A molecular basis for hemoglobin-H disease in American blacks

We have applied gene counting and restriction endonuclease mapping techniques to the study of two American black families in which there were one or more cases of HbH disease. We found deletions of three of the four normal alpha-globin genes in individuals with HbH disease. In two of these individuals, the chromosome containing the single alpha gene could have originated by crossing over between mispaired alpha genes, resulting in a deletion of about 4.2 kilobases (kb).     

Molecular basis of hemoglobin-H disease in the Mediterranean population

We investigated the molecular basis of hemoglobin-H disease by hybridization and restriction endonuclease mapping of the DNA in the Mediterranean populations. Of the 12 patients studied from Cyprus and Sardinia, 8 had the typical deletion defect with a single remaining alpha-globin gene. The nondeletion type of alpha-thalassemia was found in 3, and a "dysfunctional" gene in one. We conclude that the predominant cause of alpha-thalassemia in these populations is gene deletion.     

C4 null genes in American whites and blacks with myositis

The frequencies of C4A and C4B alleles were determined in 66 adults with myositis in relation to HLA class I and II. In whites with myositis, the C4A*Q0 allele occurred in 13/31 (47%) as compared to 25/101 (25%) normal controls (p = 0.08, relative risk = 2.7). Only 11/35 (31%) of black patients with myositis had a C4A*Q0 allele compared to 11/55 (20%) of controls (p = NS, RR = 1.8). Thus, the MHC class III genes do not appear to be the primary genetic risk factors for myositis in adults.     

Characterization of a rare single alpha-globin gene deletion in a Chinese woman with Hb H disease

A Chinese patient with Hb H (beta4) disease was found to be a compound heterozygote for a 2.4 kb alpha(+)-thalassemia (thal) deletion and the common Southeast Asian alpha0-thal deletion. The endpoints of the 2.4 kb deletion were identified by sequence analysis of the deletion junction. The deletion removes the entire alpha1-globin gene and leaves the alpha2-globin gene intact.     

Dysfunctional alpha-globin genes in hemoglobin H disease in blacks: variation in restriction fragment size permits the detection of the -alpha/-alpha T genotype

Hemoglobin H (HbH) disease is most often due to deletion of three of the four alpha-globin genes (genotype --/--alpha). In black subjects although the -alpha/chromosome is common, the --/haplotype is very rare and few examples of HbH disease have been detected. We have studied three black siblings with HbH by restriction endonuclease mapping of the alpha-like gene complex (5'-zeta-psi zeta-psi alpha 2-psi alpha 1-alpha 2-alpha 1-3') using zeta- and alpha- specific probes. The presence of size differences in the previously described hypervariable region between the zeta and psi zeta genes results in a restriction fragment length polymorphism which permitted the detection of single alpha genes on both number 16 chromosomes in these subjects. Quantitative DNA hybridization by a slot-blot technique confirmed that their genomes contained two alpha-globin genes. The results establish that in these black subjects HbH disease is associated with dysfunctional alpha-globin genes (genotype: -alpha/-alpha T).     

DNA analysis of HLA-DR and DQ genes in American blacks with systemic lupus erythematosus

We studied DNA polymorphisms of HLA-DR and DQ alleles in 63 American black patients with systemic lupus erythematosus (SLE). We found no HLA-DR beta, DQ alpha, or DQ beta restriction fragment length polymorphism (RFLP) or RFLP-determined DR or DQ specificity associated with SLE in either the patients or in 57 control subjects. DRw52b was positively associated with renal involvement and negatively associated with anti-nuclear RNP antibodies. Antibodies to Ro (SS-A) and La (SS-B) were associated with DR3(DRw17), DQw2.3. Early-onset SLE (less than or equal to 20 years of age) was associated with DRw8, and the frequency of neuropsychiatric involvement correlated negatively with a 3.7-kb Taq I DQ alpha RFLP. This suggests a role for DR and DQ genes in the clinical and serologic expression of SLE in American blacks.     

Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks

Thyroxine-binding globulin-slow (TBG-S), a variant found in 4-12% of Black and Pacific Island populations, is inherited as an X-chromosome linked trait. This variant is detected on isoelectric focusing by the characteristic cathodal shift of all its isoforms, suggesting that the difference resides in the core protein. In addition, TBG-S is slightly more thermolabile, which explains why subjects expressing TBG-S have on the average lower serum TBG, and thus reduced T4, concentrations. We now report the molecular basis for this TBG variant, deduced from sequencing the TBG-S gene of an American Black man. Sequencing of the four coding regions and all intron/exon junctions revealed a single nucleotide substitution in the codon for amino acid 171 of the mature protein. The resulting change of the codon GAC to AAC results in replacement of the normal aspartic acid by asparagine. Since the negative charge provided by the aspartic acid is lost when replaced by the neutral asparagine, this substitution seems responsible for the cathodal shift on isoelectric focusing and slower electrophoretic mobility of TBG-S. An identical nucleotide substitution was identified in an unrelated American Black man expressing TBG-S. Whether the TBG-S phenotype observed in populations from the Pacific Islands is caused by the same mutation remains to be determined.     

Rheumatoid arthritis in American blacks: a clinical and radiological study

Immunogenetic differences between American blacks and Caucasians have been described but a comparison of clinical and radiologic features between both groups has been lacking. Eighty-four American black and 166 Caucasian patients were randomly selected from our computer database and relevant clinical and demographic information obtained from records and interviews. Both groups were similar demographically, and no significant clinical differences were observed with regard to disease duration, frequency of extraarticular manifestations, use and toxicity from disease modifying antirheumatic drugs, RA related surgical procedures, disability, fatality rate and functional outcome. Our results suggest that seropositive RA is clinically and radiographically similar in both groups.     

Molecular basis of non-alcoholic fatty liver disease and metabolic syndrome in a subset of South Asians

International Journal of Diabetes in Developing Countries - Metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) are emerging threats in Pakistan. The prevalence of MetS is...     

The survival of malignant hypertension in blacks, whites and Asians in Britain

Life table analysis was used to compare survival rates in 168 whites, 39 blacks and 26 Asians with malignant phase hypertension. Amongst men, survival until death or the requirement of chronic renal dialysis was significantly worse in blacks, who initially presented with higher blood pressures and more renal impairment. There were no differences in survival in women in the three ethnic groups. Malignant hypertension remains common in Britain and still carries a poor prognosis.     

Adult chicken alpha-globin genes alpha A and alpha D: no anemic shock alpha-globin exists in domestic chickens.

Three alpha-type globin genes have been identified in the alpha-globin linkage group of chickens. No other alpha-type genes hae been directly shown to be within 10 kilobase pairs of any of these three closely linked genes. These three genes have been conclusively identified by DNA sequence analysis. The gene at the 5' end of the linkage group is an embryonic alpha-type globin gene, pi or pi', and the central gene corresponds to the minor adult alpha- globin, alpha D. The 3'-terminal gene sequence corresponds to the sequence of cDNA clones previously described as "alpha S", presumed anemic shock-induced alpha-globin gene [Salser, W. A., Cummings, I., Liu, A., Strommer, J., Padayatty, J. & Clarke, P. (1979) in Cellular and Molecular Regulation of Hemoglobin Switching, eds. Stamatoyannopoulos, G. & Nienheis, A. (Grune and Stratton, New York), pp. 621-643; Richards, R. I. & Wells, J. R. E. (1980) J. Biol. Chem. 255, 9306-9311]. Several groups of workers have isolated alpha S-type cDNA clones but no one has identified a cDNA clone corresponding to the published amino acid sequence of the major chicken alpha-globin, alpha A. We have identified the alpha S-type sequence as the only abundant alpha-like globin sequence in cDNA clones made from reticulocyte mRNA isolated from nonanemic chickens. Therefore, we suggest that the alpha S-type sequence corresponds to the true alpha A-globin species.     

The orangutan adult alpha-globin gene locus: duplicated functional genes and a newly detected member of the primate alpha-globin gene family.

We have cloned and sequenced the complete alpha 1- and alpha 2-globin genes of the orangutan, and here we compare them to the homologous genes of the human. The pattern of similarity apparent among the genes is most consistent with a model of gene correction operating on the primate alpha-globin cluster. This correction breaks down in both human and orangutan in the 3'-untranslated region at 14 base pairs downstream from the termination codon. The unit evolutionary period values calculated for either the replacement substitution or the silent substitutions are only slightly higher than the previously established molecular clock predicts. The 7-base-pair insertion in intron 2 of the human alpha 1-globin gene is not present in either orangutan gene, suggesting that this insertion is not the cause of the sequence divergence in the 3'-untranslated regions of primate alpha 2- and alpha 1-globin genes. Finally, blotting hybridization and partial DNA sequencing reveal a newly detected member of the primate alpha-globin gene family, which is located downstream from the duplicated adult alpha-globin genes.     

Similarity of blood pressure in blacks, whites and Asians in England: the Birmingham Factory Study

Factory workers aged 16-64 years were screened for ethnic differences in blood pressure. The 78% response rate was evenly spread between whites (439 men; 164 women), black West Indians (173 men; 101 women) and Asians (172 men). Mean systolic and diastolic pressures by age decade in men were similar in all three groups, but there was a modest excess of both higher and lower blood pressures in blacks and Asians. Older black women had higher blood pressures than whites, but body mass indices were 2-5 kg/m2 greater. Multiple regression analysis revealed no significant effect of ethnic group on either systolic or diastolic blood pressure variance and that the higher pressures in black women were accounted for by differences in age and body mass index. The influence of body mass index was more marked on diastolic than systolic pressure. In men, alcohol intake and a family history of hypertension had small independent positive effects on systolic pressure. The lack of black/white difference in blood pressure differs from the United States results and may be due to the similarity in social class of participants. This should be confirmed in further population samples with larger numbers of black (and Asian) subjects.     

The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes

Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.     

HLA antigens and gold toxicity in American blacks with rheumatoid arthritis

Summary An increase in the frequency of DR3 in rheumatoid arthritis (RA) patients exhibiting toxic reactions to gold salt (GS) therapy has been observed in several studies of Caucasoid patients. Likewise, the association of B35 with gold-induced mucocutaneous reactions has also been reported in Caucasoid RA patients. Similar studies in other ethnic groups have not been previously documented. The present study was performed in American black RA patients receiving GS to determine if there were similar HLA associations with toxic reactions as those reported in Caucasoids. Eighty-two seropositive and 18 seronegative American black RA patients were studied. Forty-one of the seropositive (50.0%) and six of the seronegative (33.3%) developed a toxic manifestation. No significant differences in the frequency distribution of HLA-B8, HLA-B35, DR, or DQw antigens were observed between the patients who had a toxic reaction and those who did not in either the seropositive or the seronegative RA patients. In particular, DR3 was not increased in patients with renal toxicity and B35 was not increased in patients with mucocutaneous reaction. Our study demonstrates that American black RA patients exhibiting GS toxicity do not have the same HLA associations as Caucasoids. The possibility that other genetic factor(s) may account for the occurrence of gold salt toxicity in American blacks requires further investigation.     

An alpha-globin gene initiation codon mutation in a black family with HbH disease

The molecular basis of hemoglobin H disease in a Black family of Canadian origin was investigated. Affected individuals had a combination of deletion and nondeletion alpha-thalassemia mutations on different chromosomes. Cloning and sequencing of the DNA of one member with the nondeletion form revealed a new thalassemia mutation, an A---- G substitution, in the initiation codon of the remaining alpha-globin gene of a rightward (-alpha 3.7) deletion chromosome. This mutation abolished an Ncol restriction site and therefore is detectable in genomic DNA by Southern blot analysis.     

Hb Bart's level in cord blood and deletions of alpha-globin genes

The white blood cell DNA of 36 cord blood samples with Hb Bart's in the red blood cells was studied for alpha-globin gene deletions by hybridization of DNA fragments digested by the restriction endonucleases Eco RI, Hpa I, Bam HI, and Bgl II. All 16 DNA samples from cord blood with Hb Bart's below 3% and no other abnormal hemoglobin had one alpha-globin gene deletion (alpha thal2), except one which had two alpha-globin gene deletions (alpha thal1). Most of the alpha thal2 were of the rightward deletion alpha thal2 genotype. Two new types of alpha thal2 variation was found, probably due to a polymorphism somewhere in an area outside the alpha-globin gene. All 14 cases with Hb Bart's between 3.5% and 8.5% and no other abnormal hemoglobin had two alpha-globin gene deletions (alpha thal1), except one that did not have any alpha-globin gene deletion and one that had one alpha-globin gene deletion. Three DNA samples of cord blood with Hb Bart's accompanied by Hb CoSp did not have any alpha-globin gene deletion. Sixty-five DNA samples from cord blood without Hb Bart's or other abnormal hemoglobin had no alpha-globin gene deletions, except one that had one alpha-globin gene deletion (alpha thal2). Two of the 65 DNA samples were found to have triplicated alpha-globin gene loci.     

Variant thyroxine-binding globulin in serum of Australian aborigines: a comparison with familial TBG deficiency in Caucasians and American blacks

About 40% of clinically euthyroid Australian Aborigines have low concentrations of total thyroxine (TT4) and triiodothyronine (TT3) in serum. While the finding of normal concentrations of serum thyrotropin (TSH) in such individuals is compatible with their eumetabolic state, the reason for the finding of a low free T4 index (FT4I) has been unclear. A genetic variant of T4-binding globulin (TBG) with reduced affinity for T4 has been suggested but decrease in the absolute concentration of TBG has also been reported. In this study, we measured various parameters of thyroid function in 20 serum samples from euthyroid Australian Aborigines selected for their low TT4 levels. Results were compared to those obtained in serum samples from Caucasians and American Blacks with inherited partial TBG deficiency, 15 of which were matched to the Aborigines by their TBG and 20 by their TT4 concentrations. Results were also compared with those from another group of 20 samples from Caucasians and American Blacks with normal TBG concentration, matched to the Aborigines by their serum TT4 concentration. TBG in serum from these Australian Aborigines was immunologically identical to that in Caucasians and American Blacks in terms of parallelism of serially diluted samples in the TBG radioimmunoassay (RIA).(ABSTRACT TRUNCATED AT 250 WORDS)