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PubMed2003

Self-incompatibility (S) locus region of the mutated S6-haplotype of sour cherry (Prunus cerasus) contains a functional pollen S allele and a non-functional pistil S allele.

This study characterizes the S6m-haplotype, a mutated S6-haplotype with an altered HindIII cut site, of sour cherry (Prunus cerasus). Inheritance and pollination studies of S-haplotypes from reciprocal crosses between 'Erdi Botermo' (EB; S4S6mSa) and 'Rheinische Schattenmorelle' (RS; S6SaSbSc) revealed that the S6m-haplotype conferred unilateral incompatibility with a non-functional pistil component and a functional pollen component. Expression analyses of S6-RNase and SFB6, a candidate gene for pollen-S, in the S6m-haplotype showed that SFB6 was transcribed in EB pollen, but S6-RNase was not transcribed in EB styles. These results were consistent with data from the inheritance and pollination studies. Inverse PCR for the flanking regions of S6-RNase in the S6- and S6m-haplotypes revealed an approximately 2600 bp insertion present at approximately 800 bp upstream of the S6-RNase in the S6m-haplotype, which is responsible for the alternation of the HindIII cut site and a possible cause of inhibition of the transcription of S6-RNase. SFB6 was present downstream of S6-RNase in both the S6- and S6m-haplotypes and expressed in the same way, supporting the idea that SFB is a good candidate for pollen-S in Prunus.

Alleles↗

PubMed2002

Molecular haplotyping at high throughput.

Reconstruction of haplotypes, or the allelic phase, of single nucleotide polymorphisms (SNPs) is a key component of studies aimed at the identification and dissection of genetic factors involved in complex genetic traits. In humans, this often involves investigation of SNPs in case/control or other cohorts in which the haplotypes can only be partially inferred from genotypes by statistical approaches with resulting loss of power. Moreover, alternative statistical methodologies can lead to different evaluations of the most probable haplotypes present, and different haplotype frequency estimates when data are ambiguous. Given the cost and complexity of SNP studies, a robust and easy-to-use molecular technique that allows haplotypes to be determined directly from individual DNA samples would have wide applicability. Here, we present a reliable, automated and high-throughput method for molecular haplotyping in 2 kb, and potentially longer, sequence segments that is based on the physical determination of the phase of SNP alleles on either of the individual paternal haploids. We demonstrate that molecular haplotyping with this technique is not more complicated than SNP genotyping when implemented by matrix-assisted laser desorption/ionisation mass spectrometry, and we also show that the method can be applied using other DNA variation detection platforms. Molecular haplotyping is illustrated on the well-described beta(2)-adrenergic receptor gene.

Alleles↗

PubMed1989

Renal transplantation between living-related sibling pairs matched for zero-HLA haplotypes.

The functional survival rates of kidney grafts from zero-HLA haplotype-matched sibling pairs are similar to one-haplotype-matched pairs and superior to cadaver grafts. From January 1980 to March 1988, 318 primary renal transplants from sibling donors (151 matched for two, 130 for one, and 37 for zero HLA haplotypes), and 352 cadaver graft transplants were performed at the University of Minnesota. The renal graft survival rates at two years were 94%, 91%, and 94% for the 2, 1, and 0-haplotype pairs versus 75% for cadaver graft recipients (P less than 0.04). When analyzed across the different immunosuppression protocols the same trends held up, similar graft functional survivals for 1- and 0-haplotype-matched pairs both being superior to cadaver graft recipients. The graft functional survival rates at two years of recipients of 0-haplotype-matched sibling donor grafts (n = 37) was 94% versus 80% for recipients of cadaver donor grafts matched for greater than or equal to 4 HLA antigens. In addition, for recipients of 0-haplotype-matched grafts, hospital stay was shorter, fewer patients required dialysis posttransplant, and, despite a slightly higher incidence of rejection episodes (51% versus 40%, P = ns), the creatinine values one year posttransplant were significantly lower (1.5 mg/dl versus 1.9 mg/dl, P less than 0.02) than those of recipients of cadaver grafts matched for greater than or equal to 4 HLA antigens. These data support the use of cadaver grafts for patients not having a willing sibling donor, and the use of all willing sibling donors, whether or not they are a zero-haplotype match, for patients fortunate to have that family commitment.

Antilymphocyte Serum↗

PubMed2000

The importance of H2 haplotype sharing in the induction of specific unresponsiveness by pretransplant blood transfusions.

BACKGROUND: The beneficial effect on graft survival achieved by pretransplant blood transfusions is well established. Previous studies have shown that the degree of major histocompatibility complex (MHC) (mis)-match between the transfusion donor and the recipient plays a determining role. However, other factors are also involved. In this study, we explored the hypothesis that, in addition to sharing of MHC antigens between the transfusion donor and the recipient, the MHC type of the organ donor is also of importance. METHODS: To mimic the human situation, F1 mice, rather than inbred strains, were pretreated with haplotype-shared allogeneic whole blood transfusions and transplanted with hearts of organ donors with different matched or mismatched H2 haplotypes. RESULTS: When a heart was transplanted 1 week after donor-specific transfusion (DST; blood transfusion donor=organ donor), an excellent prolongation of graft survival was obtained (median survival time: 77 days vs. 9 days in untreated mice). However, this was only the case when a haplotype was shared with the recipient; a DST given with no match between organ donor (=BT donor) and recipient did not induce any prolongation. Furthermore, in order to obtain the optimal beneficial effect of a haplotype-shared blood transfusion, the other haplotype of the transfusion donor had to be mismatched with the recipient. The immunogenetic studies showed that haplotype-shared blood transfusions in combinations where the H2 type of the organ donor differed from that of the transfusion donor are less efficient in inducing prolongation of graft survival. CONCLUSIONS: These results demonstrate that haplotype-shared blood transfusions can induce a significantly prolonged survival of cardiac allografts in F1 mice. The immunogenetic studies suggest that presentation of alloantigen-derived peptides in the context of self MHC (the indirect pathway of allorecognition) is essential for the beneficial effect of haplotype-shared blood transfusions.

Animals↗

PubMed2006

Identification and functional significance of SNPs underlying conserved haplotype frameworks across ethnic populations.

BACKGROUND: The study of genetic variation will promote our understanding of the differential predisposition to common diseases and variation in drug responses of individuals and ethnic populations. Such genetic variation is intrinsically structured into blocks of haplotypes in populations. Therefore, a comprehensive haplotype map based on the most abundant form of genetic variation, single nucleotide polymorphisms, will be useful. At the present time, however, our knowledge of the similarities and differences of haplotype structure among different ancestral populations is still inadequate. METHODS: To determine whether common underlying haplotype patterns existed across ethnic populations, we analyzed data derived from African and European Americans for twenty-two genes spanning a total of 516 kb and the HapMap ENCODE data across 500 kb on chromosome 2p16.3 from three major world populations. RESULTS AND CONCLUSIONS: We observed that strong pairwise linkage disequilibrium (LD) between SNPs selected from populations having African ancestry was highly conserved across other non-African populations. Common haplotypes described by these LD-selected SNPs demonstrated a simple evolutionary structure with up to three major frameworks, which were likely ancestral backgrounds upon which more recent mutations have been superimposed. Also, haplotype block boundaries defined in populations having African ancestry revealed completely concordant recombinant haplotypes across all populations, providing a consistent definition of block structure. Finally, a large fraction of regulatory polymorphisms described in the literature appeared to tag these conserved haplotype frameworks, strongly suggesting their significance for disease association and pharmacogenetic studies.

Black or African American↗

PubMed2005

Influence of the endothelial nitric oxide synthase gene on conventional and ambulatory blood pressure: sib-pair analysis and haplotype study.

BACKGROUND: Nitric oxide is involved in the regulation of vascular basal tone and blood pressure. Polymorphisms of NOS3, the gene that codes for endothelial nitric oxide synthase, have been associated with essential hypertension. OBJECTIVE: To look for linkage and association of three di-allelic polymorphisms (Glu298Asp, intron 4 VNTR and T-786C) and the intron 13 CA-repeat of NOS3 with blood pressure as a continuous trait. METHODS: Genotyping was performed in 110 dizygotic white twin pairs from Flanders, Belgium. The influence of NOS3 polymorphisms on conventional and ambulatory blood pressure was assessed by sib-pair analysis and haplotype association analysis. RESULTS: Genotype frequencies were similar to those previously reported in white populations. Sib-pair analysis did not show a significant influence of either polymorphism on blood pressure. Haplotype analysis disclosed a significant association between NOS3 haplotypes and daytime ambulatory diastolic (P = 0.02) and systolic (P < 0.0001) blood pressure, the latter remaining significant after multiple testing was taken into account (P = 0.032). The association between daytime ambulatory systolic blood pressure and NOS3 haplotypes was mainly attributable to four haplotypes accounting for 11.9% of all represented haplotypes. CONCLUSION: We show for the first time a highly significant association of ambulatory blood pressure with NOS3 haplotypes in well-characterized white individuals from Flanders. These results pave the way for studies looking for the influence of NOS3 on blood pressure in high-risk subsets such as diabetic or hypertensive patients. They indicate the importance of ambulatory blood pressure and haplotype analysis in revealing the moderate effect of polymorphisms on blood pressure.

Adult↗

PubMed2006

Haplotypes of the beta-2 adrenergic receptor associate with high diastolic blood pressure in the Caerphilly prospective study.

OBJECTIVES: Current evidence demonstrates that both genetic and environmental factors influence blood pressure. The sympathetic nervous system is a key player in blood pressure control and functional genetic variants of the beta-2 adrenergic receptor (B2AR) have been identified and implicated in the pathogenesis of hypertension. The present study aimed to determine the effects of common haplotypes of the B2AR gene upon blood pressure in the Caerphilly Prospective Study. DESIGN: Two thousand five hundred and twelve men (aged 45-59 years) participated in the study. We selected individuals in the upper (n = 347) and lower (n = 279) quintiles of the diastolic blood pressure distribution fixed at two time points [phase 2 (1984-88) or phase 3 (1989-93)] as cases and controls. METHODS: We analysed two functional polymorphisms (Arg16Gly and Gln27Glu) of B2AR and their haplotypes. RESULTS: We found a higher risk of hypertension in individuals homozygous for the Gln27 compared to those individuals homozygous for Glu27 [odds ratio (OR) = 1.94; 95% confidence interval (CI) = 1.34-2.81; P = 0.001]. Three haplotypes (Gly16Gln27, Gly16Glu27 and Arg16Gln27) were present in both quintile groups. Logistic regression analysis showed that haplotypes with a Gln27 allele (Gly16Gln27 and Arg16Gln27) conferred a significantly higher risk for hypertension than the Gly16Glu27 haplotype (OR = 1.55; 95% CI = 1.11-2.17, OR = 1.37; 95% CI = 1.04-1.81; P = 0.009 and P = 0.027, respectively). However, there was no evidence to support a statistically significant difference in odds ratios for the Gly16Gln27 and Arg16Gln27 haplotypes (P = 0.477), suggesting that it is the Gln27 allele alone, rather than any haplotype, which best explains the association. CONCLUSIONS: In a prospectively studied Caucasian male cohort, high diastolic blood pressure was associated with B2AR haplotypes containing the pro-downregulatory Gln27 variant.

Blood Pressure↗

PubMed2006

Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy.

OBJECTIVES: Most hypertensive patients require two or more drugs to control arterial blood pressure effectively. Although endothelial nitric oxide synthase (eNOS) haplotypes have been associated with hypertension, it is unknown whether eNOS genotypes/haplotypes are associated with resistance to antihypertensive therapy. METHODS: We studied the distribution of three eNOS genetic polymorphisms: single nucleotide polymorphisms in the promoter region (T(-786)C), and in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a). Genotypes were determined for 111 normotensive controls (NT), 116 hypertensive individuals who were well controlled (HT), and 100 hypertensive individuals who were resistant to conventional antihypertensive therapy (RHT). We also compared the distribution of eNOS haplotypes in the three groups of subjects. RESULTS: No differences were found in genotype or allele distribution among the three groups (all P > 0.05). Conversely, the 'C Glu b' haplotype was more commonly found in the NT than in the HT or RHT groups (21 versus 8 and 7%, respectively; both P < 0.00625). In addition, the 'C Asp b' haplotype was more commonly found in the HT or RHT groups than in the NT group (22 and 20%, respectively, versus 8%; both P < 0.00625). The distribution of eNOS haplotypes was not significantly different in the HT and RHT groups (P > 0.05). CONCLUSIONS: Whereas our findings suggest a protective effect for the 'C Glu b' haplotype against hypertension and that the 'C Asp b' haplotype increases the susceptibility to hypertension, our results suggest that eNOS haplotypes are not associated with resistance to antihypertensive therapy.

Drug Resistance↗

PubMed1994

The evolution of lethals in the t-haplotype system of the mouse.

The evolution of lethal haplotypes in the t-haplotype segregation distortion system of Mus is examined by mathematical and computer models. The models assume that there is reproductive compensation for the loss of lethal embryos, such that the net reproductive success of a females is not reduced in proportion to the frequency of lethal offspring which she produces. The initial population consists of a mixture of wild-type and homozygous male-sterile t-haplotypes. The failure of sterile males to reproduce may cause a higher fitness cost to mothers heterozygous for t-haplotypes than does elimination of a recessive lethal. Under certain conditions, a recessive lethal will spread and come to a polymorphic equilibrium. Wild-type, lethal and non-lethal haplotypes are all present at this equilibrium. If a second lethal mutation arises on a non-lethal t-haplotype in such an equilibrium population, it will increase in frequency and eventually displace the non-lethal t-haplotypes. A third lethal t-haplotype introduced at a low frequency into an equilibrium with two lethals can sometimes be selected for, although this is less likely if compensation is strong. The theoretical predictions are compared with data on natural populations.

Animals↗

PubMed2004

Study on the haplotypes of MICA and MICB microsatellite and HLA-B locus in the Guangzhou Han population.

The purpose of this study was to investigate the genetic polymorphisms and haplotypes of microsatellite locus in exon 5 of the MICA gene and intron 1 of the MICB gene and human leukocyte antigen-B (HLA-B) gene based on 106 samples of the Guangzhou Han population through means of polymerase chain reaction and the fluorescent technique (6-FAM). The corresponding haplotype frequencies, linkage disequilibrium values and relative linkage disequilibrium values were estimated based on population data. The results show that the genotype distributions of MICA and MICB microsatellite and HLA-B satisfy the Hardy-Weinberg equilibrium. In total, five alleles of MICA microsatellite locus and 14 alleles of MICB microsatellite locus were observed. MICA A5 was the most common allele (0.2877), whereas A4 was the least common (0.1321). MICB CA14 was the most common allele (0.3255), and CA19 and CA28 were the two least common (0.0047). CA27 was not observed at all. Five kinds of MICA-MICB haplotypes, 18 kinds of MICA-HLA-B haplotypes and 12 kinds of MICB-HLA-B haplotypes occurred at frequencies of more than 1%. The common haplotypes of MICA-MICB, MICA-HLA-B and MICB-HLA-B were A5-CA14, A5.1-CA18, A4-CA26, A9-CA15, A5-B*15(62), A5.1-B*1301/1302, A4-B*1301/1302, A6-B*51, A6-B*4403, A9-B*3802, CA14-B*4601, CA18-B*1301/1302 and CA26-B*1301/1302, and these haplotypes showed strong linkage disequilibrium. The polymorphisms and haplotype distributions of MICA and MICB microsatellite and HLA-B locus in the Guangzhou Han population have their own distinct genetic characteristics. The microsatellite locus of exon 5 of the MICA gene and intron 1 of the MICB gene could therefore be used as genetic markers in the studies of anthropology, gene linkage analysis in genetic diseases, individual identification and paternity testing in forensic medicine.

Asian People↗

PubMed2004

Chloroplast haplotype variation among monoecious and dioecious populations of Sagittaria latifolia (Alismataceae) in eastern North America.

Aquatic plants commonly have extensive geographical distributions, implying few restrictions to dispersal. Here we investigate the postglacial history of an aquatic plant with contrasting sexual systems (monoecy and dioecy), which are predicted to affect dispersal ability. We examined the distribution of cpDNA haplotypes using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) among 76 populations (32 monoecious, 38 dioecious, two mixed and four undetermined populations) of Sagittaria latifolia sampled throughout eastern North America. We also use these data to investigate the polarity of the evolutionary transition between monoecy and dioecy. Using PCR-RFLP, we identified eight cpDNA haplotypes. All haplotypes were found in unglaciated areas of the species' range, clustered primarily in the southeastern United States, providing evidence that glacial refugia probably occurred in this area. Genetic diversity (hT) was more than six times greater among monoecious compared to dioecious populations. All seven of the haplotypes for which the sexual system could be determined were represented among monoecious populations. In contrast, only four haplotypes were detected in dioecious populations and 94% of individuals from dioecious populations possessed a single haplotype. Monoecious populations possessing this widespread haplotype were restricted to the southern portion of the range, indicating that dioecy probably originated in this region and then spread northwards. The distribution of cpDNA haplotypes in dioecious populations represents a subset of the variation found in monoecious populations, a pattern expected if dioecy has evolved from monoecy in S. latifolia.

Analysis of Variance↗

PubMed2005

Nonshivering thermogenesis capacity associated to mitochondrial DNA haplotypes and gender in the greater white-toothed shrew, Crocidura russula.

A selection gradient was recently suggested as one possible cause for a clinal distribution of mitochondrial DNA (mtDNA) haplotypes along an altitudinal transect in the greater white-toothed shrew, Crocidura russula (Ehinger et al. 2002). One mtDNA haplotype (H1) rare in lowland, became widespread when approaching the altitudinal margin of the distribution. As H1 differs from the main lowland haplotype by several nonsynonymous mutations (including on ATP6), and as mitochondria play a crucial role in metabolism and thermogenesis, distribution patterns might stem from differences in the thermogenic capacity of different mtDNA haplotypes. In order to test this hypothesis, we measured the nonshivering thermogenesis (NST) associated with different mtDNA haplotypes. Sixty-two shrews, half of which had the H1 haplotype, were acclimated in November at semioutdoor conditions and measured for NST throughout winter. Our results showed the crucial role of NST for winter survival in C. russula. The individuals that survived winter displayed a higher significant increase in NST during acclimation, associated with a significant gain in body mass, presumably from brown fat accumulation. The NST capacity (ratio of NST to basal metabolic rate) was exceptionally high for such a small species. NST was significantly affected by a gender x haplotype interaction after winter-acclimation: females bearing the H1 haplotype displayed a better thermogenesis at the onset of the breeding season, while the reverse was true for males. Altogether, our results suggest a sexually antagonistic cyto-nuclear selection on thermogenesis.

Acclimatization↗

PubMed1989

Haplotypes bearing HLA-A, -B, and -DR: Bf and C4 genes in rheumatoid arthritis families.

We have compared haplotypes bearing HLA-A, -B, -DR; Bf and C4 genes in 54 rheumatoid arthritis (RA) and 24 control families. There was no statistically significant differences in C4A or C4B gene frequencies between RA and control groups, although there were trends for C4B*Q0 to be reduced and C4B2 to be increased in DR4 positive RA compared with DR4 positive controls. The lack of any strong association between C4 variants and RA overall makes it unlikely that the association between RA and genes within the MHS represents a direct effect of variants within the C4A or C4B loci themselves. On comparison of DR4-bearing haplotypes, the haplotype B15-BfS-DR4 was increased fourfold and the B44-Bfs-DR4 haplotype was less frequent in the RA group. When C4 variants were also considered, the haplotype B44-C4B*Q0-C4A3-BfS-DR4 was nine times less frequent in RA patients than in controls. The observation that different DR4 bearing haplotypes may confer either increased or decreased susceptibility to RA suggests either that it is unlikely that DR4 itself is involved in the disease process or that specific haplotypic combinations are important. Thirty-two RA patients were HLA-DR4 negative. No single DR4 negative haplotype was found to confer significantly increased susceptibility to RA.

Arthritis, Rheumatoid↗

PubMed1990

Polymorphism of HLA-DR2,DQw1 haplotypes in Asian Indians.

We examined the polymorphism of DR2,DQw1 haplotypes in Epstein-Barr virus-transformed B-lymphoblastoid cell lines (HTCs) and unrelated (32 Canadian Caucasians and 24 Asian Indians) individuals by restriction fragment length polymorphism (RFLP) and oligonucleotide typing. The data demonstrate that three subtypes of DR2,DQw1 haplotypes, DRw15(B1.1501).DQw6a(A1.0102,B1.0602),DRw15(B1.1502). DQw6b(A1.0103,B1.0601), DRw16(B1.1601).DQw5(A1.0102,B1.0502) are present in HTCs and Canadian Caucasians. Of these, DRw15(B1.1501).DQw6a (A1.0102,B1.0602) haplotype was present in majority (81.3%) of Caucasians. Among Asian Indians, this haplotype was present only in one DR2,DQw1-positive individual. In addition, three new haplotypes representing different combinations of DRB1, DQA1 and DQB1 genes were demonstrable in Asian Indians. These new haplotypes are DRw15(B1.1501).DQw6b(A1.0103,B1.0601),DRw15(B1.1501). DQw5(A1.0102,B1.0502), and DRw15(B1.1501).DQw6c(A1.0102, B1.0601). The most frequent haplotypes among Asian Indians were DRw15(B1.1502).DQw6b(A1.0103,B1.0601) and DRw15(B1.1501). DQw6b(A1.0103,B1.0601). The distribution of subtypes of DR2,DQw1 haplotypes in Asian Indians was significantly different from that in Canadian Caucasians. The results in the present study have important implications for HLA and for HLA-disease associations.

Asia↗

PubMed1993

Gametic association of HSP70-1 promoter region alleles and their inclusion in extended HLA haplotypes.

Gametic associations of a three-allele polymorphism of the HSP70-1 promoter region were analyzed in a random North Italian population, in 69 HLA homozygous cell lines and in 29 families in Boston, all typed for HLA class I, class II and complement alleles. Significant phenotypic associations were detected in the random population between HSP70-1 alleles and several HLA markers carried by extended haplotypes. The inclusion of HSP70-1 alleles in extended haplotypes, suggested by population analysis, was confirmed in genotyped cells, including 10W HLA homozygous cell lines and families, selected for the presence of the whole set of alleles reported for conserved extended haplotypes. Every tested extended haplotype was exclusively associated with a given HSP70-1 allele, except those carrying DR1. HSP70-1 C was included in both [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3] extended haplotypes, accounting for the previously observed strong association with DR3. In addition the same allele was found on the [HLA-B13, SC31, DR7], on the [HLA-B62, SB42, DR4] and on the [HLA-B60, SC02, DR13] extended haplotypes. The HSP70-1 A allele was carried by all DR4+ extended haplotypes except the one above cited. HSP70-1 B correlated with DR10, DQB1*0501 and BF*F. Thus the HSP70-1 promoter alleles provide new precisely located markers of extended haplotypes.

Alleles↗

PubMed1995

The HLA-A3, Cw6,B47,DR7 extended haplotypes in salt losing 21-hydroxylase deficiency and in the Old Order Amish: identical class I antigens and class II alleles with at least two crossover sites in the class III region.

The HLA-B47,DR7 haplotype in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency contains a deletion of most of the active CYP21 gene and the entire adjacent C4B gene. The C4A gene produces a protein which is electrophoretically C4A but antigenically C4B. In the Old Order Amish, the HLA-B47,DR7 haplotype contains no deletion, but is immunologically identical to the CAH haplotype in both areas flanking the crossover region. We compared some of the genes in the MHC Class II and Class III regions in the Amish and CAH-linked haplotypes to define further the relationships between the two. The complement factor B (Bf) proteins differed, but no Bf RFLPs were identified. The complement factor 2 genes exhibited different BamHI RFLPs. Analyses of the tumor necrosis factor-alpha genes revealed the same NcoI restriction patterns. The RD genes contained microsatellites of the same size. Portions of the MHC Class II DR and DQ, and Class III CYP21 and C4 alleles were sequenced. The exon 2 sequences of DQ2 and DR7 were identical in the two haplotypes. In the Amish haplotype, both CYP21 and C4 gene pairs were present and functionally normal. The CAH haplotype had two sequence crossovers: from CYP21P to CYP21 in the 7th intron, and from C4A to C4B between codons 1106 (exon 26) and 1157 (exon 28). A model is proposed which accounts for the CAH-linked mutant haplotype arising from a nonmutant homologue via three crossings-over.

Adrenal Hyperplasia, Congenital↗

PubMed1997

Haplotypic diversity of DQA103 and 05 subtypes differing at amino acid residue 160 encoded in the third exon in 2215 Japanese individuals.

We analyzed the frequencies and haplotypes of DQA1*03 and *05 subtypes, DQA1*03011 or DQA1*0302 and DQA1*0501 or DQA1*0503, respectively, differing only at codon 160 in the non-polymorphic third exon of the DQA1 gene. Of these, 1,862 and 337 individuals selected as DQA1*03- and DQA1*05-positive samples, respectively among 2,215 unrelated Japanese were typed for their nucleotide variation at residue 160 using PCR-SSP. As observed in other populations, all the samples carrying DQA1*03011 (Gene Frequency, GF: 7.8%) were found to share DQB1*0302, whereas those carrying DQA1*0302 (GF: 44.3%) were associated with a variety of DQB1 alleles including DQB1*0302. Both of the DQA1-DQB1 haplotypes with DQA1*03011 and DQA1*0302 carrying DRB1*0406, DQA1*03011-DQB1*0302 and DQA1*0302-DQB1*0302, showed a strong linkage disequilibrium with B62 (p < 0.001, p < 0.05). These results suggested that DQA1*03011 was generated from a single amino acid change at residue 160 in the DQA1*0302-DQB1*0302 haplotype. However, none of the haplotypes with two different DQA1*03 subtypes carrying DRB1*0403,*0405,*0802 and *0901 showed a linkage disequilibrium with any common B-locus antigens, revealing extensive haplotypic diversity of the DQA1*03 group. For example, DRB1*0802 haplotypes showed linkage disequilibria with two different B-locus antigens, B35 and B61 depending on the presence of DQA1*03011 and DQA1*0302, respectively. The GFs of DQA1*0501 and *0503 were 5.1% and 2.7%, respectively. The DQA1*05 associated haplotypes in the DR52-antigen group with DQB1*0301 were divided into two groups, depending on the bimorphism at residue 160. Such a high degree of haplotypic diversity in association with DRB1 and B alleles observed in the DQA1*03 and *05 groups related to amino acid variation at residue 160, which may affect biological function such as the interaction between CD4 and HLA-DQ molecules, seems to reflect selective pressure in the evolutionary process of HLA antigens.

Alleles↗

PubMed2005

Extended DR3-D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians.

Human leukocyte antigen (HLA)-DR3 haplotypes are associated with susceptibility to type 1 diabetes (T1D). Reports from Northern European populations show that an allele (D6S273*2) at a microsatellite mapping to HLA class III marks an extended DR3-B18 haplotype associated with increased susceptibility to T1D. Consistent with previous reports, D6S273*2 marked a highly predisposing DR3 haplotype in European origin, multiplex families from the USA. Furthermore, we observed on DR3 haplotypes that other D6S273 alleles were also significantly associated with both increased transmission (D6S273*5; P < 0.02) and decreased transmission (D6S273*7; P < 0.05) to affected individuals. The differential transmission was most evident among DR3-B8 haplotypes. Neither HLA-B*1801 nor any alleles of D6S273 were associated with increased T1D predisposition on DR4 haplotypes. These data indicate that multiple alleles of D6S273 mark a susceptibility locus whose effect we were able to detect only among DR3 haplotypes but not limited to DR3-B18 haplotypes.

Diabetes Mellitus, Type 1↗