Biomedical subjects

W Klitz

Publications and source records attributed to W Klitz.

At least 19 recordsLinked to original sources

PubMed2006

Prenatal viral exposure followed by adult stress produces glucose intolerance in a mouse model.

AIMS/HYPOTHESIS: It has been suggested that the uterine environment may influence metabolic disease occurring later in adult life, and that adult stress may promote disease outcome. Using a mouse model, we tested whether in utero exposure to Ljungan virus (LV) followed by adult exposure to stress produces diabetes. The influence of the timing of viral exposure over the course of pregnancy was also tested. MATERIALS AND METHODS: Pregnant CD-1 mice were exposed i.p. to LV on pregnancy days 4, 8, 12 or 17. Adult male mice from these pregnancies were stressed by being kept in shared cages. Stress only, LV exposure in utero only, and no-stress/no virus exposure groups were also followed. Outcome variables included bodyweight, epididymal fat weight, baseline glucose, glucose tolerance tests (60 and 120 min) and serum insulin. RESULTS: We demonstrated that male mice developed a type 2-like diabetes, including obesity, as adults if infected during pregnancy with LV. Diabetes at the age of 11 weeks was more severe in mice whose mothers were infected earlier than in those whose mothers were infected later in pregnancy. Only animals infected in utero and kept under stress developed diabetes; infection or stress alone did not cause disease. CONCLUSIONS/INTERPRETATION: This work demonstrates that a type 2 diabetes-like disease can be virus-induced in a mouse model. Early in utero viral insults can set the stage for disease occurring during adult life, but the final manifestation of diabetes is dependent on the combination of early viral exposure and stress in adult life.

Animals↗

PubMed2003

New HLA haplotype frequency reference standards: high-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans.

A collaborative study involving a large sample of European Americans was typed for the histocompatibility loci of the HLA DR-DQ region and subjected to intensive typing validation measures in order to accurately determine haplotype composition and frequency. The resulting tables have immediate application to HLA typing and allogeneic transplantation. The loci within the DR-DQ region are especially valuable for such an undertaking because of their tight linkage and high linkage disequilibrium. The 3798 haplotypes, derived from 1899 unrelated individuals, had a total of 75 distinct DRB1-DQA1-DQB1 haplotypes. The frequency distribution of the haplotypes was right skewed with haplotypes occurring at a frequency of less than 1% numbering 59 and yet constituting less than 12% of the total sample. Given DRB1 typing, it was possible to infer the exact DQA1 and DQB1 composition of a haplotype with high confidence (>90% likelihood) in 21 of the 35 high-resolution DRB1 alleles present in the sample. Of the DRB1 alleles without high reliability for DQ haplotype inference, only *0401, *0701 and *1302 were common, the remaining 11 DRB1 alleles constituting less than 5% of the total sample. This approach failed for the 13 serologically equivalent DR alleles in which only 33% of DQ haplotypes could be reliably inferred. The 36 DQA1-DQB1 haplotypes present in the total sample conformed to the known pattern of permissible heterodimers. Four DQA1-DQB1 haplotypes, all rare, are reported here for the first time. The haplotype frequency tables are suitable as a reference standard for HLA typing of the DR and DQ loci in European Americans.

Gene Frequency↗

PubMed2002

The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos.

The genetic predisposition to type 1 diabetes among Filipinos was examined by PCR/SSOP HLA class I and II typing of 90 patients and 94 general population controls. The HLA-DRB1, DQB1, and the A, B, and C loci were typed using the reverse SSO probe line-blot method while the DPB1 and DPA1 loci were typed using the SSO probe dot blot method. The Filipino population has a distinctive frequency distribution of HLA class II alleles as well as linkage disequilibrium patterns: a DR-DQ haplotype, unique to Filipinos, contains a DRB1 allele (*0405) positively associated with type 1 diabetes in other populations and DQA1 and DQB1 alleles (*0101-*0503) that are negatively associated in other populations. Specific DR-DQ haplotypes or alleles could be identified as susceptible, neutral or protective based on the distribution among Filipino patients and controls. The DR9 and DR3 haplotypes showed the most dramatic increase among patients (0.156 vs 0.063) and (0.172 vs 0.042), respectively. Among Filipinos, the DR3/9 genotype confers approximately the same risk as the well-known high-risk DR3/4 genotype, similar to that for DR3/3 and DR9/9. The common DR2 haplotype in the Philippines (DRB1*1502-DQB1*0502) was only slightly decreased in type 1 diabetic patients (0.200 in patients vs 0.270 in controls). Another DR2 haplotype, DRB1*1502-DQB1*0501, was significantly decreased among patients. In addition, haplotypes containing DQB1*06 alleles, such as the DRB1*0803-DQB1*0601 (OR = 0.1), are strongly protective. The DR4 allele group was also increased in Filipino patients compared to controls. In this population there is, as in other populations, a hierarchy of type 1 diabetes associations among the many different DR4 haplotypes (n = 15). The high-risk haplotypes in this population are the very rare DRB1*0405-DQB1*0302 and DQB1*0405-DQB1*0201, followed by the more common DRB1*0405-DQB1*0401 and DRB1*0405-DQB1*0402. The DRB1*0403-DQB1*0302 is protective. The DRB1*0405-DQB1*05031 haplotype, which is unique to Filipinos, appears to be "neutral". HLA-DPB1*0202 was significantly increased among patients (0.056 vs 0.011; with OR = 5.3); this increase does not appear to simply reflect linkage disequilibrium with high risk DR-DQ haplotypes. The observed distribution of HLA class II alleles among Filipino patients and controls strongly supports the notion that specific combinations of alleles at the DRB1, DQB1, DQA1, and DPB1 loci are critical in determining the risk for type 1 diabetes. Specific HLA class I alleles also show significant associations with type 1 diabetes in this population. HLA-A*2402 and *2403 were increased among patients; however, 2407 was decreased. Inaddition, A *1101 was significantly decreased among patients (OR = 0.51). Moreover, these HLA-A associations do not appear attributable to linkage disequilibrium with the DR-DQ region. The allele B*5801 was increased in patients while B*1301 was decreased; both of these associations, however, reflected linkage disequilibrium with high-risk and with protective DR-DQ haplotypes, respectively. The HLA-C*0102 and *0302 alleles were increased (0.089 vs 0.037 and 0.122 vs 0.064) while C*1502 and *0702 (0.028 vs 0.080 and 0.217 vs 0.330) were decreased. The observed associations of C*0102 and C*1502 do not simply reflect linkage disequilibrium with high-risk DR-DQ haplotypes. Thus, specific HLA class I-A and C alleles were associated with type 1 diabetes in the Filipinos and may, in combination with high risk DR-DQ haplotypes, significantly modify disease risk.

Alleles↗

PubMed2001

HLA diversity, differentiation, and haplotype evolution in Mesoamerican Natives.

Genetic variation of the Human Leukocyte Antigen region (HLA) in three Amerindian populations from the Southern Mexican state of Oaxaca, the Zapotec, Mixtec and the Mixe is examined. Individuals were typed using PCR-SSOP for four class II loci (DRB1, DQA1, DQB1, DPB1) and three class I loci (HLA-A, -B, and -C). Based on known HLA distributions, European admixture ranged from 1% to 10%. Individuals with European alleles were excluded from subsequent analysis. New alleles were revealed at each of the class I loci. In general, genotype frequencies were in Hardy-Weinberg equilibrium, although some deviations were detected. Allele frequency distributions at the DRB1, DQA1, DQB1 and HLA-A loci in all populations were more even than expected under neutrality, supporting a model of balancing selection at these loci. A history of directional selection for DPB1 in all three populations was indicated, as homozygosity values were significantly above expected values. Allele frequency distributions at HLA-B and HLA-C did not differ significantly from neutrality expectations. The data also provide evidence from linkage disequilibrium that strong haplotypic associations are present across the entire HLA region in each of the populations. Significant overall linkage disequilibrium exists between all pairs of loci typed in these populations, except those which include the DPB1 locus. These associations exist despite the fact that the recombination fraction between HLA-A, in the class I region, and DQB1, in the class II region, may exceed 0.02. One explanation is that selective pressures are maintaining the relationships between particular alleles at these loci in these populations. These relationships are maintained in general across the entire HLA region in the Oaxacan Amerindians, with the exception of DPB1.

Alleles↗

PubMed2001

Evolution of the CCR5 Delta32 mutation based on haplotype variation in Jewish and Northern European population samples.

The chemokine receptor 5 (CCR5) serves as a fusion cofactor for macrophage-tropic strains of HIV-1. In addition, CCR5 has been shown to mediate the entry of poxviruses into target cells. Individuals homozygous for the Delta32 deletion-mutation have no surface expression of CCR5 and are highly protected against HIV-1 infection. To gain insights into the evolution of the mutation in modern populations, the relatively high frequency of the Delta32-ccr5 allele in some European and Jewish populations is explored here by examining haplotypes of 3p21.3 constructed of five polymorphic marker loci surrounding CCR5. By sampling Ashkenazi, non-Ashkenazi and non-Jewish populations, we utilize the natural experiment that occurred as a consequence of the Jewish Diaspora, and demonstrate that a single mutation was responsible for all copies of Delta32. This mutation must have moved from Northern European populations to the Ashkenazi Jews where evidence suggests that Delta32 carriers of both groups were favored by repeated occurrence of epidemic small pox beginning in the 8th century AD.

Alleles↗

PubMed2001

Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations.

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.

Alleles↗

PubMed2001

HLA-DR and -DQ polymorphism in Cameroon.

HLA-DRB1, -DQA1 and -DQB1 allele frequencies were determined by high-resolution polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) and/or DNA sequencing in 126 healthy individuals in Cameroon. Eighteen DRB1, 11 DQA1, and 18 DQB1 alleles were observed. The most common alleles at each locus were DRB1*1503 (29%), DRB1*1301 (13%); DQA1*0102 (38%), DQA1*0302 (11%), DQA1*0401 (11%); and DQB1*0602 (31%), DQB1*0301 (13%), DQB1*0501 (12%). Forty-four different haplotypes were identified including 12 novel haplotypes demonstrating the HLA class II diversity resulting from allele combinations in this population. A single predominant DRB1*1503-DQA1*0102-DQB1*0602 haplotype was observed with a frequency of 27%. In summary, this study of HLA class II polymorphism in Cameroon demonstrates the extent of diversity in this population.

Adult↗

PubMed2001

A novel multilocus genotyping assay to identify genetic predictors of stroke in sickle cell anaemia.

We describe a novel multilocus genotyping assay permitting simultaneous identification of 60 candidate markers for stroke in sickle cell anaemia (SCA). Based on cerebral magnetic resonance imaging (MRI), 69 patients were divided into stroke and control groups. The variant allele, CBS 278thr, showed protection from stroke, whereas the apoE3 allele showed a trend towards association with increased stroke risk. Several other variant alleles [TNFalpha (-308)A, CETP (-628)A, apoCIII (-641)A] showed a trend towards significant associations with stroke risk. These preliminary results on a small group of patients suggest that a multilocus genotyping assay may be valuable in identifying genes that increase the risk of stroke in SCA.

Adolescent↗

PubMed2000

Evidence for HLA-related susceptibility for stroke in children with sickle cell disease.

Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings with SCA, suggesting genetic factors may influence risk of stroke. The authors investigated whether HLA type was associated with risk of stroke in children with SCA. Fifty-three patients with SCA underwent complete HLA typing at both HLA class I (HLA-A, B) and HLA class II (HLA-DR, DQ, DP) loci. Of the 53 patients, 22 had magnetic resonance imagining (MRI)-documented evidence of cerebral infarction, and the remaining 31 patients had negative MRI scans. Comparison of the results of HLA typing between the SCA patients with a positive and those with a negative MRI documented that the 2 groups differed with respect to the class I HLA-B (P =.012), and the class II HLA-DRB1 (P =.0008) and DQB1 (P =.029). Susceptibility associations at the HLA-DRB1 locus included both DR3 alleles, where DRB1*0301 and *0302 were both associated with an increased risk of stroke. Protective associations were found in the DR2 group, where DRB1*1501 was protective for stroke. DQB1*0201, which is in linkage disequilibrium with DRB1*0301, was also associated with stroke. Similarly, DQB1*0602, in linkage disequilibrium with DRB1*1501, was protective. Specific HLA alleles may influence the risk of stroke in children with SCA. HLA typing may prove useful in identifying SCA patients at higher risk for stroke.

Adolescent↗

PubMed2000

High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci.

The HLA region on the short arm of chromosome 6 (6p21.3) contains the most polymorphic coding sequences in the human genome. High-resolution DNA-based HLA typing of population samples of the polymorphic class I loci, HLA-A, -B, and -C has only recently become feasible. Here, we report molecular HLA typing on family-based samples of European origin (the CEPH repository), which demonstrated very high polymorphism, with 20 A alleles, 38 B alleles and 19 C alleles in the sample of 248 independent haplotypes. In general, allele frequency distributions are consistently more even (lower observed homozygosity statistic) than expected from a past of selective neutrality suggesting a history of balancing selection. This was also true for the class II loci, DRB1, DQA1 and DQB1 in these samples, but not for the DPA1 and DPB1 loci, whose allelic frequency distributions were more skewed (higher observed homozygosity statistic) than expected under a neutral model. Although linkage disequilibrium is a prominent feature across the HLA region, only 19% of the eight locus haplotypes were sampled more than once. The relative age of some of the B alleles could be inferred from the pattern of B-C haplotypic associations. We suggest that the observed patterns of linkage disequilibrium reflect the operation of selection on nearly all HLA alleles.

Alleles↗

PubMed2000

Analysis of genotype frequencies and interlocus association for the PM, DQA1, and D1S80 loci in four populations.

Allele frequencies of the LDLR, HBGG, GYPA, D7S8, GC, DQA1, and D1S80 loci are presented and genotypes are analyzed for each of four ethnic groups: African Americans (n = 200), US Caucasians (n = 200), US Hispanics (n = 200), and Japanese (n = 89). Hardy-Weinberg genotypic proportions were observed in all but two of the 28 population-locus tests undertaken. Those two instances are attributable to type I statistical error. Gametic equilibrium among loci is an assumption invoked for application of the product rule to utilize the discriminatory power from two or more loci simultaneously. Two statistical methods, a genotype matching statistic and log-linear modeling, were used to evaluate gametic disequilibrium. The match statistic, comparing observed to expected likelihood of genotypic identity for seven loci among pairs of individuals within the database, revealed only one statistically significant deviation among 20 tests. As expected, the probability of match was generally lowest in the test on all ethnic groups combined, indicating that allele frequencies differ among ethnic groups for some of the loci. This was confirmed with the statistic theta to measure ethnic stratification, in which about 0.10 of the genetic variation is apportioned among the four ethnic groups for four of the structural loci (LDLR, HBGG, GC, and DQA1), while for GYPA, D7S8, and D1S80, variation is more uniformly distributed among ethnic groups. Log-linear modeling was also applied to the five PM loci. The most parsimonious log-linear model included only three higher order terms: the two-way interactions of three of the PM loci with ethnic group. These three instances (LDLR, HBGG, and GC) indicated differences in allele frequencies between ethnic groups. No two or higher way interaction (disequilibrium) was observed among loci. In summary, the assumptions of Hardy-Weinberg and gametic equilibrium that facilitate the use of the five PM loci, DQA1 and D1S80 in forensic applications are consistent with the allele and genotype frequencies observed in these populations.

Asian People↗

PubMed1999

Ancestral Asian source(s) of new world Y-chromosome founder haplotypes.

Haplotypes constructed from Y-chromosome markers were used to trace the origins of Native Americans. Our sample consisted of 2,198 males from 60 global populations, including 19 Native American and 15 indigenous North Asian groups. A set of 12 biallelic polymorphisms gave rise to 14 unique Y-chromosome haplotypes that were unevenly distributed among the populations. Combining multiallelic variation at two Y-linked microsatellites (DYS19 and DXYS156Y) with the unique haplotypes results in a total of 95 combination haplotypes. Contra previous findings based on Y- chromosome data, our new results suggest the possibility of more than one Native American paternal founder haplotype. We postulate that, of the nine unique haplotypes found in Native Americans, haplotypes 1C and 1F are the best candidates for major New World founder haplotypes, whereas haplotypes 1B, 1I, and 1U may either be founder haplotypes and/or have arrived in the New World via recent admixture. Two of the other four haplotypes (YAP+ haplotypes 4 and 5) are probably present because of post-Columbian admixture, whereas haplotype 1G may have originated in the New World, and the Old World source of the final New World haplotype (1D) remains unresolved. The contrasting distribution patterns of the two major candidate founder haplotypes in Asia and the New World, as well as the results of a nested cladistic analysis, suggest the possibility of more than one paternal migration from the general region of Lake Baikal to the Americas.

Asia↗

PubMed1999

Evolution of HLA class II molecules: Allelic and amino acid site variability across populations.

Analysis of the highly polymorphic beta1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson's homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P < 10(-4)), DRB1 shows some evidence of balancing selection (P < 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P < 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigen-binding pocket- and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket- and non-pocket-forming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations.

Alleles↗

PubMed1999

A multilocus genotyping assay for candidate markers of cardiovascular disease risk.

A number of chronic diseases, including cardiovascular disease, appear to have a multifactorial genetic risk component. Consequently, techniques are needed to facilitate evaluation of complex genetic risk factors in large cohorts. We have designed a prototype assay for genotyping a panel of 35 biallelic sites that represent variation within 15 genes from biochemical pathways implicated in the development and progression of cardiovascular disease. Each DNA sample is amplified using two multiplex polymerase chain reactions, and the alleles are genotyped simultaneously using an array of immobilized, sequence-specific oligonucleotide probes. This multilocus assay was applied to two types of cohorts. Population frequencies for the markers were estimated using 496 unrelated individuals from a family-based cohort, and the observed values were consistent with previous reports. Linkage disequilibrium between consecutive pairs of markers within the apoCIII, LPL, and ELAM genes was also estimated. A preliminary analysis of single and pairwise locus associations with severity of atherosclerosis was performed using a composite cohort of 142 individuals for whom quantitative angiography data were available; evaluation of the potentially interesting associations observed will require analysis of an independent and larger cohort. This assay format provides a research tool for studies of multilocus genetic risk factors in large cardiovascular disease cohorts, and for the subsequent development of diagnostic tests.

Adult↗

PubMed1998

Constrained disequilibrium values and hitchhiking in a three-locus system.

Positive selection on a new mutant allele can increase the frequencies of closely linked alleles (through hitchhiking), as well as create linkage disequilibrium between them. Because this disequilibrium is induced by the selected allele, one may be able to identify loci under selection by measuring the influence of a candidate locus on pairwise disequilibrium values at nearby loci. The constrained disequilibrium values (CDV) method approaches this problem by examining differences in pairwise disequilibrium values, which have been normalized for two- and three-locus systems, respectively. We have investigated in detail the reliability of inferences based on CDV, using simulation and analytical methods. Our main results are (i) in some circumstances, CDV may not distinguish well between a selected locus and a neighboring neutral locus, but (ii) CDV seldom indicates "selection" in neutral haplotypes with moderate to large 4Nc. We conclude that, although the CDV method does not appear to precisely locate selected alleles, it can be used to screen for regions in which hitchhiking is a plausible hypothesis. We present a microsatellite data set from human chromosome 6, in which constrained disequilibrium values suggest the action of selection in a region containing the human leukocyte antigen (HLA)-A and myelin oligodendrocyte glycoprotein (MOG) loci. The connection between hitchhiking and disequilibrium has received relatively little attention, so our investigation presents opportunities to address more general issues.

Alleles↗

PubMed1998

A multilocus genotyping assay for cardiovascular disease.

In our efforts to develop diagnostic tests for complex multifactorial disorders, and to assist the research community in evaluating genetic markers for predisposition to cardiovascular disease, we have developed a prototype assay to genotype up to 35 variable sites among 15 genes. The candidate markers in this panel were selected from biological pathways likely to contribute to the development and progression of cardiovascular disease. Each sample is amplified in two multiplex polymerase chain reactions that are then hybridized to an array of immobilized oligonucleotide probes. The assay has been applied to a population-based cohort representing 238 families; allele frequencies observed among 455 unrelated parents from this cohort agree with available literature values. Data from a cohort of 142 lipid-clinic patients were used to explore locus associations with arterial occlusion, as measured by quantitative angiography. This prototype assay provides a research tool for studies to assess the association of multiple markers with disease, and for clinical studies to evaluate marker association with patient responsiveness to experimental therapies.

Adult↗

PubMed1997

Chromosome 19 single-locus and multilocus haplotype associations with multiple sclerosis. Evidence of a new susceptibility locus in Caucasian and Chinese patients.

CONTEXT: Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed. OBJECTIVE: To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE on chromosome 19ql 3.2, and MBP(myelin basic protein) on chromosome 18q23. DESIGN: Case-control association testing. SUBJECTS: A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria. MAIN OUTCOME MEASURES: Chi2 Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods. RESULTS: The HLA effect is due to the class II DR2 haplotype, DRB1*1501-DQA1*0102-DRB1*0602; contributions to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, including D19S178, D19S574, APOE, APOC2, and D19S219, differed between patient and control samples. D19S574 showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). The APOE variation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. Interaction effects between DR2 and chromosome 19q13.2 or MBP in MS susceptibility were not apparent. CONCLUSIONS: The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS.

Alleles↗

PubMed1997

Genetic variability and linkage disequilibrium within the DP region in the CEPH families.

A PCR-based SSO-assay has been developed to characterize the allelic polymorphism at the HLA-DPA1 locus. To validate the performance of this assay, 77 samples were typed side by side in a blinded fashion by the SSO assay and sequencing-based typing (SBT); 100% concordance was seen between the two methods. To address questions of genetic variability and linkage disequilibrium within the class II region, 478 members of the 37 original Caucasian Centre d'Etude du Polymorphisme Humain (CEPH) families were typed for DPA1 using the SSO assay providing information on 247 independent chromosomes. Six of the eight known DPA1 alleles were detected in this population; DPA1*0103 was the most frequent allele. Analysis of the distribution of allele and haplotype frequencies using the homozygosity statistic suggests that balancing selection does not appear to be acting on the DPA1 locus nor on the functional DP heterodimer in this population. Family data permits the unambiguous assignment of haplotypes. Of the 247 independent chromosomes analyzed, 24 distinct DPA1-DPB1 haplotypes were identified with DPA1*0103-DPB1*0401 being the most common. Twelve of the 18 DPB1 alleles identified in this population have an exclusive association with one DPA1 allele. Of the remaining six DPB1 alleles, four are present at a frequency of >3% and show preferential association with just one DPA1 allele. Calculation of the normalized disequilibrium parameter (D') shows 13 DP haplotypes to be in significant positive disequilibrium. These data suggest there is strong linkage disequilibrium between the DPA1 and DPB1 loci in this Caucasoid population and provide a basis with which to study linkage disequilibrium in other ethnic groups as well as analyze the evolutionary forces which govern allelic and haplotypic variation.

Alleles↗