Group-specific component, alpha1-antitrypsin and esterase D in Canadian Eskimos.

Three genetic markers - group-specific component (Gc), alpha1-antitrypsin, and esterase D - were examined in a population of Eskimos from Igloolik in the eastern Canadian Arctic. Gc and esterase D were found to be polymorphic. In addition to the common Gc types, an anodal variant called Gc Igloolik was found, probably identical to previously reported Gc Eskimo. Gene frequencies were Gc1: 0.6524, Gc2: 0.3373, GcIgl: 0.0104, for 338 Eskimos. Genetic types of alpha1-antitrypsin (Pi types) were mostly M, with two MS sibs who were half Caucasian, in 170 Eskimos. Frequencies of the esterase D allele in 336 Eskimos were EsD1: 0.7083, EsD2: 0.2917. The frequencies of Gc2 and EsD2 are both higher than are found in Caucasian populations.     

Genetic markers among Meiteis and Brahmins of Manipur, India

Genetic polymorphism of 16 red-cell antigens, enzymes, serum proteins and Hb variants was investigated in 214 male and female individuals belonging to the Meiteis and a Brahmin caste group living in Imphal (Manipur, Northeast India). Ethnohistorical records suggest that the Meiteis are of Mongoloid origin, while the original Brahmin settlers represent the easternmost part of the so-called Caucasoids. The markers studied are: A1A2BO, MNSs, Rh-system, Duffy, Diego; Gm, Km, Gc, Hp, Tf, Cp; Hb; aP, AK, EsD and LDH. The comparison between the two groups on the basis of the markers studied showed that the Meiteis and Brahmins are very close to each other with respect to most of the loci except Gm, EsD and Hb, where significant statistical differences were found.     

Molecular analysis of esterase D polymorphism

We have analyzed the esterase D (EsD) polymorphism at the nucleic acid level. Two common alleles, EsD¹ and EsD², are characterized by the substitution of one amino acid (Gly-to-Glu), which is caused by the point mutation of one nucleotide (G-to-A). Individuals exhibiting the EsD1 and EsD 2 phenotypes are homozygotes for EsD 1 and EsD 2 cDNAs, respectively. Individuals showing the EsD 2-1 phenotype have two kinds of cDNAs, viz., EsD 1 and EsD 2. The point mutation difference between the cDNAs of the EsD¹ and EsD² alleles results in a different SspI digestion site. A restriction fragment length polymorphism caused by this difference with respect to the SspI digestion site makes it possible to determine the EsD phenotype using DNA samples extracted from forensic materials with no EsD enzymatic activity.     

Genetic studies in Ecuador: Acetylator phenotypes,red cell enzyme and serum protein polymorphisms of Shuara Indians

Population genetic studies of Shuara Indians in Ecuador are performed for GPT, AP, PGM₁, Ak, EsD, 6-PGD, Hp, Gc, C3, Bg, ChE, Tf, Pi, Bf phenotypes, IgG, IgA, IgM, C3, C3-proactivator, C4 levels and acetylator phenotypes. Some systems having a polymorphism in many other populations showed a lack of some of those alleles in the population under study (C3, ChE, Tf, AK and almost absent 6-PGD, Bg, Bf).     

Genetic structure of the Mongols as derived from the ABO, MN, Rh, EsD, GLO1, PGM1, AcP, 6-PGD, Hp, Gc, Tf, C'3 and ChE2 loci

According to integral characterization of gene frequencies of the investigated loci AB0, MN, Rh, GLO1, PGM1, EsD, AcP, 6-PGD, Hp, Tf, Gc, C'3 and ChE2, Mongolian population has high level of polymorphism, with the exception of haplotypes R" (cdE) and Ry(CdE) at the Rh locus and TfB0-1 at the Tf locus. The data on biochemical and immunological polymorphic gene markers analysed in the population of Mongolia show that the Mongolians have some distinctive features, in comparison with the mean-in-the-world characteristics: high frequencies of the B genes at the AB0 locus; D, E, R1 and R2 at the Rh locus; GLO11, PGDc, TfDChi, E2(C5+), PGM1(1+); low frequencies of the genes A(AB0), R0(Rh), AcPc, Hp1, Gc2, C'3F, PGM 1(2-); the rest of the genes at the above-mentioned loci and the genes of the locus MN have the mean-in-the-world frequencies.     

The immunogenetics of multiple sclerosis

The discoveries in the 1970s of strong associations between various diseases and certain human leukocyte antigen (HLA) factors were a revolution within genetic epidemiology in the last century by demonstrating for the first time how genetic markers can help unravel the genetics of disorders with complex genetic backgrounds. HLA controls immune response genes and HLA associations indicate the involvement of autoimmunity. Multiple sclerosis (MS) was one of the first conditions proven to be HLA associated involving primarily HLA class II factors. We review how HLA studies give fundamental information on the genetics of the susceptibility to MS, on the importance of linkage disequilibrium in association studies, and on the pathogenesis of MS. The HLA-DRB1*1501 molecule may explain about 50% of MS cases and its role in the pathogenesis is supported by studies of transgenic mice. Studies of polymorphic non-HLA genetic markers are discussed based on linkage studies and candidate gene approaches including complete genome scans. No other markers have so far rivaled the importance of HLA in the genetic susceptibility to MS. Recently, large international collaborations provided strong evidence for the involvement of polymorphism of two cytokine receptor genes in the pathogenesis of MS: the interleukin 7 receptor alpha chain gene (IL7RA) on chromosome 5p13 and the interleukin 2 receptor alpha chain gene (IL2RA (=CD25)) on chromosome 10p15. It is estimated that the C allele of a single nucleotide polymorphism, rs6897932, within the alternative spliced exon 6 of IL7RA is involved in about 30% of MS cases.     

VDBP,CYP27B1, and 25-Hydroxyvitamin D Gene Polymorphism Analyses in a Group of Sicilian Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic demyelinating disease of central nervous system regarded as one of the most common causes of neurological disability in young adults. The exact etiology of MS is not yet known, although epidemiological data indicate that both genetic susceptibility and environmental exposure are involved. A poor vitamin D status has been proposed as the most attractive environmental factor. Several evidence have highlighted the importance of mutations in vitamin D-regulating genes for vitamin D status. The purpose of our study was to assess the genetic variants of VDBP and CYP27B1 in MS patients and in a control group. A total of 192 subjects, including 100 MS patients and 92 healthy controls, were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Serum 25-hydroxyvitamin D levels were measured in MS patients and controls by high-performance liquid chromatography. We did not observe any statically significant difference in the distribution of genotypic VDBP variants between the study groups. 25(OH)D plasma levels were significantly higher in the control group versus MS patients; MS patients who carried Gc2 showed lower 25(OH)D plasma levels and those who carried Gc1f showed higher levels. We observed only wild-type allele for CYP27B1 mutations analyzed both in MS patients and in the control group. In conclusion, our findings do not support a role of an independent effect of the investigated vitamin D-related gene variants, VDBP and CYP27B1, in the risk of MS.     

Genetic differentiation of the Mongolian population. Comparative analysis of the geographic distribution of biochemical markers of genes and restriction fragment length polymorphism of nuclear DNA in the Mongolian population]

The geographical distribution of the gene frequencies from loci: Hp, Tf, Gc, Pi, AcP1, GLO1, EsD, 6-PGD, PGM1 and RFLP's of the nuclear DNA of the loci HBG-2 (HindIII), HBB (AvaII), ApoB (XbaI), D7S8 (PstI), LDLR (HincII) and AT-3 was analysed in the Mongolian population. These data revealed the homogeneity of 18 local groups in Mongolia and extremely low genetic differences measured by GST. There was no differences in the average GST values between protein markers and nuclear DNA markers.     

Population distribution of the human vitamin D binding protein: anthropological considerations

The polymorphism of the serum vitamin D binding protein (DBP) in humans is based on the existence of three common alleles, Gc1F, Gc1S, and Gc2, and 84 rare alleles. The geographical distribution of Gc1F, Gc1S, and Gc2 alleles shows north to south clines, together with a balanced equilibrium between the Gc1F or Gc1S allele frequency and the Gc2 frequency. The distribution of the FST values shows high variability within a geographical area. For European and North Asiatic groups, the FST values are the lowest observed, and the reason may be a long process of homogenization. Aboriginal populations from Australia and New Guinea and groups from both North Africa and South America show the greatest heterogeneity of their allele frequencies. Systematic factors such as genetic drift and selection may account for this distribution. In contrast with the three main DBP alleles, the distribution of the rare alleles corresponds to patterns of human migrations that occurred during prehistoric and historic periods. Thus, the rare mutants are of particular relevance to anthropological and genetical investigations.     

Human red cell esterase D polymorphism in Denmark, its use in paternity cases and the description of a new phenotype

Red cell esterase D (EsD) phenotypes were determined in a Danish population sample of 3,116 unrelated adults by starch-gel electrophoresis. A new phenotype was discovered, which appeared to be determined by the EsD1 allele and a new allele EsDCph. The gene frequencies observed were EsD1 = 0.9007, EsD2 = 0.0992, EsDCph = 0.0001. Investigation of 1,111 mother-child pairs and 59 families with 157 offspring added further support to the genetic model of two common alleles at an autosomal locus. The applicability of the EsD polymorphism to paternity testing was investigated on 960 cases of disputed paternity. An estimate of the EsD null allele frequency (0.001) in European populations was made on the basis of observations made on 5,864 mother/child combinations and 762 matings with 1,882 offspring. The influence of this allele on the reliability of exclusions of paternity was determined.     

Genetic structure of Quechua-speakers of the Central Andes and geographic patterns of gene frequencies in South Amerindian populations

A sample of 141 Quechua-speaking individuals of the population of Tayacaja, in the Peruvian Central Andes, was typed for the following 16 genetic systems: ABO, Rh, MNSs, P, Duffy, AcP1, EsD, GLOI, PGM1, AK, 6-PGD, Hp, Gc, Pi, C3, and Bf. The genetic structure of the population was analyzed in relation to the allele frequencies available for other South Amerindian populations, using a combination of multivariate and multivariable techniques. Spatial autocorrelation analysis was performed independently for 13 alleles to identify patterns of gene flow in South America as a whole and in more specific geographic regions. We found a longitudinal cline for the AcP1*a and EsD*1 alleles which we interpreted as the result of an ancient longitudinal expansion of a putative ancestral population of modern Amerindians. Monmonnier's algorithm, used to identify areas of sharp genetic discontinuity, suggested a clear east-west differentiation of native South American populations, which was confirmed by analysis of the distribution of genetic distances. We suggest that this pattern of genetic structures is the consequence of the independent peopling of western and eastern South America or to low levels of gene flow between these regions, related to different environmental and demographic histories.     

Population genetics of taiga hunters and reindeer breeders in central Siberia. The biochemical markers of genes Hp, Tf, Gc, A1b, GLO1, PGM1, AcP and EsD

Biochemical markers of gene systems Alb, Tf, Gc, Hp, GLO1, PGM1, EsD, AcP were analysed in the native population of Evenc national region. It is shown that native population of Central Siberia, in spite of its mongoloid racial type, posseses the complex of gene frequencies for protein loci studied which is not typical for mongoloids. The complex may be called "central-siberian" and its origin may be connected with the process of adaptation to environment of the Central Siberian geographical region. The system of gene markers analysed may be considered as a sensitive one in the studies of processes of gene adaptation to the local environmental factors and, in this connection, being perspective in these studies among native population of Siberia.     

Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).

A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5'' flanking polymorphism [5''FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5''FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.     

Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP)

Human vitamin D binding protein (DBP) displays considerable polymorphism with 120 described alleles. Among these, three alleles are frequently observed, Gc 1F (pI 4.94–4.84), Gc 1S (pI 4.95–4.85) and Gc 2 (pI 5.1). Differences between these genetic forms of the protein in affinity for vitamin D metabolites have been detected by electrophoretic methods. The constant affinity (Ka) values determined in this study confirm these differences. The affinities of six rare variants were also examine. Those of the DBP genetic forms to the vitamin D derivatives 25-OH-D₃ and 1,25-(OH)₂-D₃ seem to be related to the isoelectric point of the proteins: a high affinity corresponding to a low isoelectric point. The Gc 1A9 and 1A11 mutants were associated with higher affinity for the vitamin D derivatives and the Gc 1C1 and 1C21 mutants were deficient.     

Selecting SNPs for association studies based on population frequencies: a novel interactive tool and its application to polygenic diseases

Common complex polygenic diseases as autoimmune diseases have not been completely understood on a molecular level. While many genes are known to be involved in the pathways responsible for the phenotype, explicit causes for the susceptibility of the disease remain to be elucidated. The susceptibility to disease is thought to be the result of genetic epistatic interactions between common polymorphic genes. This polymorphism is mostly caused by single nucleotide polymorphisms (SNPs). Human subpopulations are known to differ in the susceptibility to the diseases and generally in the distribution of single nucleotide polymorphisms. The here presented approach retrieves SNPs with the most divergent frequencies for selected human subpopulations to help defining properties for the experimental verification of SNPs within defined regions. A web-accessible program implementing this approach was evaluated for multiple sclerosis (MS), a common human polygenic disease. A link to a summary of data from "The SNP Consortium" (TSC) with sex-dependencies of SNPs is available. Associations of SNPs to genes, genetic markers and chromosomal loci are retrieved from the Ensembl project. This tool is recommended to be used in conjunction with microarray analyses or marker association studies that link genes or chromosomal loci to particular diseases.     

The search for disease susceptibility genes. Medical and ethical problems of predictive medicine

Thanks to major progress in genetics, a great number of disease susceptibility genes have been characterized. However, the concept of genetic defect is challenged by the elusive boundary between genetic diseases and allelic polymorphism which represents a major adaptative response to the diversity of environmental pressures. The detection of disease susceptibility alleles should be performed only if appropriate prevention can be initiated. Otherwise predictive medicine together with insufficient protection of the person's rights against the use of genetic markers may prove to be socially and psychologically detrimental. Ethical and social issues of predictive medicine definitely deserve to be fully debated.     

IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report “allelic heterogeneity” at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.     

Gc subtyping in south Indian tribal and caste populations

Seven tribal (Konda Kammara - 2 samples; Koya Dora - 3 samples; Lambadi) and caste (Madiga) populations from Andhra Pradesh (South India) have been analyzed for the distribution of Gc subtypes. The observed heterogeneity in the distribution of Gc1F, Gc1S and Gc2 alleles was found to be statistically significant. Comparisons are made with North Indian populations as well as with those of other racial affiliation. The anthropological impact of the Gc subtype polymorphism is discussed.     

Genetic polymorphism in the Karelian population]

Distribution of the genetic markers of blood groups (AB0, MNSs, Rhesus, P, Lewis, Duffy, Kell-Cellano, Kell-Kp, Kell-Sutter, Kidd, Lutheran); of serum proteins (Hp, Tf, Gc, C'3, Pi); red-cell enzymes (6-PGD, EsD, GLO, AcP, subtypes of PGM) was studied in Karels from the South part of Karelian ASSR. The results of comparison of Karels with the other finno-ugric peoples revealed peculiarities of gene pool in Karelian population.     

Genetic polymorphism of the vitamin D binding protein (Gc protein) in pig plasma determined by agarose isoelectrofocusing

Genetic polymorphism of the pig plasma vitamin D binding protein Gc was demonstrated by agarose isoelectrofocusing followed by either autoradiography or immunofixation with specific human Gc antiserum. Three different types F, FS and S were observed. Family data supported the genetic theory that the Gc types are controlled by two autosomal codominant alleles GcF and GcS. Both alleles are present in Yorkshire and Duroc. In Danish Landrace and Hampshire only the GcF allele was observed.