Diego Rey

Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association

The HLA-G gene displays several peculiarities that are distinct from those of classical HLA class I genes. The unique structure of the HLA-G molecule permits a restricted peptide presentation and allows the modulation of the cells of the immune system. Although polymorphic sites may potentially influence all biological functions of HLA-G, those present at the promoter and 3′ untranslated regions have been particularly studied in experimental and pathological conditions. The relatively low polymorphism observed in the MHC-G coding region both in humans and apes may represent a strong selective pressure for invariance, whereas, in regulatory regions several lines of evidence support the role of balancing selection. Since HLA-G has immunomodulatory properties, the understanding of gene regulation and the role of polymorphic sites on gene function may permit an individualized approach for the future use of HLA-G for therapeutic purposes.

The Origin of Amerindians and the Peopling of the Americas According to HLA Genes: Admixture with Asian and Pacific People

The classical three-waves theory of American peopling through Beringia was based on a mixed anthropological and linguistic methodology. The use of mtDNA, Y chromosome and other DNA markers offers different results according to the different markers and methodologies chosen by different authors. At present, the peopling of Americas remains uncertain, regarding: time of population, number of peopling waves and place of peopling entrance among other related issues. In the present review, we have gathered most available HLA data already obtained about First Native American populations, which raise some doubts about the classical three waves of American peopling hypothesis. In summary, our conclusions are: 1) North West Canadian Athabaskans have had gene flow with: a) close neighboring populations, b) Amerindians, c) Pacific Islanders including East Australians and d) Siberians; 2) Beringia was probably not the only entrance of people to America: Pacific Ocean boat trips may have contributed to the HLA genetic American profile (or the opposite could also be true); 3) Amerindians entrance to America may have been different to that of Athabaskans and Eskimos and Amerindians may have been in their lands long before Athabaskans and Eskimos because they present and altogether different set of HLA-DRB1 allele frequencies; 4) Amerindians show very few “particular alleles”, almost all are shared with other Amerindians, Athabaskans and Pacific Islanders, including East Australians and Siberians; 5) Our results do not support the three waves model of American peopling, but another model where the people entrance is not only Beringia, but also Pacific Coast. Reverse migration (America to Asia) is not discarded and different movements of people in either direction in different times are supported by the Athabaskan population admixture with Asian-Pacific population and with Amerindians, 6) HLA variability is more common than allele veriability in Amerindians. Finally, it is shown that gene genealogy analises should be completed with allele frequency analyses in population relatednes and migrations studies.

Distribution of HLA Class II Alleles and Haplotypes in Mexican Mestizo Population: Comparison with Other Populations

We describe the analysis of the Major Histocompatibility Complex (MHC) class II polymorphism in Mexican Mestizo population. The study provides the HLA-DRB1, DQA1 and DQB1 allele frequencies in 99 Mexican Mestizos. DNA from these individuals was typed by PCR followed by hybridization using sequence specific oligonucleotides (PCR-SSO). The relationship with other worldwide populations was studied by using HLA data from 69 different populations and calculating neighbor-joining dendrograms and correspondence multidimensional values. The highest frequencies were for DRB1*0802 (allele frequency = 0.151), DRB1*0701 (allele frequency = 0.111) and DRB1*0407 (allele frequency = 0.106). Among the eight DQA1 alleles detected, the most frequent were DQA1*03011 (allele frequency = 0.257), DQA1*0501 (allele frequency = 0.227) and DQA1*0401 (allele frequency = 0.166). Twelve DQB1 alleles were found and four of them, DQB1*0302 (allele frequency = 0.237), DQB1*0301 (allele frequency = 0.176), DQB1*0201 (allele frequency = 0.166) and DQB1*0402 (allele frequency = 0.166) showed the highest frequencies. The haplotype DRB1*0802-DQA1*0401-DQB1*0402 (0.151) predominated clearly, followed by DRB1*0701-DQA1*0201-DQB1*0201 (0.111) and DRB1*0407-DQA1*03011-DQB1*0302 (0.101). Both genetic distances and correspondence analyses showed that Mexicans clustered with Amerindian population. These results suggest that the Mexican Mestizo population be principally characterized by haplotypes presents in Amerindian and Caucasian populations with a low frequency of Black haplotypes. In summary, the HLA class II haplotype frequencies demonstrated the tri-racial component existing in Mexican Mestizos.

Amerindians show association to obesity with adiponectin gene SNP45 and SNP276: population genetics of a food intake control and “thrifty” gene

Adiponectin gene polymorphisms SNP45 and SNP276 have been related to metabolic syndrome (MS) and related pathologies, including obesity. However results of associations are contradictory depending on which population is studied. In the present study, these adiponectin SNPs are for the first time studied in Amerindians. Allele frequencies are obtained and comparison with obesity and other MS related parameters are performed. Amerindians were also defined by characteristic HLA genes. Our main results are: (1) SNP276 T is associated to low diastolic blood pressure in Amerindians, (2) SNP45 G allele is correlated with obesity in female but not in male Amerindians, (3) SNP45/SNP276 T/G haplotype in total obese/non-obese subjects tends to show a linkage with non-obese Amerindians, (4) SNP45/SNP276 T/T haplotype is linked to obese Amerindian males. Also, a world population study is carried out finding that SNP45 T and SNP276 T alleles are the most frequent in African Blacks and are found significantly in lower frequencies in Europeans and Asians. This together with the fact that there is a linkage of this haplotype to obese Amerindian males suggest that evolutionary forces related to famine (or population density in relation with available food) may have shaped world population adiponectin polymorphism frequencies.

Mixtec Mexican Amerindians: an HLA alleles study for America peopling, pharmacogenomics and transplantation.

HLA-A, -B and -DRB1 alleles have been studied in a Mixtec Mexican Amerindian population by indirect DNA sequencing. HLA relatedness has been tested by comparing results with other Amerindians and worldwide populations; a total of 15,681 chromosomes have been used. Genetic distances between populations, Neighbour Joining (NJ) dendrograms and correspondence analyses have been carried out. Conclusions are: 1) Our Mixtec sample from Oaxaca Coastal Mexican area shows an HLA profile different to that of Oaxaca Central Mountains area showing that genes and languages do not correlate which is inferred both by plane genetic distances and NJ dendrograms and correspondence analyses. 2) Genetic distances and NJ dendrograms join together Mazatecan Mexican Amerindians with our studied Coastal Mixtec group; it fits with the historical relationship between Mixtec and Mazatecans. 3) A*24:02-B*35:14-DRB1*04:11, A*02:01-B*15:15-DRB1*04:11 and A*68:03-B*39:08-DRB1*08:02 extended HLA haplotypes have been “de novo” found in our Mixtec Coastal sample. 4) Shared HLA alleles are found between our Pacific Coast Mixtec Amerindians and Pacific Islanders. 5) These results are useful for establishing a future area transplantation waiting list, for the study of HLA linked diseases epidemiology and for pharmacogenomics in certain drug therapy.

Las Alpujarras region (South East Spain) HLA genes study: evidence of a probable success of 17th century repopulation from North Spain

Conquest of Granada Muslim Kingdom (1492 AD) finished with Muslim occupation; they were mostly North African Berbers who had reached Iberia by 711 AD. A politics of Iberian Christianization followed after this date: Jewish were expelled in 1492 and Moriscos (Spaniards practicing Muslim religion or speaking Arab) were expelled from all Spanish territory on 1609 AD. Las Alpujarras is a southern Spain mountainous secluded region, which underwent a repopulation from North Spain and a specific Muslim (Moriscos)–Christian war took place according to historical records. Both Las Alpujarras repopulation by northern Iberians and Moriscos expulsion success have been debated and are regarded as non-clarified episodes. In this study, we have addressed the question whether the repopulation succeeded by determining HLA genes of present day Las Alpujarras inhabitants and compared with those of other Mediterranean populations HLA frequencies and genealogies. HLA frequencies show ambiguous results because of extant HLA similar gene frequencies there exist in North Africa and Spain. This is reflected by the finding of North and South western Mediterraneans close relatedness of HLA dendrograms and correspondence analyses. However, the genealogical study of extended HLA haplotypes particularly Alpujarran high frequency of HLA-A29-B44-DRB1*0701-DQA1*02-DQB1*02 (not found in Algerians but frequent in North and Central Spain) and Alpujarran low frequency extended haplotype HLA-A3-B7-DRB1*1501-DQA1*0102-DQB1*0602 (frequent in North Europe) reveals that a significant HLA gene flow from North Spain is observed in present day Alpujarrans: both haplotypes are characteristic of North Spain and North Europe, respectively. This may indicate that enforced Alpujarran repopulation from North Spain may have been a success, which was started by Spanish King Philip II in 1571 AD.

HLA in Jaidukama: an Amerindian secluded Colombian population with new haplotypes and Asian and Pacific-shared alleles

America first inhabitants and peopling are still debated. In order to increase knowledge about these questions, we have aimed to detect HLA genes of an Amerindian secluded community: Jaidukama, who lives in North Colombia Equatorial forest. HLA genotyping and extended haplotype calculations were carried out in 39 healthy individuals belonging to 13 families. HLA frequencies were compared to other Amerindians and worldwide populations by calculating genetic distances, relatedness dendrograms and correspondence analyses. Only four DRB1 alleles were found (*0404, *0407, *1402 and *1602); however a total of 17 Amerindian different extended class I–class II HLA haplotypes were directly counted from the family studies, nine of them were specific of Jaidukamas. Some of the alleles or group of alleles within an extended haplotype (i.e. DQB1–DRB1) were also found in Asians and Pacific Islanders, further supporting existence of Asian and Pacific gene flow with Amerindians or a common founder effect. It is further supported that HLA extended haplotypes vary faster than alleles in populations. It is concluded that this unique model of Amerindian secluded families study suggests that rapid HLA haplotype variation may be more important than allele variation for survival (starting immune responses). This work may also be useful for future transplant programs in the area.

Gorgan (Turkmen in Iran) HLA genetics: transplantation, pharmacogenomics and anthropology

HLA class I and II alleles have been studied in a population from Gorgan (North East Iranian city bordering Turkmenistan). This population is composed of mainly Turkmen who speak Oghuz Turkish language. Comparison of Gorgan people HLA profile has been carried out with about 7984 HLA chromosomes from other worldwide populations; extended haplotypes and three dimension genetic distances have been calculated by using neighbor-joining and correspondence relatedness analyses. Most frequent extended HLA haplotypes show a Siberian/Mediterranean admixture and closest populations are Chuvashians (North Caspian Sea, Russia) and other geographically close populations like Siberian Mansi, Buryats and other Iranians. New extended HLA haplotypes have been found, such as: A*31:01-B*35:01-DRB1*15:01-DQB1*03:01, A*01:01-B*35:01-DRB1*03:01-DQB1*02:01. Relationships of Turkmen with Kurgan (Gorgan) archaeological mounds, Scythians and Sarmatians are discussed. This study is also useful for a future transplantation Gorgan waiting list, Gorgan HLA and disease epidemiology and HLA pharmacogenomics.

Amerindians show no association of PPAR-γ2 gene Ala12 allele and obesity: an “unthrifty” variant population genetics

Obesity is for many scholars the most important starting status that gives rise to Metabolic Syndrome (MS) and Type 2 Diabetes (T2D). In the present paper, a genetically homogeneous Amerindian population, as defined by HLA genes, has been genotyped for one of the MS and T2D predisposing genes: PPAR-γ Ala12 and Pro 12 variants. Ala12 has been negatively associated with obesity, but other authors do not find such an association. Notwithstanding, a meta-analysis that used many subjects clearly demonstrated that PPAR-γ Ala12 bearing ones had a reduced risk for T2D. Our results show that Amerindians do not have association of PPAR-γ2 Ala12 and obesity; the latter was measured by waist circumference values after taken specific Amerindian normal waist parameters. Also, a population genetics study indicates that Pro12 allele was the wild allele, which must have occurred before modern humans left Africa. Ala12 may have appeared in Caucasoids later on, according to our comparisons. Negroids tend to show low or null Ala 12 allele frequencies, while most other populations have a significant frequency, particularly European Caucasoids. This may suggest that appearance of Ala12 allele occurred after populations adapted to an agricultural feeding.

HLA in Georgians (Caucasus) and their relationship with Eastern Mediterraneans.

AbstractHLA-A, -B, -DQB1, and –DRB1 typing has been performed in a sample of Georgian population (South Caucasus). Allele frequencies, neighbour joining and correspondence relatedness analyses and extended HLA haplotypes have been obtained with comparison with other Middle East and Mediterranean populations. Our Georgian sample tends to be genetically related in these analyses with Eastern Mediterraneans and Middle East people. This is important for future regional transplant programs, and Georgian HLA and disease epidemiology and pharmacogenomics.