Specific haplotypes of the CALPAIN-5 gene are associated with polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The aim of the present study was to investigate the role of CALPAIN-5 (CAPN5) gene in PCOS susceptibility. METHODS: We analysed four intronic polymorphisms of the CAPN5 gene in 148 well-characterized women with PCOS and 606 unrelated controls. We performed a case-control study and an intracohort analysis of clinical characteristics associated with PCOS. RESULTS: Analysis of haplotypes distribution between PCOS population compared to controls showed a strong deviation (P = 0.00029). The haplotypes GGCA and GGTG were overrepresented in PCOS patients (P = 0.009 and P = 0.001, respectively). In addition, we identified several CAPN5 haplotypes associated with phenotypic differences observed between PCOS patients, such as the presence of obesity (P = 0.02), cardiovascular complications (P = 0.02), familial antecedents of obesity (P = 0.003) and of hypertension (P = 0.007) and type 2 diabetes mellitus aggregation (P = 0.04). CONCLUSIONS: These results suggest a role of CAPN5 gene in PCOS susceptibility in humans. Moreover, novel candidate risk alleles have been identified, within CAPN5 gene, which could be associated with important phenotypic and prognosis differences observed in PCOS patients.     

alpha-Synuclein gene haplotypes are associated with Parkinson's disease

We report haplotype analysis of the alpha-synuclein gene in Parkinson's disease (PD), extending earlier reports of an association with a polymorphism within the gene promoter. This analysis showed significant differences in haplotypes between PD cases and controls. Our analyses demonstrate that genetic variability in the alpha-synuclein gene is a risk factor for the development of PD. These genetic findings are analogous to the tau haplotype over-represented in progressive supranuclear palsy and further extend the similarity in the etiologies and pathogeneses of the synucleinopathies and tauopathies.     

CYP4A11基因多态性与心肌梗死相关

目的 研究在不同性别中CYP4A11基因多态性与心肌梗死的关系.方法 166例心肌梗死患者和158例对照组,选择CYPA11基因的3个SNPs(rs9332978、rs3890011和rs1126742),应用TaqMan SNP基因分型法进行基因分型,并应用病例对照的研究方法进行相关性分析.结果 rs3890011的基因分型在心肌梗死组和对照组之间的分布存在明显差异(P＜0.05),心肌梗死组携带GG基因型(GG vs CC+ GC)高于对照组(P＜0.05),在排除吸烟、高血压、糖尿病等混杂因素后,仍存在显著性差异(95％ CI:1.138～2.432,P＜0.01).结论 CYP4A11基因的rs3890011多态性与心肌梗死相关,rs3890011的GG基因型可作为心肌梗死易感基因标记.     

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.     

The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction

P-selectin is an adhesion molecule, expressed at the surface of activated cells, that mediates the interaction of activated endothelial cells or platelets with leukocytes. P-selectin expression is increased in atherosclerotic plaques, and high plasma levels of this molecule have been observed in patients with unstable angina. We investigated the P-selectin gene as a possible candidate for myocardial infarction (MI). The P-selectin gene is situated on chromosome 1q21-q24, spans >50 kb and contains 17 exons. The sequences of the 5'-flanking region and exons of 40 alleles from patients with MI were screened for polymorphisms using polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) and sequencing. Thirteen polymorphisms were identified: five in the 5'-flanking and eight in the exonic sequences. Four polymorphisms (Ser290Asn, Asn562Asp, Leu599Val and Thr715Pro) predicted a change in the amino acid sequence of the P- selectin protein. All P-selectin polymorphisms as well as a common E- selectin polymorphism, Ser128Arg which has been reported as being associated with an increased risk of premature coronary heart disease (CHD), and is in tight linkage disequilibrium with several P-selectin polymorphisms, were investigated in 647 patients with MI and 758 control subjects from four regions of France and Northern Ireland (the ECTIM study). The entire set of P-selectin polymorphisms provided a heterozygosity of 91%. The polymorphisms were tightly associated with one another and displayed patterns of linkage disequilibrium suggesting the existence of highly conserved ancestral haplotypes. The five polymorphisms in the 5'-flanking region of the gene were unrelated to MI or any relevant phenotype measured in the ECTIM study. We inferred that the four missense variants identified in the coding region predicted eight common forms of the P-selectin protein. The Pro715 allele which characterizes one of these forms was less frequent in France than in Northern Ireland ( P < 0.002) and in cases than in controls ( P < 0.002; P < 0.02 after correction for the number of tests). We conclude that the P-selectin gene is highly polymorphic and hypothesize that the Pro715 variant may be protective for MI. Whether this variant affects the properties of the P-selectin protein in a way which is compatible with this hypothesis needs to be checked experimentally.      

Functional polymorphisms and haplotypes in the promoter of the MMP2 gene are associated with risk of nasopharyngeal carcinoma

Matrix metalloproteinases (MMPs) play important roles in cancer initiation and development. Several polymorphisms in the promoters of a number of MMP genes, which can affect the respective MMP production in an allele-specific manner, have been well characterized. We examined whether these functional polymorphisms were related to the risk of nasopharyngeal carcinoma (NPC) in Chinese populations. Eight polymorphisms in the promoter of MMP1, MMP2, MMP3, MMP7, MMP9, MMP12, and MMP13 were genotyped in two independent case-control populations; one is from Guangxi province (593 patients with NPC and 480 controls), and the other is from Guangdong province (239 patients and 286 controls). We observed significantly increased susceptibility to NPC for the MMP2 -1306CC (rs243865:C>T) (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.30-3.10) and -735CC (rs2285053:C>T) (OR = 1.56, 95% CI = 1.17-2.09) genotype carriers compared with noncarriers in the Guangxi population. This association was confirmed in the Guangdong population (for -1306CC: OR = 2.19, 95% CI = 1.21-3.96; for -735CC: OR = 1.60, 95% CI = 1.13-2.28). The C(-1306)-C(-735) haplotype was also significantly associated with increased susceptibility to NPC in both the Guangxi (OR = 1.64, 95% CI = 1.35-1.99) and Guangdong population (OR = 1.68, 95% CI = 1.29-2.19). Furthermore, stratified analysis indicated that the increased susceptibility to NPC related to the -1306CC and -735CC genotype and the C(-1306)-C(-735) haplotype was more pronounced in heavier smokers. Our findings suggest that the genetic polymorphisms or haplotype in the MMP2 promoter may play a role in mediating the susceptibility to NPC in Chinese populations.     

VAMP-8 gene variant is associated with increased risk of early myocardial infarction

Introduction

Single nucleotide polymorphism in the 3’ untranslated region of the vesicle-associated membrane protein gene (VAMP-8) has been associated with increased risk of early-onset myocardial infarction (MI). In this study the risk of early onset MI conferred by VAMP-8 gene polymorphism was investigated in a group of 171 male subjects.

Material and methods

Male patients with a history of MI who underwent coronary angiography were enrolled and divided into early (incident < 55 years of age) and late (incident ≥ 55 years of age) MI onset groups. Apart from the RFLP-PCR based analysis of the VAMP-8 variant, history of hypertension, lipid abnormalities, smoking and body mass index were recorded. In statistical analyses odds ratios and relative risk were used as a measure of genotype-MI association while logistic regression was implemented for evaluation of MI risk factor strength.

Results

VAMP-8 A allele frequency proved to be significantly higher in the early-onset MI group and conferred higher relative risk of early MI in the investigated cohort, when calculated for the individual A allele (p = 0.029). In logistic regression analyses no association between risk genotypes and traditional risk factors was observed.

Conclusions

In this study VAMP-8 A variant was identified as a risk allele for early MI in male subjects.     

Polymorphisms of the lipoprotein lipase gene are associated with atherosclerotic cerebral infarction in the Chinese

BACKGROUND: Lipoprotein lipase (LPL), which plays an essential role in plasma lipoprotein metabolism and transportation, appears to be a risk factor for ischemic vascular diseases. Several studies have recently reported the presence of relationship between HindIII, PvuII, Ser447Ter (C-->G) polymorphisms of LPL and ischemic vascular diseases. PURPOSE: We first studied the relationship between LPL polymorphisms and the risk of atherosclerotic cerebral infarction (CI) by detecting the frequencies of LPL HindIII, PvuII and Ser447Ter genotypes and combined genotypes in the Chinese. METHODS: We recruited 185 CI patients, confirmed by cranial computed tomography or magnetic resonance imaging/angiography, or both, and 186 control subjects. Polymerase chain reaction-restriction fragment length polymorphisms technique was used to detect HindIII, PvuII and Ser447Ter polymorphisms of the LPL gene. RESULTS: The frequencies of the H+H+ genotype and H+ allele did not differ between CI and control groups. The frequencies of the P+P+ genotype and P+ allele gene were significantly higher in the CI group (P=0.040, P=0.015). The frequencies of CG+GG genotype and G allele were lower in the CI group (P<0.001, P<0.001). In the CI group, the individuals with P+P+ genotype had a significantly higher level of plasma triglyceride (TG) and a lower level of plasma high density lipoprotein cholesterol (HDL-c). CG+GG genotypes were correlated with significantly higher levels of plasma total cholesterol (TC), HDL-c and low density lipoprotein cholesterol (LDL-c) in the CI group. The frequencies of H+/C and P+/C combined genotypes were higher in the CI group than in controls (P<0.001, P<0.001). The frequency of H+/P+/C combined genotype was significantly higher in the CI group than in controls (P<0.001). CONCLUSIONS: Our study suggests that PvuII and Ser447Ter polymorphisms are associated with lipid profile and CI.     

Specific haplotypes of the RET proto-oncogene are over-represented in patients with sporadic papillary thyroid carcinoma

Background: Papillary thyroid carcinoma (PTC), which may be sporadic (95%) or familial (5%), has a prevalence adjusted for age in the general population of 1:100 000. Somatic rearrangements of the RET proto-oncogene are present in up to 66% of sporadic tumours, while they are rarely found in familial cases.

Purpose: In order to determine if some variants of this gene, or a combination of them, might predispose to PTC, we looked for an association of RET haplotype(s) in PTC cases and in controls from four countries matched for sex, age, and population.

Methods: Four single nucleotide polymorphisms (SNPs) across the RET coding sequence were typed and haplotype frequencies were estimated. Genotype and haplotype distributions were compared among these cases and controls.

Results: Ten haplotypes were observed, the seven most frequent of which have been previously described in sporadic Hirschsprung patients and controls. The single locus analyses suggested association of exon 2 and exon 13 SNPs with sporadic PTC. The haplotype analysis showed over-representation of one haplotype in French and Italian sporadic PTC, whereas a different haplotype was significantly under-represented in French familial PTC.

Conclusions: Our data suggest that some variants of RET and some specific haplotypes may act as low penetrance alleles in the predisposition to PTC.

     

Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension

Abnormal renal reabsorption of sodium (Na(+)) is likely to play a role in the pathogenesis of salt-sensitivity. In the kidney, chloride channels CLC-Ka (gene CLCNKA) and CLC-Kb (gene CLCNKB) and their subunit Barttin (gene BSND) have important effects on the control of Na(+) and water homeostasis. We investigated if single nucleotide polymorphisms (SNPs) or haplotypes within CLCNKA, CLCNKB and BSND loci affect salt-sensitivity in hypertensive subjects. Associations between blood pressure (BP) change after Na(+)-load and 15 SNPs spanning the length of CLCNKA and CLCNKB and six SNPs spanning the length of BSND were studied in 314 never treated essential hypertensives who underwent an i.v. infusion of saline (300 mm NaCl in 2 l H(2)O in 120 min). Four SNPs were significantly associated with BP change after Na-load. Rs848307 (P = 0.0026) and rs1739843 (P = 0.0023) map upstream the 5' of CLCNKA. Non-coding Rs1010069 (P = 0.0006) and non-synonymous rs1805152 (Thr447Ala; P = 0.0078) map within CLCNKA. Moreover, basal plasma renin activity and heart rate (measured before Na-load) were significantly lower in patients carrying the alleles associated with the larger mean BP increase after Na-load, indicating that such alleles are associated with chronic volume expansion. This study supports the candidacy of CLCNKA as a new susceptibility gene for salt-sensitivity.     

HLA haplotypes are associated with differential susceptibility to Trypanosoma cruzi infection

We explored a possible role of HLA class II genes in determining the susceptibility to Trypanosoma cruzi infection as well as in the development of chagasic heart disease in a rural mestizo population from Arequipa (Southern Peru). HLA-DRB1 and DQB1 polymorphisms were determined in 85 seropositive (asymptomatic, n=52; cardiomyopathic, n=33) and 87 seronegative individuals. We observed that the DRB1*14-DQB1*0301 haplotype correlates with not having T. cruzi infection in a highly endemic area (OR= 0.26 (0.124.63); Pc=0.01). This protective association is a dominant trait. We found no differences in the allelic or haplotypic distributions we examined between asymptomatic and cardiomyopathic patients in this population. Our data offer indirect but compelling evidence that polymorphism in HLA region is involved in a differential susceptibility to T. cruzi chronic infection.     

A haplotype of the CYP4F2 gene associated with myocardial infarction in Japanese men

This study assessed associations between the CYP4F2 gene and myocardial infarction (MI), using a haplotype-based case-control study of 234 MI patients and 248 controls genotyped for 5 single-nucleotide polymorphisms (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). For men, G allele frequency of rs2108622 and frequency of the T-C-G haplotype were significantly higher, and frequency of the T-C-A haplotype was significantly lower for MI patients than for controls (P = 0.006, P = 0.001 and P = 0.002, respectively).     

Geographic variation in the incidence of myocardial calcification associated with acute myocardial infarction

There is reason to believe that calcium influx into heart muscle during acute myocardial infarction (AMI) can aggravate myocyte injury. Furthermore, the degree of such influx might correlate with the occurrence of microscopic myocyte calcification observed at autopsy. We have searched for evidence of myocyte calcification in hearts of patients found to have AMI at autopsy at the Veterans Administration Medical Center in Salt Lake City (SLCVA), a region with a low myocardial infection death rate, and at the George Washington University Medical Center in Washington, DC (GWUMC), a region with a high myocardial infection death rate. Of 23 consecutive cases examined under "blind" conditions at the GWUMC in which AMI was found, there were 15 instances of cardiac myocyte calcification observed in von Kossa-stained sections. Not a single example of myocyte calcification was found in 23 comparable cases at the SLCVA. The basis of this difference in myocyte calcification is unknown, but may be related to the fact that the Salt Lake City drinking water contains a higher level of magnesium, which is known to protect against soft tissue calcification, than does that of Washington, DC. This may be the basis for the apparent protection that dietary magnesium exerts against myocardial infarction death.     

Common polymorphisms in the cannabinoid CB2 receptor gene (CNR2) are not associated with myocardial infarction and cardiovascular risk factors

Myocardial infarction (MI) is a complex disease. Multiple genes and their interaction with various environmental factors influence the pathogenesis of MI that is thought to be tightly regulated by inflammatory pathways. Recent progress in genetic analysis includes the use of large-scale genome-wide association studies that have proven to be powerful tools even in the analysis of multifactorial phenotypes. However, certain genes are only sparsely represented on the available gene chips and additional candidate gene approaches are necessary. One such example is the CNR2 gene, encoding the cannabinoid receptor 2 (CB2), which has been implicated in mediating anti-inflammatory and anti-atherosclerotic effects in vivo. We therefore hypothesized that genetic variations within the CNR2 gene are associated with the development of MI or classic cardiovascular risk factors. In a large case-control study, 1,968 individuals from the German MI family study were examined with 13 single nucleotide polymorphisms (SNPs) covering CNR2 and the adjacent genes. The association of these SNPs with MI or cardiovascular risk factors, such as arterial hypertension, obesity, hypercholesterolemia and diabetes mellitus, was determined. In allelic and genotypic models, none of the SNPs showed a significant association with MI. Separate analyses for men and women revealed no gender-specific relationship between common genetic variations within the CNR2 gene and MI. Moreover, no significant association between CNR2 gene variants and common cardiovascular risk factors was observed. We therefore provide evidence in a large German population that common polymorphisms within the CNR2 gene confer no susceptibility to MI or to cardiovascular risk factors.     

Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction

Levels of apolipoprotein B, the protein component of low-density lipoproteins, correlate with the risk of coronary heart disease. We examined whether genetic variation in apolipoprotein B is associated with myocardial infarction by studying apolipoprotein B-gene restriction-fragment-length polymorphisms in 84 patients with myocardial infarction and an equal number of matched controls. Southern blot analysis with apolipoprotein B-gene probes, performed after DNA was digested with the endonucleases XbaI and EcoRI, revealed alleles that we designated as X1, X2, and X3 and as R1 and R2, respectively. Similar studies with the endonuclease MspI revealed alleles of many different sizes (the difference was due to an insertion-deletion polymorphism), which we grouped as larger and smaller alleles and designated as ID1 and ID2, respectively. The frequencies of the X1, R1, and ID1 alleles were all significantly higher (P less than 0.01) in the cases than in the controls. None of the alleles, however, was significantly associated with variation in levels of low-density lipoprotein cholesterol or apolipoprotein B, and the functional importance of these alleles is therefore uncertain. Nonetheless, in addition to quantitative variation in apolipoprotein B levels in plasma, genetic variation at the apolipoprotein B locus may be a new and independent risk factor for myocardial infarction.     

ADAM33 haplotypes are associated with asthma in a large Australian population

The ADAM33 gene has recently been identified as being a potentially important asthma candidate gene, and polymorphisms in this gene have been shown to be associated with asthma and bronchial hyperresponsiveness in Caucasian individuals from several populations. We performed chip-based matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry using the MassARRAY system and multiplexed genotyping assays to investigate the association between 10 single nucleotide polymorphisms (SNPs) in the ADAM33 gene (F_+1, Q_-1, S_1, ST_+4, ST_+7, V_-2, V_-1, V_2, V_4, V_5) and asthma and asthma severity in a large Australian Caucasian population of nonasthmatic controls (n = 473), and patients with mild (n = 292), moderate (n = 238) and severe (n = 82) asthma. No significant association was found between any one of the 10 SNPs and asthma or asthma severity, however, there was a significant global haplotypic association with asthma (P = 0.0002) and disease severity (P = 0.0001), driven by the combination of two key SNPs, V_-1 and ST_+7. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity, likely to reflect population stratification. Our analysis of ADAM33 haplotypes further suggests a likely role for ADAM33 in the asthma phenotype, although it does not exclude an association with another locus in linkage disequilibrium with ADAM33.