PPAP2B基因单核苷酸多态性与冠心病的关联研究

目的研究PPAP2B基因单核苷酸多态性(SNP)位点与中国汉族人冠心病(CHD)发病的相关性。方法共收集525例CHD患者和650例正常对照(NC),采用病例-对照关联研究的方法 ,选取PPAP2B基因的4个标签SNP,包括已有报道的rs17114036位点,采用单碱基延伸法(SNaPshot)进行基因分型,并分析其与冠心病的相关性。结果 PPAP2B基因4个标签SNP:rs6588635、rs17114036、rs2404715和rs17407790的基因型分布均符合Hardy-Weinberg平衡(P>0.05)。其等位基因频率在CHD组与NC组间有显著差异(rs6588635P=0.00167、rs17114036P=0.00581、rs2404715P=0.0174、rs17407790P=0.00124)。通过单倍体型分析发现,这4个SNP位点处于同一个连锁不平衡区域,其中风险单倍体型TACC可以增加冠心病易感性0.73倍(P=0.0012),而保护型的单倍体型CGTT可降低冠心病的患病风险47%(P=0.0025)。结论 PPAP2B基因SNP位点与冠心病发病显著相关,其危险等位基因可增加冠心病的易感性。     

广西梧州籍汉族α-地中海贫血患者HLA-A、B等位基因多态性及单倍型分析

目的分析广西梧州籍汉族α-地中海贫血患者人类白细胞抗原（HLA）-A、B在高分辨基因分型水平上的等位基因多态性和单倍型的分布特征。方法采用聚合酶链反应-直接测序分型法（PCR-SBT）,对广西梧州籍汉族117例α-地中海贫血患者的HLA-A、B位点进行高分辨基因分型,用直接计数法计算等位基因频率,应用Arlequin V3.5软件,以最大似然法分析单倍型频率。结果在117例α-地中海贫血患者中共检出高分辨HLA-A等位基因17个,HLA-B等位基因33个。A位点等位基因频率最高的是A＊11：01（27.35%）,B位点等位基因频率最高的是B＊40：01（15.38%）和B＊46：01（14.96%）。频率最高的HLA-A-B单倍型有A＊33：03-B＊58：01（11.49%）、A＊02：07-B＊46：01（8.33%）、A＊11：01-B＊40：01（6.34%）。连锁不平衡最显著的单倍型是A＊33：03-B＊58：01、A＊02：07-B＊46：01、A＊74：02-B＊51：01、A＊02：03-B＊38：02、A＊11：02-B＊27：04。结论广西梧州籍汉族α-地中海贫血患者HLA-A、B等位基因具有较高的多态性,其双座位单倍型具有地区性遗传特征。     

A Novel Approach to Rapid Determination of βS‐Globin Haplotypes: Sequencing of the Aγ‐IVS‐II Region

β‐Globin gene cluster haplotypes were originally determined by restriction endonuclease mapping with Southern blots of polymorphic sites around the gene cluster. Over the years, haplotyping has been found to be useful, not only in population genetics but also in predicting the severity of hemoglobinopathies such as sickle cell disease. The sickle mutation occurs on five distinct haplotypes. The hitherto used methods are cumbersome and time‐consuming, making haplotype determination a tedious procedure. We report our experience with a novel, rapid approach to haplotyping based on sequence polymorphisms in the ^Aγ‐IVS‐II region. We provide an algorithm that allows rapid assignment of the four African haplotypes carrying the sickle mutation.     

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.     

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.     

Beta-2 adrenergic receptor gene (ADRB2) polymorphism and risk for lung adenocarcinoma: a case-control study in a Chinese population

The incidence of lung adenocarcinoma (AC) has been increasing over recent decades. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent carcinogens and reproducibly induces a high incidence of lung AC in laboratory animals. In addition to its genotoxic effects, NNK has also epigenetic effects on lung cells by functioning as an agonist for beta adrenergic receptors and stimulating the signal pathways that lead to lung AC. Beta-2 adrenergic receptor (ADRB2) expressed on bronchial smooth muscle is a well-defined target for asthma treatment that has epidemiological implications in lung cancer development. And biochemical effect and pharmacogenetic relevance of regulatory and coding variants of ADRB2 have been well documented. Aiming to test whether the genetic variants of ADRB2 modify risk of lung AC, we compared the manifestation of three common single nucleotide polymorphisms (SNPs) of ADRB2 (G-1023A, G-654A, and A46G (Gly16Arg)) between 313 patients with lung AC and 321 controls. Overall association was not observed between risk and either individual of the three SNPs or their combined haplotypes. However, in the subgroup of young subjects ≤50 years old, significant association was observed for G-1023A (allele based OR, 1.82; 95% CI, 1.12–2.95), A46G (Gly16Arg) (allele based OR, 0.64; 95% CI, 0.40–1.03), and the haplotype A⁻¹⁰²³A⁴⁶ (OR 2.62; 95% CI 1.30–5.27). Our results do not support a major independent role of ADRB2 polymorphisms in lung AC risk, suggesting that functional variants of other genes involved in the NNK epigenetic pathway of carcinogenesis should be investigated.     

Novel mutations of RET gene in Korean patients with sporadic Hirschsprung's disease

Background/Purpose

Hirschsprung's disease (HSCR) is a congenital abnormality that can cause an intestinal obstruction. Although HSCR demonstrates a sex-modified polygenic inheritance with contributions from multiple genes, mutations in the RET gene are believed to be the major sign of susceptibility in the development of disease. The allele frequency of polymorphisms was mostly tested in the American and European population, but the data of an ethnically diverse nonwhite population are unclear.

Methods

All 21 exons and intron/exon boundaries of the RET gene in 18 Korean patients with sporadic HSCR and 84 normal individuals were screened using polymerase chain reaction amplification and direct sequencing.

Results

A total of 11 different nucleotide substitutions were identified. Of these, 2 were new missense mutations (C558Y, cysteine-rich domain; R844W, tyrosine kinase domain) and 9 previously described variants. This study also analyzed the haplotypes for the association between the variants identified with HSCR, but the estimated RET haplotypes did not show any disease risk.

Conclusions

This study identified additional mutations of RET gene, which represents the first comprehensive genetic dissection of sporadic HSCR disease in Koreans.     

Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy

Aims/hypothesis Substantial evidence exists for the involvement of the renin–angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy.Materials and methods We used a cross-sectional, case–control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a ²-test-based tool.Results None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA₁c.Conclusions/interpretation In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.Electronic Supplementary Material Supplementary material is available for this article at .