Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis
Montse Camiña-TatoCarlos Morcillo-SuárezMarta F. BustamanteIsrael OrtegaArcadi NavarroAura MuntasellMiguel López‐BotetÁlex Sánchez‐PlaPaco CarmonaEva JuliàTeresa TórtolaLaura Audı́Jorge R. OksenbergRoland MartinꝉXavier MontalbánManuel Comabella
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The granule-dependent exocytosis pathway is an important mechanism to induce apoptosis by CD8(+) T cells and NK cells and involves lytic molecules such as perforin. In the current study, we investigated the perforin 1 gene (PRF1) as a candidate for multiple sclerosis (MS) susceptibility in the Spanish population. We genotyped three PRF1 single nucleotide polymorphisms (rs885822, rs10999426, and rs3758562) in 420 patients with MS and 512 controls. Associations of PRF1 polymorphisms with the disease were restricted to male patients with MS, and the finding was consistently observed at the allele, genotype, and haplotype levels. Gender-associated differences were validated in an additional replication cohort comprised of 292 MS cases and 300 controls. In addition, we identified minor risk haplotypes strongly associated with male patients having primary progressive MS (PPMS). Further characterization of male patients with PPMS carrying the risk haplotypes by means of gene expression microarrays revealed overrepresentation of the cell killing gene ontology category among downregulated genes in these patients compared with male patients with PPMS carrying protective haplotypes. Moreover, PRF1 mRNA expression levels were significantly lower in patients with risk haplotypes, and changes in perforin protein expression by CD8(+) T cells mirrored those observed in gene expression. These findings suggest a gender dimorphism in the PRF1 association with MS and point to the presence of a generalized defect in the expression of genes that code for proteins involved in cell killing in a subgroup of male patients with PPMS.SNP
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Phenylalanine hydroxylase
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In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A5 in a Japanese population, we sequenced the proximal promoter region, all exons, and the surrounding intronic regions using genomic DNA from 187 Japanese subjects. Thirteen SNPs, including seven novel ones: 13108T>C, 16025A>G, 16903A>G, 16993C>G, 27448C>A, 29782A>G, and 31551T>C (A of the translational start codon of GenBank Accession # NG_000004.2 is numbered "1" according to the CYP Allele Nomenclature), were identified. The most common SNP was 6986A>G (key SNP for CYP3A5*3), with a 0.759 frequency. Two novel SNPs, 29782A>G (I456V) and 31551T>C (I488T), as well as 12952T>C (*5 marker) were found, but these alterations were always associated with the *3A marker SNPs, 6986A>G and 31611C>T. Using these 13 SNPs, haplotype analysis was performed and five novel *1 haplotypes (subtypes) (*1e to *1i) and six novel *3 haplotypes (subtypes) (*3d to *3i) were identified. Our findings suggest that CYP3A5*3 is the major defective allele and that other functional exonic SNPs are rare in the Japanese. © 2003 Wiley-Liss, Inc.
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AIM: To identify the susceptible gene (s) for type 2 diabetes in the prevousely mapped region, 1p36.33-p36.23, in Han population of North China using single nucleotide polymorphisms (SNPs) and to analyze the haplotypes of the gene (s) related to type 2 diabetes.METHODS: Twenty three SNPs located in 10 candidate genes in the mapped region were chosen from public SNP domains with bioinformatic methods, and the single base extension (SBE) method was used to genotype the loci for 192 sporadic type 2 diabetes patients and 172 normal individuals, all with Hah ethical origin, to perform this casecontrol study. The haplotypes with significant difference in the gene (s) were further analyzed.RFSULTS: Among the 23 SNPs, 8 were found to be common in Chinese Han population. Allele frequency of one SNP,rs436045 in the protein kinase C/ζgene (PRKCZ) was statistically different between the case and control groups (P＜0.05). Furthermore, haplotypes at five SNP sites of PRKCZ gene were identified.CONCLUSION: PRKCZgene may be associated with type 2 diabetes in Hah population in North China. The haplotypes at five SNP sites in this gene may be responsible for this association.
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Objective The aim of this study is to investigate the single nucleotide polymorphisms(SNPs) located at the GH1 gene proximal to promoter region in Chinese Han population, and to explore its haplotype association with adult height. Methods SNP typing was performed by direct DNA sequencing in a control Chinese population of 109 unrelated male adults. By using both allele-specific PCR and the Haploview software, the haplotypes on the basis of the SNPs were obtained. Haplo.stats software was employed to analyze the association between haplotype and adult height. Results 69 samples were successfully genotyped with 34 samples bearing at least two polymorphic sites. 13 SNPs were found in the GH1 gene proximal to promoter region in Chinese Han population, and three of them located at sites of-261,-250 and +20, were discovered for the first time. The same results of haplotypes were obtained by using both allele-specific PCR and Haploview software. Three tag SNPs were found at-278,-57 and-6 sites. Seven haplotypes were detected(GGA、GGG、GTA、TGA、TGG、TTA、TTG), and statistical results indicated that people with TTA, GGG and TTG haplotypes were significantly shorter in height than those with GTA, the most common type in Chinese Han population(P0.05). Conclusions Computation of haplotypes on SNPs based on the population data is relatively correct and can be applied to the haplotype analysis independently. The GH1 gene proximal to promoter region in Chinese Han population is highly polymorphic and differs among races, and its haplotypes may contribute to the human height. Taken together, this paper provides essential data on the associations between human height and GH1 proximal haplotypes.
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Abstract: Gametic associations of a three‐allele polymorphism of the HSP70‐I 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 11 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‐I C was included in both [HLA‐B8. SCOI, DR3] and [HLA‐B18, FlC30, DR3] extended haplotypes, accounting for the previously observed strong association with DR3. In addition the same allele was found on the [HLA‐B13, SC31, DR71, on the [HLA‐B62, SB42, DR4] and on the [HLA‐B60, SC02, DR131 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*E Thus the HSP70‐1 promoter alleles provide new precisely located markers of extended haplotypes.
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Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2–1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2* 1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA‐B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B*2 whilst the Bw22 haplotypes mostly carry C4A*4, C4B*4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA‐A locus alleles on these C2*2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2*2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA‐B and HLA‐DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.
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Abstract: 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.
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Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) is associated with the HLA-DR3 and DR4 haplotypes. The HLA-DR2 haplotype is negatively associated with IDDM, an association that has been interpreted as dominant protection. Here, we describe the molecular analysis of the HLA class II genes in an unusual family with three HLA-DR1/2 siblings, all of whom have IDDM. With polymerase chain reaction amplification and sequence analysis to characterize the class II alleles, we identified a novel DQB1 allele on the DR1 haplotype and an unusual DQB1 allele on the DR2 haplotype. However, the DRB1 alleles on these DR1 and DR2 haplotypes are the conventional alleles (*0101 and *1501, respectively). These results suggest that it is the conventional DQB1 allele (*0602) not the DRB1 allele (*1501) on the protective DR2 haplotype that confers protection in the general population and, furthermore, that these unusual DQB1 alleles may confer susceptibility to IDDM in this family. The unusual DQB1 allele on this DR2 haplotype encodes Asp at position 57, indicating that it is the allele DQB1*0602 and not simply the presence of this residue that is responsible for the protective effect.
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