HLA-B27 is strongly associated to ankylosing spondylitis (AS) and represents a family of eleven B27 alleles (B*2701-11). Our aim was to analyze the distribution of B27 subtypes by PCR/SSOP and genomic sequencing in a large group of populations (n = 17). 711 B27-positive samples from Caucasoid, Asian, African, Amerindian and Polynesian populations were selected to ascertain transracial gene mapping of the B27 subtypes. 476 of these were AS patients, chosen to investigate the contribution of B27 alleles to AS susceptibility. Some significant new findings have arisen from this study: 1) B*2705 was the predominant subtype in circumpolar and subarctic areas. B*2702 was found to be practically restricted to Caucasian populations, showing a higher frequency in Middle-East (Jews) and North Africa (Arabs/Berbers) groups. 2) B*2703 appears associated with AS in Western Africans. This is of remarkable interest since it was suggested that B*2703 would be negatively disease-associated. 3) Although B*2706 appears negatively associated with AS in Thais, we identified two patients from northern China carrying it. This may be a reflection of a disease heterogeneity and could indicate that more than one pathogenic agent can be involved in AS. B*2709 has been recently described as negatively associated with AS in Sardinians. The molecular changes His114Asp (B*2706) and Asp116His (B*2709) could modify the genetic susceptibility to AS.

In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations.

HLA class I and class II alleles have been studied for the first time in the Turkish-speaking Tuvinian population, which lives in Russia, North of Mongolia and close to the Altai mountains.Comparisons have been done with about 11 000 chromosomes from other worldwide populations, and extended haplotypes, genetic distances, neighbor joining dendrograms and correspondence analyses have been calculated. Tuvinians show an admixture of Mongoloid and Caucasoid characters, the latter probably coming from the ancient Kyrgyz background or, less feasibly, more recent Russian Caucasoid admixture. However, Siberian population traits are not found and thus Tuvinians are closer to Central Asian populations. Siberians are more related to Na-Dene and Eskimo American Indians ; Amerindians (from nowadays Iberian-America) are not related to any other group, including Pacific Islanders, Siberians or other American Indians. The' more than one wave ' model for the peopling of the Americas is supported. The HLA system is the most polymorphic genetic system described in humans and consists of several closely linked loci. The strength of the multiallelic HLA system to single out individuals for paternity testing has been shown to be greater than the additive strength of many other polymorphic enzymes and blood group systems. The discovery of new loci and the presently available DNA typing and sequencing of new alleles have dramatically increased the variety of The contribution by Jorge Martinez-Laso, Martina Sartakova and Luis Allende is equal and the order of authorship is arbitrary.Correspondence : A. Arnaiz-Villena, Departamento de Inmunologı!

AIMTo study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.METHODSMale diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.RESULTSIn 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.CONCLUSIONThe DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.

Immunopathogenesis of chronic viral hepatitides was studied by modern immunological, molecular, genetic methods. We revealed an imbalance in the production of immunoregulatory cytokines by mononuclear leukocytes (primarily of the Th2 type). The risk of progression and chronic course of viral hepatitides in Caucasian population was associated with alleles of promoter regions -330G and -592A in the IL-2 and IL-10 genes, respectively, as well as with the T/T genotype of the polymorphic region C590T in the IL-4 gene. The C/C genotype of the IL-10 gene promoter region C592A was shown to be a factor determining resistance to long-term persistence of hepatitis B and C viruses.

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The distribution of allele variants of promotor sites of interleukins 4 (C-590T) and 10 (C-597A) and tumor necrosis factor-alpha (G-308A) genes was studied in HIV-infected patients and normal subjects of the Europeoid population in Russia. Some deviations in the distribution of genotypes of the studied polymorphism were revealed in HIV-infected patients compared to the control. The distribution of genotypes in these groups is different for men and women, which is significant for inheritance of allele variants of the cytokine gene.

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