HLA-DRB1 and DQB1 allele distribution in the Muong population exposed to malaria in Vietnam.

The distribution of 30 HLA-DRB1 alleles in 85 individuals and of 10 HLA-DQB1 alleles in 91 individuals of the Viet Muong population was studied and compared with those of nine other Asian populations, including 103 Viet Kinh belonging to the major ethnic group in Vietnam. In terms of genetic distance, our data are consistent with a close ethnogeographic relationship between Viet Muong, Buyi and Dai Lue, two Southern Chinese ethnic groups. Conversely, these three populations are distant from the Northern Chinese population. The Viet Kinh belong to an intermediate group, together with North-eastern Thais, Thais and present day Thais. The striking presence of the HLA-DQ1*0502 allele (48% frequency) in the Viet Muongs is possibly anthropological or environmental in origin: the Viet Muongs have been submitted to endemic malaria for centuries, and the survivors carry the protective trait of glucose-6-phosphate dehydrogenase deficiency. This raises the hypothesis of a possible resistance to lethal or severe forms of the disease, where the association with a specific HLA-DQB1 allele may play a role.

Hispano-Indian admixture in Paraguay studied by analysis of HLA-DRB1 polymorphism.

The genetic polymorphism of the Paraguayan population results from the admixture between South American Indians named Guaranis and Spaniards. In order to evaluate the genetic predominance in the Paraguayan population, we typed 50 healthy Paraguayans for HLA-DRB1 by molecular biology and compared their HLA-DRB1 polymorphism to that of the Guaranis and of two Spanish populations. Six significant differences of alleles frequencies were observed between Paraguayans and Guaranis--DRB1*01, 06 (13, 14), 15, 16, 07--whereas only one difference was observed with the Spaniards (DRB1*14). The DRB1*14 frequency was higher in Paraguayan than in the Spanish populations essentially due to the presence of DRB1*1402 related alleles (1402,06,13). These alleles are extremely rare in the Spanish populations whereas frequent in the Guaranis from Brazil and in South American Indian tribes living in the lymitrophe regions of Paraguay (Toba, Wichi and Terena). Thus, the presence of the DRB1*1402 related alleles (6%) in the Paraguayan population constitutes the major Indian contribution to the HLA-DR polymorphism of the Paraguayan population. The genetic distances between Paraguayans and the two Spanish populations were closer (.494 and .415) than that between Paraguayans and Guaranis (.958). Altogether these results suggest the predominance of the Spanish genetic in the Paraguayan population. Historical events are discussed to explain this predominance.

HLA-DRB1 and DQB1 genotypes in patients with insulin-dependent neonatal diabetes mellitus. A study of 13 cases.

Insulin-dependent neonatal diabetes mellitus (NDM) is a rare form of diabetes with a heterogeneous genetic background. The HLA-DRB1 and DQB1 genotypes were determined for 13 patients with NDM, from 9 unrelated families. Four patients had permanent NDM (PNDM) and 9 patients had transient NDM (TNDM). No excess of HLA susceptibility markers for type 1 diabetes (IDDM) was observed in this series of patients, whatever the forms of diabetes PNDM or TNDM. Paternal isodisomy of chromosome 6 was observed in two TNDM cases. These observations are consistent with the current hypothesis that there is a recessive susceptibility gene, at least in the transient form of the disease, unlinked to the MHC locus on chromosome 6. Although established in a short series, our results do not support an additive role of IDDM1 in the progression of the disease.

A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families.

A sample of 100 individuals from 50 French families of known pedigrees were typed for 14 loci of the HLA region (DPB1, DQB1, DQA1, DRB1, DRB3, 4, 5, C4B, C4A, Bf, C2, TNFa, TNFb, B, Cw, A). Linkage disequilibrium in each pair of loci was investigated by an exact test using a Markov chain algorithm. The results indicate no disequilibrium between DPB1 and the other loci, whereas the other class II genes are all significantly linked to each other. Linkage disequilibrium is also detected between some pairs of class I and class II-class I loci despite the long physical distance separating the loci (e.g. A-B, Cw-DRB1). On the other hand, some contiguous loci of the class III region are found to be in equilibrium with each other. Several hypotheses including selection, but also unequal allelic diversity at different MHC loci are discussed to explain this complex pattern of linkage disequilibrium.

Mitochondrial DNA polymorphism in the Vietnamese population.

The mitochondrial DNA variation was screened in a sample of 50 unrelated individuals of the Vietnamese population originating from Hanoi. A combination of long and standard PCR and restriction endonuclease digests with the enzymes HpaI, BamHI, HaeII, MspI, AvaII and HincII were used to reveal mtDNA variation. Twenty enzyme morphs were detected, three of which (HaeII-13Viet, MspI-19Viet and MspI-20Viet) are new and are produced by a single mutational event in already known enzyme morphs. Ten already known and four new mitotypes [93Viet (1-1-2-4-1), 94Viet (2-1-13Viet-1-1), 95Viet (2-1-13Viet-19Viet-1) and 96Viet (1-1-2-20Viet-12)] were found in the Vietnamese population. The 9-bp deletion occurring in the COII/tRNALys region of the mitochondrial genome was also analysed and 10 samples were found to have this deletion. The comparison of the Vietnamese with other East Asian populations showed a close genetic relationship of the population under investigation with other Orientals. However, the Vietnamese population can be differentiated by the significantly higher frequency of the enzyme morph HincII-5 and by seven new markers. These results strongly support the hypothesis of a dual ethnic origin of the Vietnamese population from the Chinese and Thai-Indonesian populations based on HLA markers and linguistic evidence.

Mitochondrial DNA polymorphisms of a west Algerian population (Oran region).

Mitochondrial DNA codes for enzymes involved in the cellular energetic pathway. The polymorphism of this genome has been extensively analyzed for disease associations, but can also be used to characterize anthropological distances between populations. This study presents the results of mitochondrial DNA (mtDNA) sequence variation for a population sample of 50 unrelated individuals originating from western Algeria. The samples were studied with the recently developed long PCR technique followed by RFLP analysis using six restriction endonucleases: HpaI, BamHI, HaeII, MspI, AvaII and HincII. One new morph for HpaI (named HpaI-9Alg) was detected, and was found to be derived from the combination of the already known morphs 3 and 4. mtDNA restriction endonuclease fragment patterns were analyzed for potential site gain or loss and classified into 18 mtDNA types by the sequence-comparison method. Three mtDNA types (97Alg; 2-1-7-1-1, 98Alg; 2-1-1-8-37 and 99Alg; 9Alg-1-1-1-3) were detected for the first time. Another mtDNA marker--the presence of the 9 bp deletion in the COII/tRNA(Lys) region--was also studied in the Algerian sample. No deletions were observed. Our results indicate that the Algerians are genetically related to the Israeli-Arab population, with certain characteristics found in southern Europeans and others found in sub-Saharan Africans.

A new predictive model for insulin-dependent diabetes mellitus susceptibility based on combinations of molecular HLA-DRB1 and HLA-DQB1 pockets.

With a view to establishing an accurate evaluation of the genetic predisposition to insulin-dependent type I diabetes (IDDM), we have built a model based on the characteristics of the relevant pockets of HLA-DR and -DQ molecules. Three independent populations were investigated. Group I and group II were Caucasoids, while group III was Japanese, including a total of 1,166 IDDM patients and 2,391 healthy controls. We formulate the hypothesis that suceptibility to IDDM is not only explained by the absence of Aspartate 57 (negative charge) from pocket 9 of DQB1 (P9DQ), but also by the presence of an electric charge (+/- vs. neutral), generated by residues 70, 71 and 74 in pockets 4 of DRB1 (P4DR) and DQB1 (P4DQ) molecules. The respective weight of each pocket, was evaluated in a multivariate analysis based on the logistic regression method. The 4 components (2 loci and 2 pockets) were systematically analysed in the computer model. It was clearly shown that the structural characteristics of pockets P9DQ-P4DR and, to a lesser degree that of P4DQ, account for IDDM predisposition. On applying the model to the whole international series, it appears that the highest risk concerns individuals with P9DQ non-Asp 57 and both the charged P4 of DRB1 and P4 of DQB1, conferring a 80% prediction of susceptibility. Conversely, P9DQ Asp and neutral P4DR and P4DQ give the lowest risk with a predictive value of 5%. This model of risk susceptibility prediction fits remarkably well with the observed distribution in a worldwide study. It allows a better evaluation of the respective role of HLA-DR and -DQ molecules as a major component of susceptibility to IDDM.

[HLA-C allele recognition using DNA sequencing]. / Reconnaissance des allèles HLA-C par séquençage de l'ADN.

The HLA-C locus was sequenced in 106 normal unrelated members of the French CEPH families. Following generic PCR amplification, exons 2 and 3 were amplified separately then sequenced using the ALF Expres sequencer. The Sequi Typer program was used for data analysis. Of the 72 alleles identified to date, 20 were recognized in the panel studied. Results were compared to those provided by the lymphocytotoxicity test, which had a 13.5% error rate and failed to reach the level of specific recognition. Sequencing preceded by amplification allowed immediate unambiguous allele assignment in 96% of cases. In four cases, a complementary method was required to resolve ambiguities. Reproducibility was high. The sequencing strategy described herein is a significant advance and may be particularly valuable for achieving perfect donor/recipient matching for allogeneic stem cell transplants.

Familial versus sporadic longevity and MHC markers.

We have studied the polymorphism of HLA-A, B, in 2 elderly populations (> or = 90 years) compared to a control series of 429 healthy unrelated individuals less advanced in age. The aged population issued from the CHRONOS cohort consisted of 336 centenarians without familial history of longevity, and 102 nonagenarians index cases randomly selected from families. Almost all individuals (310) were previously typed for HLA-DRB1. The increased allelic frequency of HLA DR11 was observed in familial nonagenarians (18.3%) compared to controls (10%) (p < .001) and to sporadic centenarians (11.8%). Concerning HLA Class I alleles, only rare alleles (A30, B70) remain significantly different from the controls after correction of the p value. No distortion of the Mendelian sharing of haplotypes was observed among sibling pairs of familial nonagenarians. A protective effect of the HLA-DR11 molecule itself, presenting adequately immunogenic-infectious peptides, is probable rather than genes in disequilibrium. Our study strongly supports the heterogeneity of longevity, the association of HLA-DR11 in its familial form in aged populations.

Mitochondrial DNA polymorphism in the French population.

One hundred unrelated individuals of French origin were screened for mtDNA variation as restriction fragment length polymorphisms (RFLPs) with the restriction enzymes HpaI, BamHI, HaeII, MspI, AvaII and HincII. Twenty enzyme morphs were detected, four of which (AvaII-37Fr, -38Fr, HincII-18Fr and -19Fr) are new. Of the 17 mitotypes detected, five are new and they were named 1-19Fr, 6-18Fr, 100Fr-2 (2-1-2-4-1-2), 101Fr-2 (2-1-1-1-38Fr-2) and 102Fr-2 (2-1-1-4-37Fr-2). All new morphs and mitotypes derive from those already known due to a single nucleotide substitution. The French population was compared with other European, Mediterranean and Caucasian populations. Calculation of the genetic distances showed close genetic affinity with European-Mediterranean populations and especially with Calabrians, Majorcans and northern Italians (at negative values).

[Revision of public health safety measures]. / Renforcement de la Sécurité Sanitaire.

RESTRUCTURING PUBLIC HEALTH: A reorganization of administrative management has been set up by the french law 98-535, in order to improve the vigilance of the population health and the safety control of products for human use. MANDATORY DECLARATION OF ACTIVITIES: In addition to the declaration of some infectious diseases, the activities in the field of human products, cells and tissues, have also now to be declared. SAFETY CONTROL OF FOOD: For the first time the control of human products, as well as that of food are placed under the rule of a single law.

HLA class II DRB1, DQA1 and DQB1 polymorphisms in the Polish population from Wielkopolska.

HLA DRB1, DQA1 and DQB1 alleles were determined by DNA PCR-SSO typing in a sample of 99 individuals originating from Wielkopolska (midwestern Poland). A high number of alleles (38 DRB1, 8 DQA1 and 14 DQB1) was detected at each locus, many of them presenting notable frequencies in this population. The three HLA loci are thus characterized by very high heterozygosity levels (93% for DRB1, 85% for DQA1, and 88% for DQB1), which confirms the results found for other European populations. A total of 6 DRB1-DQA1-DQB1 haplotypes are detected with an estimated frequency higher than 5%, namely, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*0701-DQA1*0201-DQB1*0201, DRB1*0101-DQA1*0101-DQB1*0501, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*03011-DQA1*0501-DQB1*0201, and DRB1*1301-DQA1*0103-DQB1*0603. A genetic distance analysis between the Polish and other world populations tested for HLA class II indicates that the Wielkopolska community is close to geographically close, rather than linguistically related populations from Europe. More generally, a good agreement between genetics and geography is found for DRB1 and DQB1 polymorphisms in Europe, suggesting that these two loci are highly informative for assessing historical relationships among humans.

HLA-G gene polymorphism segregation within CEPH reference families.

HLA-G, a nonclassical HLA class I antigen, presents tissue-restricted expression on human trophoblasts and may play an important role in immune tolerance of mother-versus-fetus. In this work we have demonstrated extensive HLA-G genomic polymorphism within three CEPH reference families, by PCR-SSCP analysis and direct sequencing. Among six unrelated parents we assigned eight HLA-G alleles, seven of which are new. We observed the segregation of HLA-G alleles of heterozygous parents among their offspring that matched the segregation of the HLA class I haplotypes. Only one of the mutations observed was found to be nonsynonymous indicating low polymorphism of the HLA-G molecule.

HLA-DR and -DQB1 DNA polymorphisms in a Vietnamese Kinh population from Hanoi.

We report here the DNA polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) typing of the HLA-DR B1, B3, B4, B5 and DQB1 loci for a sample of 103 Vietnamese Kinh from Hanoi, and compare their allele and haplotype frequencies to other East Asiatic and Oceanian populations studied during the 11th and 12th International HLA Workshops. The Kinh exhibit some very high-frequency alleles both at DRB1 (1202, which has been confirmed by DNA sequencing, and 0901) and DQB1 (0301, 03032, 0501) loci, which make them one of the most homogeneous population tested so far for HLA class II in East Asia. Three haplotypes account for almost 50% of the total haplotype frequencies in the Vietnamese. The most frequent haplotype is HLA-DRB1*1202-DRB3*0301-DQB1*0301 (28%), which is also predominant in Southern Chinese, Micronesians and Javanese. On the other hand, DRB1*1201 (frequent in the Pacific) is virtually absent in the Vietnamese. The second most frequent haplotype is DRB1*0901-DRB4*01011-DQB1*03032 (14%), which is also commonly observed in Chinese populations from different origins, but with a different accessory chain (DRB4*0301) in most ethnic groups. Genetic distances computed for a set of Asiatic and Oceanian populations tested for DRB1 and DQB1 and their significance indicate that the Vietnamese are close to the Thai, and to the Chinese from different locations. These results, which are in agreement with archaeological and linguistic evidence, contribute to a better understanding of the origin of the Vietnamese population, which has until now not been clear.