out among 629 Malays of Minangkabau descent in the Ulu Jempul District of Kuala Pilah, in the state of Negri Sembilan in West Malaysia.. Several abnormal haemoglobins were found with the following frequencies: Hb E 5.25%, Hb CoSp 2.38%, Hb A2 indonesia 0.80%, a fast moving Hb with a Mobility between A and Bart's 0.64% and Hb Q 0.16%. Hereditary ovalocytosis was found in 13.2% of these people. None of the persons with hereditary ovalocytosis had any evidence of haemolysis.

Topics: Adolescent; Adult; Child; Elliptocytosis, Hereditary; Female; Hemoglobin E; Hemoglobins, Abnormal; Humans; Malaysia; Male; Middle Aged

A survey of abnormal hemoglobins, G6PD deficiency and hereditary ovalocytosis was carried out among the Dayaks of Sarawak. The only abnormal hemoglobin found was Hb Co Sp, which occurred in 0.35% of the Land Dayaks and 0.83% of the Sea Dayaks. G6PD deficiency occurred in 5.3% of the male Land Dayaks and 5.0% of the male Sea Dayaks; no electrophoretic variant of G6PD was found in any of the 285 Land Dayaks and 240 Sea Dayaks examined. Hereditary ovalocytosis was found in 12.7% of the Land Dayaks and 9.0% of the Sea Dayaks.

Topics: Elliptocytosis, Hereditary; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins, Abnormal; Humans; Malaysia; Male; Thalassemia

Topics: Adult; Electrophoresis; Electrophoresis, Paper; Elliptocytosis, Hereditary; Ethnicity; Female; Gels; Genes; Hemoglobins, Abnormal; Humans; Malaysia; Male; Pedigree; Population Surveillance; Starch

Topics: Adult; Elliptocytosis, Hereditary; Hemoglobins, Abnormal; Humans; Malaysia; Male