The β-GLobin Gene Haplotypes Associated With Hb D-Los Angeles [β121(GH4)Glu→Gln] in Western Iran

Hb D-Los Angeles is characterized by the substitution of glutamine for glutamic acid at position 121 of the β-globin chain. The present investigation is the first study on the β-globin gene haplotypes associated with β-D-Los Angeles in Western Iran. Thirty two individuals from 11 unrelated families from Western Iran were studied. The Hb D-Los Angeles status of all cases was confirmed using polymerase chain reaction (PCR) followed by digestion with EcoRI. The haplotype of the β‐globin gene cluster was determined by a PCR-RFLP (restriction fragment length polymorphism) procedure. The haplotype background of the β^A chromosomes was also determined in 35 normal subjects from the same geographic region. The β-globin gene haplotype analysis demonstrated that all β-D-Los Angeles genes (23 genes) were in linkage disequilibrium with haplotype I [+????++]. Among the 70 β^A chromosomes, 30 chromosomes (42.9%) were associated with haplotype I. The present study indicates the unicentric origin of the β-D-Los Angeles gene in Western Iran. It seems that this mutation may have occurred at the same chromosomal background common in the local population.     

Identification of a founder mutation for Pendred syndrome in families from northwest Iran

ObjectiveMutations in the SLC26A4 gene cause both Pendred syndrome and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB4 locus. The SLC26A4 mutations vary among different communities. Previous studies have shown that mutations in the SLC26A4 gene are responsible for the more common syndromic hereditary hearing loss in Iran. This study assesses the possibility of a founder mutation for Pendred syndrome in northwest Iran.Materials and methodsIn this study, we performed comprehensive clinical and genetic evaluations in two unrelated families from northwest Iran with nine members affected by hearing loss (HL). After testing short tandem repeat (STR) markers to confirm linkage to the SLC26A4 locus, we screened the SLC26A4 gene by Sanger sequencing of all 21 exons, exon–intron boundaries and the promoter region for any causative mutation. We identified the same causative mutation in these two families as we had detected earlier in two other Azeri families from northwest Iran. To investigate the possibility of a founder effect in these four families, we conducted haplotype analysis, and 14 single nucleotide polymorphisms (SNPs) throughout the SLC26A4 gene were genotyped.ResultsPatients in the two families showed the phenotype of Pendred syndrome. A known frameshift mutation (c.965insA, p.N322Fs7X) in exon 8 was identified in the two families, which was the same mutation that we detected previously in two other Azeri families. The results of haplotype analysis showed that all 15 patients from four families shared the founder mutation. Common haplotypes were not observed in noncarrier members.ConclusionsBased on the results of our two studies, the c.965insA mutation has only been described in Iranian families from northwest Iran, so there is evidence for a founder mutation originating in this part of Iran.     

Candidate gene analysis of SPARCL1 gene in patients with multiple sclerosis

Recently, proteomic analysis in cerebrospinal fluid (CSF) from patients with MS identified four proteins which are present in MS but not in normal human CSF, including SPARCL1, an extracellular matrix-associated protein member of the SPARC family. One hundred eighty-six patients with MS and 185 age-matched controls were genotyped for A/G single nucleotide polymorphism (SNP) in exon 1 (rs1049539), C/G SNP in exon 4 (rs1049544), resulting in a substitution of an aspartate with an histidine, and A/G substitution in the exon 5 (rs1130643), leading to the substitution of alanine with threonine. No significant differences in either allelic or genotypic frequency of the three SNPs were found (P>0.05), even in stratifying MS patients according to the course of the disease. Stratifying according to gender, a trend towards a decreased frequency of the C/C genotype of the rs1049544 was observed in male patients as compared with male controls (30.2% versus 44.0%; P=0.217). Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. However, the frequency of the C/C genotype of rs1049544 was decreased in male patients, possibly conferring a lower risk of developing MS in male population. Further studies are needed to clarify this issue.     

Interferon-gamma receptor 1 promoter polymorphisms: population distribution and functional implications

Different polymorphisms have been described in the minimal promoter region (MPR) of the interferon-gamma receptor 1 (IFNGR1), a molecule that plays a critical role in mycobacterial control. We sequenced the IFNGR1 MPR from African American, Caucasian and Korean controls, and from mycobacteria-infected patients. Six different single nucleotide polymorphisms (SNPs) were detected in the IFNGR1 MPR. The three ethnic groups showed different SNP distribution patterns, but no significant differences were detected between mycobacterial cases and controls. Two polymorphisms were found in all populations (G-611A, T-56C). We cloned the four allelic variants (var) of haplotype G-611A/T-56C into a luciferase reporter vector and determined their promoter activity. Polymorphisms at position -611 had a stronger effect on the promoter activity than those at position -56, and constructs carrying G-611 produced a stronger promoter activity than -611A constructs. The IFNGR1 MPR is a polymorphic region with at least two SNPs influencing its activity, but these are not associated with increased mycobacterial susceptibility.     

产后抑郁与雌激素受体β基因单核苷酸多态性的关联研究

目的探讨产后抑郁可能存在的雌激素受体β（Estrogen Receptor Beta,ERβ）基因遗传易感性。方法从刚进行过临床试验的746例连续整群抽样的产妇整体中,随机选择产后抑郁者68例和非产后抑郁者93例,采用聚合酶链反应-限制性酶切多态性（PCR-RFLP）的方法进行ERβ的2个SNPs（rs1256030和rs3020444）基因分型。采用病例-对照关联分析和两点单体型关联分析获得产后抑郁的遗传易感性。结果ERβ基因rs3020444（T/C）多态＂T/T＂基因型与产后抑郁关联,导致产妇患产后抑郁的风险是其它基因型的2.91（1.22-6.91）倍（P〈0.05）;＂T＂等位基因导致产妇患产后抑郁的风险是＂C＂等位基因的2.72（1.19-6.18）倍（P〈0.05）。未发现rs1256030（C/T）的等位基因或基因型与产后抑郁存在关联。基于rs1256030（C/T）和rs3020444（T/C）的单体型＂C-C＂对产后抑郁具有保护作用,OR=0.306（0.113-0.827）,P=0.019。结论ERβ基因有可能参与了产后抑郁的发病。但需要扩大样本进一步验证。     

北京汉族人群ROR2基因SNPs等位基因及单体型频率研究

目的为病因学研究中ROR2基因SNPs的确定和分析提供依据。方法利用Hap loview软件对HapM ap数据库中北京汉族人群（CHB）ROR2基因SNPs基因型数据进行分析。结果和讨论ROR2基因404个SNPs中,103个（25.5%）SNPs为纯合基因型,在中国人群中进行研究时,应避免选择这些SNPs作为遗传标记。263个合格SNPs中,MAF高于10%的SNPs为189个,占71.9%,有足够的标记可供选择。利用263个合格SNPs,本研究共确定77个标签SNPs,构建了5个单体域,各单体域均以前两种单体型为主,累计频率在68.1%-92.3%之间。结论对北京汉族人群ROR2基因SNPs数据进行的全面分析,为该人群中基因与相关疾病的病因学研究打下了基础,也为其它基因的初步研究提供了方法。     

Haplotype analysis of French,British and other European patients with familial amyloid polyneuropathy (met 30 and tyr 77)

Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder originally and most frequently described in Portugal. The usual constituent amyloid fibril protein is transthyretin (TTR) and the most frequent mutation in the TTR gene associated with FAP (including all Portuguese cases) is that at position 30 (met 30). Three different TTR haplotypes have been described in association with the met 30 mutation in European patients. We studied the haplotypes of 27 families (24 French, 2 British and 1 Greek) with FAP met 30 by analysing three polymorphisms in introns of the TTR gene. We also studied 6 families (2 British, 3 French and 1 Spanish) with FAP tyr 77. There were two main haplotypes in French patients with FAP met 30, one most commonly seen in the French families of Portuguese descent which was the same haplotype as previously described in Portuguese patients (haplotype I) and another haplotype (III) detected in most informative French families not of Portuguese origin. The age of onset of symptoms was consistently later in French than in Portuguese patients and in patients with haplotype III as the disease-associated haplotype rather than haplotype I. British and French patients with the tyr 77 mutation had different haplotypes. The most likely explanation of these findings is multiple founders of both mutations.     

T cell receptor α chain polymorphisms in multiple sclerosis

Numerous studies have implicated the major histocompatibility complex (MHC) class II alleles, DR2 and DQw1, as multiple sclerosis (MS) susceptibility loci, however, the involvement of other loci is implied by twin studies and the relative lack of haplotype sharing for MHC. To evaluate the role that the TCR alpha chain genes may have in MS susceptibility, three variable (V) alpha polymorphisms were examined for associations in MS patients. Genotype and allele frequencies were compared to four different control groups: unaffected siblings and parents of the MS patients, patients with insulin-dependent diabetes mellitus (IDDM) and healthy unrelated Caucasians. No significant differences in allele and genotype frequencies at these three loci were observed in the MS population compared to the control groups. In addition, we analysed the distribution of haplotype sharing in affected sibling pairs. Among 30 informative families, there was no significant increase in haplotypes shared by affected siblings over that expected based on random segregation. Our results do not support suggestions that germline TCR alpha chain genes contribute to genetic susceptibility in MS.