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.

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.

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

HLA genetic profile of Mapuche (Araucanian) Amerindians from Chile.

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(∗)01:05N null allele in Mayans (Guatemala) and Uros (Titikaka Lake, Peru): evolution and population genetics.

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.

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.

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.

Amerindians show no association of PC-1 gene Gln121 allele and obesity: a thrifty gene population genetics.

PC-1 Gln121 gene is a risk factor for type 2 diabetes, obesity and insulin resistance in European/American Caucasoids and Orientals. We have aimed to correlate for the first time this gene in Amerindians with obesity and their corresponding individuals genotypes with obesity in order to establish preventive medicine programs for this population and also studying the evolution of gene frequencies in world populations. Central obesity was diagnosed by waist circumference perimeter and food intake independent HDL-cholesterol plasma levels were measured. HLA genes were determined in order to more objectively ascertain participants Amerindians origin. 321 Amerindian blood donors who were healthy according to the blood doning parameters were studied. No association was found between PC-1 Gln121 variant and obesity. Significant HDL-cholesterol lower values were found in the PC-1 Lys121 bearing gene individuals versus PC-1 Gln121 bearing gene ones (45.1 ± 12.7 vs. 48.7 ± 15.2 mg/dl, p < 0.05). Population analyses showed a world geographical gradient in the PC-1 Gln121 allele frequency: around 9% in Orientals, 15% in European Caucasoids and 76% in Negroids. The conclusions are: (1) No association of PC-1 Gln121 gene is found with obesity in Amerindians when association is well established in Europeans. (2) PC-1 Gln121 gene is associated to higher levels of HDL-cholesterol than the alternative PC-1 Lys121 allele. This may be specific for Amerindians. (3) Amerindians have an intermediate frequency of this possible PC-1 Gln121 thrifty gene when compared with Negroid African Americans (78.5%) or Han Chinese (7.5%, p < 0.0001). Historical details of African and other groups may support the hypothesis that PC-1 Gln121 is indeed a thrifty gene.

Amerindians normalized waist circumference and obesity diagnosis standarized by biochemical and HLA data.

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.