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HLA-G allele frequencies were studied in Yucatán (Mexico) Maya Amerindians by a direct exon DNA sequencing technique. It is described that Mayas are probably one of the first populations together with Olmecs that populated Meso America and that important HLA genetic differences between Mexican and Guatemalan Mayas support that Maya languages were imposed to several neighbouring Amerindian groups. HLA-G*01:01:02, HLA-G*01:01:01 and HLA-G*01:04:01 are the most frequent alleles in this population. It is remarkable that HLA-G*01:05N allele was not found in the population in accordance with similar results found in another Amerindians. Also, protein allele HLA-G*01:04 frequency is found not to differ to those found in another far or close living Amerindians in contrast to other World populations. It seems that while high HLA-G*01:05N frequency is found in Iran and Middle East populations, probably where this allele appeared within an ancestral HLA-A*19 group of alleles haplotype and it is maintained by unknown evolutionary forces, Amerindians do not have a high frequency because a founder effect or because required natural evolutionary forces do not exist in America. Finally, we believe useful to study HLA-G evolution for its physiopathology understanding in addition to the many papers on statistics on HLA-G and in vitro models that are yearly published.

HLA-G immune modulatory genes and molecules are presently being studied by a widespread number of research groups. In the present study, we do not aim to be exhaustive since the number of manuscripts published every year is overwhelming. Instead, our aim is pointing out facts about HLA-G function, polymorphism and pathology that have been confirmed by several different researchers, together with exposing aspects that may have been overlooked or not sufficiently remarked in this productive field of study. On the other hand, we question whether performing mainly studies on HLA-G and disease associations is going to give a clear answer in the future, since 40 years of study of classical HLA molecules association with disease has still given no definite answer on this issue.

HLA-G is a non-classical class I HLA molecule that induces tolerance by acting on receptors of both innate and adaptive immune cells. When overexpressed in tumors, limits surveillance by the immune system. The HLA-G gene shows several polymorphisms involved in mRNA and protein levels. We decided to study the implication of two polymorphisms (rs371194629; 14bp INS/DEL and rs1063320; +3142 C/G) in paired tissue samples (tumoral and non-tumoral) from 107 Spanish patients with gastric adenocarcinoma and 58 healthy control individuals, to assess the possible association of the HLA-G gene with gastric adenocarcinoma susceptibility, disease progression and survival. The presence of somatic mutations involving these polymorphisms was also analyzed. The frequency of the 14bp DEL allele was increased in patients (70.0%) compared to controls (57.0%, p=0.025). In addition, the haplotype formed by the combination of the 14bp DEL/+3142 C variants is also increased in patients (54.1% vs 44.4%, p=0.034, OR=1.74 CI95% 1.05-2.89). Kaplan-Meier analysis revealed that 14bp DEL/DEL patients showed lower 5-year life-expectancy than INS/DEL or INS/INS (p=0.041). Adjusting for TNM staging (Cox regression analysis) disclosed a significant difference in death risk (p=0.03) with an expected hazard 2.6 times higher. Finally, no somatic mutations were found when comparing these polymorphisms in tumoral vs non-tumoral tissues, which indicates that this is a preexisting condition in patients and not a de novo, tumor-restricted, event. In conclusion, the variants predominant in patients were those increasing HLA-G mRNA stability and HLA-G expression, clearly involving this molecule in gastric adenocarcinoma susceptibility, disease progression and survival and making it a potential target for immunotherapeutic approaches.

Mexican Mixtec population from coastal Jamiltepec (Oaxaca) Amerindians was studied for its HLA profile. They show genetic characteristics close to Pacific Islanders and other Mexican Isthmus Amerindians (Mazatecans, Zapotecans and Mayas). Interestingly, this coastal Oaxaca Mixtec population is genetically closer to Mazatecans than to Oaxaca Mixtec from mountains according to HLA genes. Mixtec HLA frequent extended haplotype A*24:02-B*35:14-DRB1*16:02 has been also found in Jaidukama North Colombia forest Amerindians and in Guatemala Mayas; A*24:02, DRB1*04:03, DRB1*04:04 and DRB2*16:02 are frequent alleles also common to Pacific Inhabitants. Notwithstanding, Mixtecs show deep cultural and genetic roots with Mesoamerican Amerindians and all of them probably contributed to construct Monte Alban culture around an important Pyramid Complex close to Oaxaca City.

Quechua Amerindians established Inca Empire and chose Cuzco as their capital. Their language is closely related to that of Aymara ethnic group and both of them were originated from Titikaka Lake Altiplano area. In the present study we have analyzed Bolivian Quechua HLA profile and found that it has common characters with other Andean and Pacific Amerindians (Uros, Aymaras, Lamas, Mapuches, Athabascan), and Pacific Islanders, including Easter Islanders: relatively high frequency of HLA-A*24 (:02), class II haplotypes DRB1*08:02-DQB1*04:02, and DRB1*04:03-DQB1* 03:02. Titikaka Lake area prehistoric populations: Quechua, Aymaras and Uros are closely related according to HLA Nei DA genetic distances and other HLA traits: they built up Tiwanaku culture, which resembles that of Easter Island (i.e.: similar giant heads); later, Quechuas also moved to Cuzco. This genetic reletedness together with Easter Island and Titikaka Lake Tiwanaku (Bolivia, Peru) cultural common similarities support a prehistoric Pacific people/Amerindians gene flow.

Huastecos or Teenek Amerindians are presently living at North East Mexico (San Luis Potosi State). They have probably one of the most ancient culture of Mexico and Central America together with Mayas and Olmec groups with which also show close relationships. Proximity to Atlantic Ocean/Mexican Gulf originated that Spaniards had very early contact with them at about 1519 CE or before. In the present paper we have aimed to study HLA gene profile which may be useful for HLA and disease epidemiology and transplant programs in Teeneks. HLA-DRB1*04:07, -DRB1*14:06 and -DRB1*04:11 have been found in high frequency like in other Amerindian groups. High frequency typical Amerindians HLA extended haplotypes have been found, such as A*02-B*35-DRB1*04:07-DQB1*03:02; A*68-B*39-DRB1*04:07-DQB1*03:02 and A*02-B*39-DRB1*04:07-DQB1*03:02; also new haplotypes have been described, like A*02-B*52-DRB1*04:11-DQB1*03:02, A*68-B*35-DRB1*14:02-DQB1*03:01 and A*68-B*40-DRB1*16:02-DQB1*03:01. Genetic proximity is observed not only to linguistically close Mayans, but also to Mazatecans, Mixtecans and Zapotecans, who speak an altogether different languages; it shows once more that genes and languages do not correlate. This population was greatly diminished after European contact between 1500 and 1600 years CE; in fact, North and South America First Inhabitants population was brought from 80 down to 8 million people because of diseases (i.e.: measles, smallpox or influenza), slavery and war.

Gorgan (Iran) have been studied for HLA-A, -B, -C, -DRB1 and -DQB1 genes for the first time. They are Turkmen and originated in East Asia around Altai Mts; they originally spoke a Turk language classified within the Turkish-Oguz group. Peripheral blood samples were collected from Gorgan City (Iran) and HLA typed by standard methodology. HLA allele frequencies were compared with 7984 chromosomes of other World populations and it was shown existence of admixture of Siberian and Mediterranean HLA characters in this population, probably due to longlasting contact with Persians. Three new HLA extended haplotypes were found: A*01:01-B*35:01-DRB1*03:01-DQB1*02:01, A*30:01-B*13:01-DRB1*15:01-DQB1*02:01 and A*31:01-B*35:01-DRB1*15:01-DQB1*03:01. Gorgan (Iran) were most close to Chuvashians (Noth Caspian Sea, Russia) and Siberians, like Tuvinians, Mansi and Buryats in Neighbour Joining and Vista analyses. It is established a relationship of this population with Kurgan (Gorgan, Iran) archaeological mounds culture. However, their kinship with Scythians (2nd century BC) and Sarmatians (4th century AD) is obscure although both of them spoke a Persian language.

Mapuche Amerindians live now widespread in Central South Chile and Argentina and speak “Mapudungun”, an unclassified language. A group of Chilean Mapuche was studied for HLA genes using standard techniques. Typical Amerindian HLA genes and haplotypes are found in the population, like HLA-DRB1*14:02, −08:02 and class II haplotype DRB1*08:02-DQB1*04:02. However, these and other genes are also common in Pacific Islanders. Thus, relatedness of First America Inhabitants with some Pacific Islanders is stressed. Evidences of Pacific and Atlantic cultural and genetic exchange, probably in both directions, and California Man settlements found since 130,000 years ago makes it necessary a revision of Americas peopling. This study may be also useful for medical Mapuche use in Transplantation and HLA and disease Epidemiology.

Background:HLA autosomic genes are unique because they conform the most polymorphic human system. Importance of this system is recognized in Medicine for Transplantation, Epidemiology (HLA and disease linkage), Pharmacogenomics (HLA linked to drug side effects) and for defining the origin of populations in both male and female lineages.Objectives:Studying HLA profile of a isolated Amerindian group from North Colombia (Wiwa) in order to draw conclusions about its Preventive Medicine, the genetic relationship with Worldwide populations and America peopling, since this last issue is hotly debated.Methodology:A total of 14,660 HLA chromosomes were included. Peripheral blood was obtained from volunteer blood donors belonging to Wiwa (also named Arsario) ethnic group. HLA-A, -B, -C, -DRB1 and -DQB1 genes were analyzed by standard methods. Wiwa Amerindians relationships with others were calculated by using Arlequin, Dispan and Vista software computer packages.Results:Extended HLA, -A, -B, -C, -DRB1 and -DQB1 haplotypes have been studied for the first time in this population. Classical Amerindian haplotypes have been found and also new Wiwa (Arsario) Amerindian haplotypes. New haplotypes are A*68:01 - B*15:01 - C*03:03 - DRB1*14:02 - DQB1*03:02, A*11:01 - B*07:02 - C*07:02 - DRB1*15:03 - DQB1*06:02 and A*68:01 - B*15:01 - C*03:04 - DRB1*14:02 - DQB1*03:01.Conclusion:They have been reached after exhaustive comparisons of Wiwa with other Amerindians and Worldwide populations by using genetic distances, Neighbor Joining trees, correspondence analysis and specific group of alleles which are common and frequent in both Amerindians and Pacific Islanders. They are: 1) The Americas First Inhabitants have been probably come through Bering Strait and also through Pacific (from Austronesia and Asia) and Atlantic (from Europe) routes. A bidirectional gene flow is not discarded. 2) Genetic HLA Amerindian profile is separated from that of other Worldwide populations. 3) Amerindians geographical proximity groups’ relatedness is not concordant with HLA genetic relatedness, neither with language. This may be explained by a substantial population decrease that occurred after Europeans invaded America in 1492 and carried new pathogens and epidemics. 4) Our results are also useful for Wiwa and other Amerindians future preventive medicine (HLA linked diseases), HLA pharmacogenomics and transplantation regional programs.

HLA-A,-B,-C,-DRB1 and -DQB1 alleles have been studied in Chimila Amerindians from Sabana de San Angel (North Colombian Coast) by using high resolution molecular typing. A frequent extended haplotype was found:HLA-A*24:02-B*51:10-C*15:02-BRB1*04:07-DQB1*03:02 (28.7%) which has also been described in Amerinndian Mayos Mexican population (Mexico, California Gulf, Pacific Ocean). Other haplotypes had already been found in Amerindians from Mexico (Pacific and Atlantic Coast), Peru (highlands and Amazon Basin), Bolivia and North USA. A geographic pattern according to HLA allele or haplotype frequencies is lacking in Amerindians, as already known. Also, five new extended haplotypes were found in Chimila Amerindians. Their HLA-A*24:02 high frequencies characteristic is shared with aboriginal populations of Taiwan; also, HLA-C*01:02 high frequencies are found in New Zealand Maoris, New Caledonians and Kimberly Aborigines from Australia. Finally, this study may show a model of evolutionary factors acting and rising one HLA allele frequency (-A*24:02), but not in others that belong to the same or different HLA loci.

Several studies confirmed the association of HLA-DRB1 and -DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Arabs. This is a systematic review and meta-analysis aimed at comprehensively evaluating this association with T1D, using molecular HLA data. Relevant studies were identified through systemic search of Medline/PubMed, Cochrane, Science Direct, ResearchGate, and EMBASE databases. Statistical analysis was carried out using RevMan, and Comprehensive Meta-analysis programs. Given the heterogeneity of African Arabs, we also performed subgroup analysis according to ethnicity. Analysis of sensitivity, heterogeneity, and publication bias were performed to validate the outcome of the findings. This meta-analysis included 862 T1DM cases, along with 1,390 normoglycemic control, and comprised ten comparisons. Our study indicates that DRB1*03 (OR = 2.86), DRB1*04 (OR = 2.78), and DQB1*02 (OR = 2.29), are positively associated with increased risk of T1DM, while DRB1*07 (OR = 0.48), DRB1*11 (OR = 0.20), DRB1*13 (OR = 0.47), DRB1*15 (OR = 0.30), DQB1*05 (OR = 0.39), and DQB1*06 (OR = 0.27) were negatively associated with T1D, suggesting a protective role against T1D. This meta-analysis was characterized by low heterogeneity, sensitivity, and publication bias, indicating the robustness and reliability of the results. Background: Several studies confirmed the association of HLA-DRB1 and –DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Arabs. This is a systematic review and meta-analysis aimed at comprehensively evaluating this association with T1D, using molecular HLA data. Methods: Relevant studies were identified through systemic search of Medline/PubMed, Cochrane, Science Direct, ResearchGate, and EMBASE databases. Statistical analysis was carried out using Revman, and Comprehensive Meta-analysis programs. Given the heterogeneity of African Arabs, we also performed subgroup analysis according to ethnicity. Analysis of sensitivity, heterogeneity, and pub¬lication bias were performed to validate the outcome of the findings. This meta-analysis included 862 T1DM cases, along with 1,390 normoglycemic control, and comprised ten comparisons. Results: Our study indicates that DRB1*03 (OR = 2.86), DRB1*04 (OR = 2.78), and DQB1*02 (OR = 2.29), are positively associated with increased risk of T1DM, while DRB1*07 (OR = 0.48), DRB1*11 (OR = 0.20), DRB1*13 (OR = 0.47), DRB1*15 (OR = 0.30), DQB1*05 (OR = 0.39), and DQB1*06 (OR = 0.27) were negatively associated with T1D, suggesting a protective role against T1D. Conclusion: This meta-analysis was characterized by low heterogeneity, sensitivity, and publication bias, indicating the robustness and reliability of the results.

HLA genes (class I and II) have been studied in a Kurd population from Iran (North West towns of Saqqez and Baneh, close to Irak border). Kurds speak an Iranian language. HLA Kurd profile has been compared with those of Central Asians, Siberians, Mediterraneans and other worldwide populations; a total of 7746 chromosomes were used for computer comparisons. Both Neighbor-joining and correspondence genetic analyses place Kurds in the Mediterranean population cluster, close to Iranians, Europeans and Caucasus populations (Svan and Georgian). New extended HLA haplotypes are described, being A*02:01-B*35:01-DRB1*01:01-DQB1*05:01 and A*24:02-B*18:09-DRB1*11:01- DQB1*03:01 the most frequent ones; other Kurd extended haplotypes are also found in Azeris and Palestinians. This research work may be useful for: 1) future Iranian Kurds transplantation regional programs, 2) HLA pharmacogenomics in order to practise a preventive Medicine and drug side effects, and 3) Epidemiology of HLA-associated diseases in Kurds.

Azeris from Iran North West provinces (Tabriz city) have been studied for HLA alleles. A total of 8.902 HLA-bearing chromosomes (Chr 6) have been used for comparing their relatedness with other Middle East, Caucasus, Mediterranean and Central Asia populations. Mediterranean, Central Asian and Caucasus extended HLA haplotypes were found, i.e.: A*24:02-B*35:01-DBR1*11:01-DBQ1*03:01 and A*01:02-B*08:01-DRB1*03:01-DQB1*02:01. Genetic distances, Neighbour Joining and Correspondence analyses also showed that Azeris were close to Kurds, who have shown a closer Mediterranean/Caucasus HLA profile, and Gorgan (Turkmen) who have shown a closer Central Asia profile, as expected. It is shown that three different Iranian populations according to Language, History and Geography: Gorgans, Kurds and Azeris are genetically close. In fact, old Azeri language (Adari) was an Iranian language and not a Turkic one, which they nowadays speak. Also, present study does not support “Aryan” invasion from the East in accordance with many other previous studies. Finally, our results are useful for establishing Preventive Medicine programs in Transplantation and HLA and Pharmacogenomics/Disease linkage. Keywords : HLA, Pharmacogenomics, Disease, Transplantation, Iran, Irak, Georgia, Turkey, Azerbajan, Azeris, Gorgan, Kurds, Yazd, Baloch, Aryan, Dene Caucasian, Zoroastro,Persia.

Kurds from Iraq (Dohuk and Erbil Area, North Iraq) have been analyzed for HLA genes. Their HLA genetic profile has been compared with that of other Kurd groups from Iran and Tbilisi (Georgia, Caucasus) and also Worldwide populations. A total of 7,746 HLA chromosomes have been used. Genetic distances, NJ dendrograms and correspondence analyses have been carried out. Haplotype HLA-B∗52-DRB1∗ 15 is present in all three analyzed Kurd populations. HLA-A∗02-B∗51-DRB1∗ 11 is present in Iraq and Georgia Kurds. Haplotypes common to Iran and Iraq Kurds are HLA DRB1∗ 11-DQB1∗03, HLA DRB1∗03-DQB1∗02and others in a lower frequency. Our HLA study conclusions are that Kurds most probably belong to an ancient Mediterranean/Middle East/Caucasian genetic substratum and that present results and those previously obtained by us in Kurds may be useful for Medicine in future Kurd transplantation programs, HLA Epidemiology (HLA linked diseases) and Pharmacogenomics (HLA-associated drug side effects) and also for Anthropology. It is discussed that one of the most ancient Kurd ancestor groups is in Hurrians (2,000 years BC). © 2017 Arnaiz-Villena et al.

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.

HLA-G and HLA-A frequencies have been analysed in Amerindians from Ecuador. HLA-G allele frequencies are found to be closer to those of other Amerindians (Mayas from Guatemala and Uros from Peru) and closer to European ones than to Far East Asians groups, particularly, regarding to HLA-G*01:04 allele. HLA-G/-A haplotypes have been calculated for the first time in Amerindians. It is remarkable that HLA-G*01:05N "null" allele is found in a very low frequency (like in Amerindian Mayas and Uros) and is also found in haplotypes belonging to the HLA-A19 group of alleles (HLA-A*30, -A*31, -A*33). It was previously postulated that HLA-G*01:05N appeared in HLA-A*30/-B*13 haplotypes in Middle East Mediterraneans. It may be hypothesized that in Evolution, HLA-G*01:05N existed primarily in one of the HLA extant or extinct -A19 haplotype, whether this haplotype was placed in Middle East or other World areas, including America. However, the highest present day HLA-G*01:05N frequencies are found in Middle East Mediterraneans.

HLA-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.

Amerindian Mapuche (Araucanians) are now living in Chile and Argentina at both sides of Andean Mountains. They are anthropologically and genetically different from southernmost South America Patagonian Amerindians. Most of the HLA alleles found in our Mapuche sample are frequent or very frequent in North and South America Amerindians: (1) Class I: A*02:01, A*03:01, A*68:01, B*39:09, B*51:01, (2) Class II: DRB1*03:01, DRB1*04:03, DRB1*07:01, DRB1*08:02, DRB1*14:02, DRB1*16:02. One of the nine most frequent extended haplotypes seems to be from European origin, suggesting the existence of a degree of admixture with Europeans in our Mapuche sample. It has been calculated of about 11 % admixture. Three of the extended haplotypes are also found in other Amerindians and five of them are newly found in Mapuche Amerindians: A*68:01-B*39:09-DRB1*08:02-DQB1*04:02; A*68:01-B*51:01-DRB1*04:03-DQB1*03:02; A*29:01-B*08:01-DRB1*03:01-DQB1*02:01; A*02:01-B*15:01-DRB1*04:03-DQB1*03:02; A*33:01-B*14:02-DRB1*07:01-DQB1*03:03. The medical importance of calculating HLA profile is discussed on the diagnostic (HLA and disease) and therapeutical bases of HLA pharmacogenomics and on the construction of a virtual transplantation HLA list profile. Also, anthropological conclusions are drawn.

HLA-G molecules seem to have a protective effect for the semi-allogeneic fetus by mother immunosuppression. Also, pregnancy pathologies have been associated to HLA-G(∗)01:05N "null allele". In addition, other general regulatory immune functions have been associated to HLA-G in infections, tumors and autoimmunity. Thus, it is striking that HLA(∗)01:05N allele is maintained in a substantial frequency in certain human populations. In the present work, we have analysed HLA-G allele frequencies in Amerindian Mayans from Guatemala and in Uros from Titikaka Lake "totora" (reed) floating islands (Peru). No HLA-G(∗)01:05N has been found in both of these Amerindian populations. Further studies in Worldwide populations show that the highest HLA-G(∗)01:05 allele frequencies are found in Middle East; these findings have a bearing in future clinical/epidemiological studies in Amerindians. This would suggest that either this area was close to the "null" allele origin (as predicted by us) and/or some evolutive pressures are maintaining these high frequencies in Middle East. However, the fact that Cercopithecinae primate family (primates postulated as distant human ancestors) has also a MHC-G "null" allele in all individuals suggests that this allele may confer some advantage either at maternal/fetal interface or at other immune HLA-G function level (tumors, infections, autoimmunity). Human HLA-G(∗)01:05N may produce HLA-G isoforms, like Cercopithecinae monkeys may, which may suffice for function.

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.

Metabolic syndrome (MS) and obesity are principal causes of morbidity all over the World, particularly for their association to cardiovascular risk. Amerindians are often living in countries and remote areas with unavailable sophisticated diagnoses methodologies. However, waist-circumference is a reliable and easy to record parameter of visceral obesity and MS. Waist circumference normal values are not yet established in Amerindians: South Asian and Japanese values have been recommended for Amerindian use. The purpose of this study is to objectively define for the first time the waist circumference measure cut-off points for Amerindians. A total of 303 unrelated Amerindian adults recently immigrated to Madrid were studied; they were healthy, since they were questioned and tested as appropriate for blood donation. Waist-circumference was measured in these voluntary blood donors after written consent. Chosen subjects for study had HLA quasi-specific Amerindian genes and not gained weight since their relatively short time living in Spain. Amerindians with Type I or II diabetes or family antecedents were removed from the study. The biochemical parameter used to define normality for MS was the reliable serum HDL-cholesterol levels, whose values are diet independent. A Receiver Operating Characteristic analysis was used to compare the predictive validity and to find out the optimal cut-off points of waist circumference normal values. Cut-off points were ≤88.5 cm in males and ≤82.5 cm in females; these values were close to the median values (88 and 82.2 cm, respectively). Obtained waist circumference values recorded here in normal Amerindians are different to those previously recommended indirectly (those of South Asian/Japanese populations). These parameters may be of great value for American countries health care in order to predict and control MS and its cardiovascular complications. Other countries having a heavy Amerindian immigration (i.e.: USA, Spain) may also benefit for establishing specific Preventive Medicine programs.

The major histocompatibility complex genes are located on the short arm of the human sixth chromosome; they are highly polymorphic and therefore have been very advantageous in population genetic studies.A Mazahua group established in North Mexico State and also in nearby Michoacan state in the rainy mountain highlands (Mexico) was studied for their human leukocyte antigen (HLA)-DRB1 alleles. The relationship with other Amerindians and worldwide populations was studied by using 14,996 chromosomes from 75 different populations and calculating neighbor-joining dendrograms and correspondence multidimensional values.Five principal HLA allele frequencies were found in our group: DRB1*0802 (the most frequent one in this population), DRB1*0407, DRB1*0403, DRB1*0101, and DRB1*1406. Both genetic distances and correspondence analyses clearly show that our Mazahua group is genetically close to some of the most ancient groups living in Mexico (Mayos, Zapotecans, Tennek) and South American Amerindians. Amerindians remain as a group apart from the rest of the world.The results analyzing the HLA-DR locus suggest that Mazahua language (Otomangue) does not correlate with those of the most closely HLA-correlated ethnic groups. The present data may be useful for future transplantation programs, HLA and disease diagnosis, and pharmacogenetic studies.

Amerindians immigrated to Madrid (Spain) region are about 10% of the present day population. Amerindians are believed to be the first American inhabitants, before Na-Dene speakers, Aleuts and Eskimo. They may initially have arrived to America from Siberia and also from other parts of Pacific Sea (South Asia, Polynesia and Australia). Nowadays, they populate America from Canada to Tierra del Fuego (South America tip South). Most Amerindian immigrants to Madrid have come from Andean Countries in the last 10 years (mainly Ecuador, Bolivia, Peru and Colombia). They show an HLA profile with "quasi-specific alleles", which makes them different to the rest of the World. In the present work, we have aimed to determine the immigrants HLA profile in order to establish a virtual transplantation waiting list which may be useful for their therapeutic transplants, particularly bone marrow transplantation. This would be carried out together with Amerindian immigrants to other parts of Spain and with their own countries in order to build up transplantation programs. Specific epidemiology programs on HLA linked disease will also be established. Immigrant volunteer unrelated blood donors contributed to the present study. HLA typing was performed by standard methods and their HLA profile obtained and obtained and compared with 15,108 HLA chromosomes from the rest of the World, including Spaniards. The immigrants showed a typical Amerindian profile similar to isolated Amerindian ethnic groups and altogether different to other World inhabitants (including Spaniards). These are the first bases to set up transplantation and epidemiology studies in collaboration with their original population in America. Finally, the HLA profile found in these Amerindians does not indicate their American specific original area, as it is expected from previous studies, i.e.: they do not relate more with Andean than with other Amerindians in Neighbour Joining dendrograms or correspondence analyses.

Major histocompatibility complex (MHC)-G and -C molecules bear ligands to natural killer immunoglobulin receptors (KIR). MHC-G evolution in primates shows some anomalies. In New World monkeys MHC-G molecules show a high polymorphism and most likely are classical antigen presenters; they also cluster closer to MHC-E in a relatedness dendrogram. Their genes lack intron 2 deletion, which is typical of all other primates in regard to MHC-G. Medium-sized Eurasian-African monkeys (Cercopithecinae) show stop codons in exon 3: only MHC-G isoforms without exon 3 are possible. Big apes such as the orangutan, gorilla, and chimpanzee as well as human beings show limited HLA-G polymorphism. HLA-C has not been found in medium-size Eurasian-African monkeys, but we have found MHC-C DNA sequences in more evolutionary ancient New World monkeys. Taking into account that the KIR inhibitory receptors signal is dominated by MHC-C in human beings, this suggests that both MHC-C molecules and their ligands within natural killer lymphocyte KIR also exist in the most evolutionary ancient apes (New World monkeys were present on Earth before 40 million years ago), as KIR receptors also appeared before 130 million years ago in evolution. Indeed, KIR receptor genes have recently been found in a New World monkey.

Aleuts HLA profile has been compared with that of neighboring and worldwide populations. Thirteen thousand one hundred and sixty-four chromosomes have been used for this study. Computer programs have obtained HLA allele frequencies, genetic distances between populations, NJ relatedness dendrograms, correspondence analysis and most frequent HLA extended haplotypes. Aleuts have inhabited Aleutian Islands since about 9000 years BP according to fossil and genetic (mtDNA) records. They are genetically different to Eskimo, Amerindian and Na-Dene speakers according to their HLA profile; this correlates with cultural and anthropological Aleut distinctiveness. No typical Amerindian HLA alleles have been found in a significant frequency. Their HLA relatedness to Saami (or Lapps, northern Scandinavians), Finns and Pomors (North-West Russia) indicates an ancient possible origin from the Baikal Lake Area (southern Siberia) around the present day Buryat peopling area; other origins are not discarded. Aleuts characteristic HLA profile may influence future transplantation programs in the region and be useful to study diseases linked to HLA epidemiology.

Human leukocyte antigen (HLA)-E is a nonclassical class I (Ib) gene with a restricted polymorphism. Only eight DNA alleles and three proteins of this gene have been described and their frequencies analyzed in Caucasian, Oriental, Asian Indian, and Negroid populations. In the present study, HLA-E polymorphism has been analyzed in six Amerindian and Mestizo populations from North and South America and compared with previously described populations. HLA-E*0101 is the most frequent allele found in all populations except in Afrocolombian and Wayu Amerindians, in which blood group analyses show a high admixture with Caucasian and African populations. Mazatecan and Mapuche (two Amerindian groups from North and South America, respectively) presented similar HLA-E frequencies, whereas Wayu Indians are more similar to the Afrocolombian population. The Mexican and Colombian Mestizo show similar allele frequencies to Amerindians with high frequencies of HLA-E*0101 and HLA-E*010302 alleles. Also, frequencies in Negroids and Asian Indians present a similar distribution of HLA-E alleles. These data are in agreement with worldwide restricted polymorphism of HLA-E because no new allele was detected in the six populations studied. The allelic frequencies show differences among Caucasian, Oriental, Mestizo and Indian populations. Ape major histocompatibility complex-E allelism is also very restricted: common chimpanzee (one allele); bonobo (two alleles); gorilla (two alleles); orangutan (one allele); rhesus monkey (eight alleles); cynomolgus monkey (two alleles); and green monkey (two alleles).

Caribbean Islands including Cuba were first inhabited by Meso-American and later by Arawak-speaking Amerindians from nowadays Venezuela. Spanish invaders brought to almost extinction to the Amerindian population after 1492. Black slaves from West Africa were taken into Cuba by Europeans. The degree of admixture among populations is approached. HLA alleles were studied by DNA techniques. Comparison with other worldwide populations (a total of 14.094 chromosomes) included genetic distances, Neighbour-Joining dendrograms, correspondence analyses and calculation of extended haplotypes. While African-European HLA features were clearly found, Amerindian HLA characteristics are less evident, indicating that Amerindian devastation was particularly marked after 1492 AD. However, typical Amerindian alleles have been found in our Cuban sample, i.e. DRB1*0403, DRB1*0404, DRB1*0407, DRB1*0411, DRB1*0802 and DRB1*1602. The presence of Amerindian alleles in Cubans [corrected] may have a bear in the making up of transplantation registries (both for bone marrow and solid organ transplantation) at the regional level and also be important for epidemiological studies of diseases linked to HLA.

We have studied the relationship between the histocompatibility class I and II antigens and Sneddon's syndrome (SS) in a Spanish patient with SS and her relatives (13 available members of an extensive 3-generation pedigree with diverse autoimmune hypercoagulation abnormalities). The patient and her father were diagnosed with a primary antiphospholipid antibody syndrome and were HLA-A30-B13-Bw6. In addition, a HLA-Bw6-DQ1 association was present in all the members of this kindred. These data suggest that the combination of the histocompatibility class I and II antigens in this family may be a marker for predisposition to SS.

HLA-G polymorphism has been found to be relatively low in all world populations. In the present paper two new HLA-G molecules are described in ancient American natives. A new HLA-G molecule from a Ecuador Amerindian individual (male) showed four codon changes with respect to HLA-G*010101. Silent changes at α1 domain (residue 57, Pro, CCG → CCA) and α2 domain (residue 93, His, CAC → CAT and residue 100, Gly, GGC → GGT) and one productive change in α3 domain (residue 219 changed from Arg to Trp). This α3 change may dramatically alter HLA-G interactions with beta-2 microglobulin, CD8, ILT-2 and ILT-4 ligands present in subsets of T, B, NK, monocytes, macrophages and dentritic cells. Another HLA-G new molecule was found in a woman from Hispaniola Island, Dominican Republic (Sto Domingo) it presented a silent change at α2 domain residue 107, Gly, GGA → GGT and non-silent change at residue 178, Met → Thr (with respect to HLA-G*010101) which is close to class I molecule/clonotypic T cell receptor interaction sites. Functional implications of these findings are discussed. © 2016 American Society for Histocompatibility and Immunogenetics

Background HLA-DMB proteins are important for intracellular microbial metabolism in order other major histocompatibility complex (MHC) molecules present peptides to lymphocytes. In addition, HLA-DMB alleles have been found linked to diseases in some ethnic groups and HLA-DMB molecules may be important to explain HLA disease association. Objective To detect HLA-DMB alleles profile in Amerindians for the first time and compare them to other populations. This will establish the bases to study HLA-DMB linkage to disease in Amerindians. Method A group of 168 voluntary Amerindians have been typed for HLA-DMB alleles. They have been characterized both, by genetic and genealogical bases. Cloning and automated HLA-DMB DNA (exons 2, 3 and 4) sequencing have been performed for allele assignation. Results HLA-DMB*01:01:01 and HLA-DMB*01:03:01 show the highest frequencies. These have been compared to other World wide populations. HLA-DMB*01:03:01 is tightly associated to certain specific HLA-DRB1 alleles in Amerindians. Conclusion The specific Amerindian HLA-DMB allele frequencies and their linkage disequilibrium with other MHC alleles may be crucial to determine HLA-DMB World wide variation, evolution and specific linkage to disease in Amerindians and other populations.

The HLA allele frequency distribution of the Mexican Teenek Indians has been studied and compared with those of other First American Natives and worldwide populations (a total of 15694 chromosomes from 73 different populations were analyzed). This study corroborate the restricted HLA polymorphism in the Amerindian populations and demonstrate how the Amerindians show a relatively homogeneity as opposed to other First Native American groups. Finally, the present data support previous ones that state the lack of complete correlation between language and genetics in micro-environmental studies; Teenek Mayan language does not correspond with a close Mayan (Guatemala) relatedness.

A stem cell registry population from Hong Kong, of Chinese ethnicity, was examined for HLA-A and HLA-B alleles using a two-stage sequence-specific oligonucleotide probe system. Comparison of the HLA-A and HLA-B frequencies with different populations showed a close relationship with a Chinese population from Singapore, although there were several differences in the presence/absence of alleles at the HLA-B locus. Having the data available on these registry donors will influence the search strategy and the ongoing compilation of new donors to the registry. In addition, knowing which alleles do/do not occur in this population will aid in the distinction of ambiguities which result from the use of many of the typing kits available.

HLA-A, -B, -DRB1, -DQA1 and -DQB1 alleles have been studied in three relatively isolated populations of northern Spain from Cantabria ( Pas Valleys inhabitants or Pasiegos and Cabuernigos) and from the Basque Country (Arratia Valley inhabitants). These populations have been compared with neighbouring ones and other Mediterraneans by using neighbour-joining dendrograms and plane genetic distances.

HLA genes allele distribution has been studied in Mediterranean and sub-Saharan populations. Their relatedness has been tested by genetic distances, neighbour-joining dendrograms and correspondence analyses. The population genetic relationships have been compared with the history of the classical populations living in the area. A revision of the historic postulates would have to be undertaken, particularly in the cases when genetics and history are overtly discordant. HLA genomics shows that: 1) Greeks share an important part of their genetic pool with sub-Saharan Africans (Ethiopians and west Africans) also supported by Chr 7 Markers. The gene flow from Black Africa to Greece may have occurred in Pharaonic times or when Saharan people emigrated after the present hyperarid conditions were established (5000 years B.C.). 2) Turks (Anatolians) do not significantly differ from other Mediterraneans, indicating that while the Asians Turks carried out an invasion with cultural significance (language), it is not genetically detectable. 3) Kurds and Armenians are genetically very close to Turks and other Middle East populations. 4) There is no HLA genetic trace of the so called Aryan invasion, which has only been defined on doubtful linguistic bases. 5) Iberians, including Basques, are related to north-African Berbers. 6) Present-day Algerian and Moroccan urban and country people show an indistinguishable Berber HLA profile.

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.

The study of the MHC-G gene evolution during nearly 40 million years does not support a role for the full molecule. The MHC-G-like proteins of New World monkeys are probably classical presenting molecules. Old World Cercopithecinae monkeys do not have a full MHC-G molecule and human individuals homozygous for the HLA-G null allele are healthy and do not show birth pathologies.

The frequency of reticulin (ARA), endomysium (EmA), and gut epithelial cell (GECA) autoantibodies, and gliadin antibodies (AGA), was investigated in 86 Spanish diabetic patients by indirect immunofluorescence (IFI) and ELISA, along with their HLA phenotype. Four patients (5%) showed ARA-IgG (R1 pattern), eight (9%) showed AGA-IgG, and eight (9%) showed AGA-IgA. No EmA or GECA-positive patients were found. In diabetic patients, HLA-DR7 is increased in ARA-IgG+ vs. ARA-IgG- (though not significantly), and HLA-DR6 and HLA-DQ1 are significantly increased in the AGA-IgG+ group vs. the AGA-IgG- group. Comparison with a non-diabetic coeliac group showed that HLA-DR4 and HLA-DQ3 are significantly increased in the AGA-IgA+ group, whereas HLA-DQ2 shows a significant decrease in the AGA-IgG+ and AGA-IgA+ patients. Finally, when compared to the healthy group, HLA-DR7 frequency is decreased in the ARA-IgG- group, while HLA-DQ3 is significantly increased and HLA-DR6 and HLA-DQ1 significantly decreased in the AGA-IgG- group.Altogether, these data suggest that the genetic background leading to the appearance of coeliac-specific autoantibodies in Spanish diabetic patients differ depending on the autoantibody produced and is also different to the genetic background leading to diabetes in Spain.

HLA-G is a class Ib (nonclassical) major histocompatibility complex (MHC) protein expressed at the materno-fetal interface that may inhibit natural killer (NK) cell-mediated lysis in an allotype-independent manner. The human MHC-G transcript is differentially spliced, giving rise to at least six different forms. In order to study the evolutionary importance of this phenomenon, the presence of alternative splicing in MHC-G mRNA molecules from Pongidae (Chimpanzee, Gorilla, and Orangutan) has been investigated in the present work, and three alternative spliced isoforms (i.e.: G1, G2, and G3) have been found, but not the G4 and the soluble G5 and G6 ones. In addition, a novel MHC-G isoform is described in Gorilla, “G2 short.” This molecule is similar to the G2 isoform, but it lacks 29 amino acids normally encoded by exon 4. Our findings suggest that soluble isoforms are not necessary for MHC-G function(s) in Pongidae or that MHC-G is not a functional protein, because G1 is not necessary for survival in humans and Cercopithecinae bear stop codons in MHC-G exon 3.

Non-classical MHC class I HLA-E, -F, and -G molecules differ from classical class I histocompatibility antigens by specific patterns of transcription, protein expression, and immunological functions. Restriction of the expression pattern of these non-classical antigens may play a key role in modulation of immune responses during pregnancy and diseases but remains to be additionally defined. A specific component of the second International Conference on HLA-G and the 13th HLA-G Histocompatibility Workshop will be dedicated to the analysis of transcription and expression of non-classical class I genes in normal and pathological tissues. In a first step, referred to as the preworkshop, we here report the analysis and conclusions of a working group which was constituted to gather and validate optimal reagents and protocols allowing RT-PCR analysis of HLA-E, -F, -G transcript levels and flow cytometry and immunochemistry analysis of HLA-G expression in cells and tissues. As a result of this work, use of specific primers and probes detecting alternative transcripts of HLA-E, -F, and G have been validated in transfected cells expressing differential pattern of HLA class I antigens. Analysis of the specificity and affinity of collected antibodies has allowed definition of reagents to be proposed for immunochemistry and flow cytometry analysis of HLA-G expression in normal and pathological tissues during the workshop. This work has allowed constitution of an extended workshop group which is now initiating analysis of non-classical class I transcription and expression in various cells and tissues, a collective contribution that will additionally refine our view of the expression of these antigens in normal and pathological situations.

HLA-G is expected to play an important role during fetal development. Recently, a healthy individual homozygous for the HLA-G*0105N allele has been described, suggesting that HLA-G expression was not essential for fetal survival. We now report studies of one family with five healthy siblings homozygous for HLA-G*0105N, who had been normally delivered; three of these siblings were females who also had normal deliveries. In addition, HLA-G*0105N cDNA has been fully sequenced, and normal G1 membrane anchored protein cannot be translated since after the codon 130 cytosine deletion (exon 3) a reading frameshift is observed leading to the existence of premature stop codon at position 189 (beginning of exon 4). Other protein isoforms (G2, G3 and G6), all containing the leader peptide and the α1 domain, are possible and their messenger mRNAs were found; any of these may undertake the necessary HLA-G functions. Our data show that the membrane anchored HLA-G molecule is not necessary in either mother or fetus for a normal pregnancy and survival. Also, individuals homozygous for HLA-G*0105N are healthy and with no indications of immunodeficiency or autoimmunity ( Note).

HLA class I and class II expression was analyzed weekly by cytofluorometry on spermatozoa samples from four donors during a 15-wk trial. On the same day that semen samples were studied, and to analyze whether this expression was hormone-controlled, serum levels of testosterone, LH, FSH, inhibin B, activin, and pro-alphaC on the one hand, and seminal plasma levels of inhibin B, activin, and alpha-inhibin on the other, were also measured. Inhibin B and related peptides were quantitated using a novel two-site assay with monoclonal antibodies to the alpha and beta subunits of inhibin. Our results showed that HLA class I and class II molecules were expressed on the spermatozoa's surface, following a cyclic pattern, and that there was a simultaneous and coordinated expression of both types of molecules (r = 0.801, P < 0.0001). Furthermore, when the expression of these molecules was plotted against the different hormone levels, serum inhibin B showed a clear inverse correlation with HLA class I (r = -0.612, P < 0.0001) and class II (r = -0.534, P < 0.0001). This finding reveals unexpected functions of inhibin B, which may be relevant in the fertilization process and on male fertility control.

HLA-E and -G genes show a restricted polymorphism encoding for molecules whose variability is limited at the peptide binding site. Fourteen alleles that give rise to only three productive proteins for HLA-G (*0101, *0103 and *0104) and five alleles with three different proteins for HLA-E (*0101, *0102 and *0103) have been described. Expression of these molecules is low and found in many tissues for HLA-E: HLA-G protein is expressed in extravillous trophoblast cells and thymic epithelium. Molecular studies have shown how HLA-G and HLA-E bind to natural killer (NK) cells immunoglobulin and lectin-type inhibitory receptors. HLA-E may act as a sentinel of the cell; if classical class I and HLA-G are being expressed, HLA-E molecules may reach the cell surface and inhibit the lysis by NK cells. Most findings are consistent with the hypothesis that HLA-E and -G proteins may be tolerogenic molecules at either the T-cell receptor (TcR) (inflammation, graft rejection) or NK level, switching off cells which usually attack foreign (including foetus) or self (autoimmune) antigens. A low HLA-E and -G polymorphism is observed in humans, and their allele frequencies are mostly homogeneous in the populations tested so far. Many studies to detect these alleles are now being performed in isolated populations and also in pregnancy-associated pathologies. In the present paper, standard and detailed techniques to detect HLA-E and -G DNA polymorphism are reported and discussed.

The HLA profile of the Azoreans has been compared with those of other world populations in order to provide additional information regarding the history of their origins. The allele frequencies, genetic distances between populations, correspondence analyses and most frequent haplotypes were calculated. Our results indicate that the Azorean population most likely contains an admixture of high-frequency Caucasoid, Mongoloid and, to a lesser degree, Negroid HLA genes. The middle Atlantic Azores Archipelago was officially colonized by the Portuguese after 1439 and historical records are concordant with the existence of Caucasoid and Negroid population. However, Mongoloid genes were not suspected, but the Oriental HLA haplotypes A24-B44-DR6-DQ1, A29-B21-DR7-DQ2 and A2-B50-DR7-DQ2 are the fourth, fifth and sixth most frequent ones in Azores. A correspondence analysis shows that the Azorean population is equidistant from Asian and European populations and genetic distances are in some cases closer to the Asian than to European ethnic groups, and never are significantly different; also, B*2707 subtype is found in Asians and Azoreans (but not in Europeans) and the same Machado-Joseph Disease founder haplotypes (Chr 14) are found in both Japanese and Azoreans. It is proposed that a Mongoloid population exists in Azores; whether, the arrival occurred prior to discovery is undetermined.

The Cretan HLA gene profile has been compared with those of other Mediterranean populations in order to provide additional information regarding the history of their origins. The allele frequencies, genetic distances between populations, relatedness dendrograms and correspondence analyses were calculated. Our results indicate that the Indoeuropean Greeks may be considered as a Mediterranean population of a more recent origin (after 2000 B.C.), while all other studied Mediterraneans (including Cretans) belong to an older substratum which was present in the area since pre-Neolithic times. A significant Turkish gene flow has not been detected in the Greek or Cretan populations, although Greeks and Turks have two high frequency HLA-DRB-DQB haplotypes in common. It is proposed that Imazighen (Caucasoid Berbers living at present in the North African coast and Saharan areas) are the remains of pre-Neolithic Saharan populations which could emigrate northwards between about 8000-6000 B.C., when desert desiccation began. They also could be part of the stock that gave rise to Sumerians, Cretans and Iberians; this is supported by both linguistic and HLA genetic data.

The HLA-B locus is the most polymorphic of the class I genes encoded within the human major histocompatibility complex. This polymorphism is mainly located in exons 2 and 3, which code for the molecule's alpha1 and alpha2 domains and includes the antigenic peptide binding site. However, information about adjacent non-coding regions (introns 1 and 2) has not been extensively reported but could be very important in establishing an understanding of the evolutionary mechanisms involved in the polymorphism generation of HLA-B and the Mhc loci. In the present work, introns 1 and 2 of 14 HLA-B alleles are studied and their significance is discussed; 10 have been sequenced in our own laboratory and the other 4 have been previously reported by others. Different serological families share the complete intron 1 sequence; at this region, 12 out of 14 HLA-B alleles could be included in four groups with the same intron 1 sequence: a) B*0702, B*4201, B*4801; b) B*27052, B*4002, B*4011; c) B*40012, B*4101, including B*4501, B*5001 (these latter two alleles have specific characteristics in both introns 1 and 2, which may reflect a common evolutionary pathway); and d) B*44031, B*44032. The other alleles, B*1402, and B*1801, do not have identical intron 1 sequences compared to any of the described groups, but share many similarities with them. The B*1801 evolutionary pathway seems to be very specific since it branches separately from other alleles both in intron 1 and intron 2 dendrograms. On the other hand, HLA-B allelic group distribution and similarities according to intron 1 sequences were not confirmed when using intron 2, especially in the cases of B*4002, B*4101 and B*4801. This would suggest that both point mutations fixed by genetic drift and gene conversion events are involved in HLA-B diversification. The latter events could be supported by the strong homology between intron 1 and, to a lesser extent, intron 2, and also the CG content within them. Finally, the precise knowledge of these non-coding regions could be important for developing DNA base typing strategies for the HLA-B alleles.

HLA-G non classical class I locus shows a comparatively low polymorphism. It encodes for tolerogenic HLA molecules that may be important in autoimmunity and transplant (and foetal) rejection control. HLA-G molecules give negative signals to Natural Killer and T lymphocytes. In the present paper, a new allele, HLA-G*08, is described, which may be useful for monitoring transplants and for HLA and disease studies.

The presence of HLA-G mRNA has been studied in thyroid follicular cells from autoimmune patients with Graves' disease. Investigating the possible role of the expression of the HLA-G gene in tissue inflammation, we have found four of the six HLA-G mRNA isoforms described: G1, G2, G3 and G4, but not the soluble ones G5 and G6. Soluble G isoforms may be responsible for inducing tolerance and inflammation control and their absence in autoimmune thyroid follicular cells may induce failure of such control. In addition, the complete coding sequence of HLA-G*01012 has been obtained from thyrocytes and it shows only four synonymous changes with respect to the HLA-G*01011 allele; this further supports the existence of an evolutionary pressure for invariance on HLA-G genes.