Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar‐I disorder: A follow‐up study on chromosome 18

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP‐I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome‐wide analysis are instructive for genome‐wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP‐I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP‐I locus on 18q12.2 is also described. © 2001 Wiley‐Liss, Inc.     

Meditation training and essential hypertension: A methodological study

Meditation training appears to be a promising psychological approach to the control of hypertension. However, most studies to date have had serious deficiencies. This study attempted to correct many of these deficiencies. Forty-one unmedicated hypertensives referred by general practitioners were randomly allocated to three groups. The treatment group (SRELAX) underwent training procedures based on Transcendental Meditation; a placebo control group (NSRELAX) underwent identical training but without a mantra. Both procedures were compared with a no-treatment control group. The results showed modest reductions in blood pressure in both SRELAX and NSRELAX groups, compared with the no-treatment controls, with diastolic percentage reductions reaching significance (p<0.05). There was considerable subject variation in response, with overall a mean decline in diastolic blood pressure of 8–10% on 3-month follow-up. Possible indicators to predict the response of subjects are considered and reasons for the similarity in the effectiveness of the SRELAX and NSRELAX conditions are discussed.This research was funded by a grant from the Auckland Medical Research Foundation.     

白细胞介素-1基因多态性与原发性高血压关联

目的研究白细胞介素-1(IL-1)基因多态性与原发性高血压的相关关系。方法采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,检测150例原发性高血压患者和160例健康对照者IL-1基因多态性。结果IL-1α基因-889C/T多态性在两组人群中的分布差异显著(P<0.05);等位基因频率的相对风险分析发现,T等位基因携带者患原发性高血压的风险是C等位基因的2.102倍(OR=2.102,95%CI:1.231~3.590),携带CT+TT基因型的原发性高血压患者收缩压水平显著高于CC基因型者[(168.9±19.8)mmHg比较(160.2±18.9)mmHg],(P<0.05)。结论IL-1α基因-889C/T多态性与原发性高血压的发病具有相关性,其中T等位基因可能是原发性高血压发病的遗传易感基因,携带T等位基因的个体可能通过促进收缩压的升高进而增加了原发性高血压的发病风险。     

Association of polymorphisms in the solute carrier organic anion transporter family member 1B1 gene with essential hypertension in the Uyghur population

Solute carrier organic anion transporter family member 1B1 (SLCO1B1) is an important hepatic uptake transporter that can transport a wide variety of endogenous compounds, including thyroid hormones and prostaglandin E2. Dysregulation of thyroid hormones and prostaglandin E2 plays a role in the development of hypertension, suggesting that SLCO1B1 might contribute to the aetiology of essential hypertension (EH). In this study, we selected five single nucleotide polymorphisms (SNPs) at the SLCO1B1 gene promoter or coding regions and performed a case-control association study involving 731 unrelated Uyghur subjects, including 374 hypertensive and 357 normotensive individuals, to investigate the potential genetic contribution of SLCO1B1 to the aetiology of EH. Of the five polymorphisms, only one (i.e., rs4149014) showed correlation with EH. The minor allele of SNP rs4149014 at the SLCO1B1 promoter showed association with increased risk for EH (adjusted OR 1.88; 95% CI 1.36-2.60; P= 1.22 × 10(-4)). This study provides preliminary genetic evidence for the role of variant of SLCO1B1 in the susceptibility to human EH in Uyghurs.     

Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p

Essential (primary) hypertension is an important risk factor for cardiovascular morbidity and mortality. Blood pressure is largely heritable; however, the genetic factors contributing to essential hypertension are mostly unknown. We examined a large Chinese kindred (n=387) and selected a subset of 94 individuals for genotyping. An additional 32 Chinese nuclear families with essential hypertension were also recruited. Genome-wide parametric linkage analysis identified a new locus for primary hypertension on chromosome 12p (parametric LOD score 3.44). This locus overlaps with the assigned locus that causes severe autosomal-dominant hypertension and brachydactyly, the only form of monogenic hypertension known to date that resembles primary hypertension. We suggest that this genomic region, spanning 18 annotated genes, will be of great relevance in elucidating new mechanisms for primary hypertension.     

EMILIN1基因多态性与蒙古族原发性高血压相关性研究

目的 探讨蒙古族人群中EMILIN1基因的3个单核苷酸多态性(single nucleotide polymorphism,SNP)位点与原发性高血压的关系.方法 在内蒙古自治区蒙古族人群中选取201例原发性高血压患者和202名血压正常者进行病例对照研究,应用聚合酶链反应-限制性片段长度多态方法检测rs3754734、rs2011616和rs2304682这3个SNP位点的等位基因和基因型分布,并构建单倍型.结果 在这3个SNP位点中,rs2304682位点的基因频率和基因型频率在高血压组和对照组间差异有统计学意义(P＜0.05),并且在rs3754734和rs2304682这2个SNP位点构建的单倍型中,G-C和G-G单倍型在高血压组和对照组之间差异有统计学意义(P＜0.05).在舒张压偏高组和舒张压正常组间,rs2304682位点的基因型和等位基因分布差异有统计学意义(P＜0.05),而在收缩压偏高组和收缩压正常组间,各个SNP的基因型和等位基因分布差异无统计学意义(P＞0.05).结论 在蒙古族人群中,EMILIN1基因rs2304682多态性位点以及rs3754734和rs2304682这2个SNP位点构建的G-G单倍型可能与原发性高血压的易感相关联,rs2304682的多态性与蒙古族原发性高血压的舒张压的高低可能有关联.

Abstract：

Objective To explore the relationship between genetic polyrnorphisms of 3 single nucleotide polymorphisms (SNPs) in the elastin microfibril interfacer 1 (EMILIN1)gene and essential hypertension. Methods A case-control study was conducted in which 201 hypertensive patients and 202 healthy controls in Mongolian population were enrolled, and the genotypes of rs3754734, rs2011616 and rs2304682 loci were analyzed using polymerase chain reaction-restriction fragment length polyrnorphism (PCR-RFLP) and direct sequencing techniques. Results There were significant differences in the frequencies of alleles and genotypes for the rs2304682 between the hypertensives and normotensives in the population(P＜0. 05). The frequency of the G-G haplotype established by rs3754734 and rs2304682 was significantly higher in the hypertensive patients (P＜0. 05). The frequencies of alleles and genotypes for the rs2304682 also had significant differences between the group with high diastolic blood pressure and normal diastolic blood pressure (P＜0.05). There were no significant differences in the frequencies of alleles and genotypes for the 3 SNPs between the group with high systolic blood pressure and normal systolic blood pressure (P＞0.05). Conclusion The rs2304682 locus in the EMILIN1 gene, as well as the haplotypes G-G constructed using rs3754734 and rs2304682, may associate with the susceptibility of essential hypertension in the Mongolian population. Also, rs2304682 may associate with the level of the diastolic blood pressure.     

Association of the renin gene polymorphism with essential hypertension in a Chinese population

To study the association of renin gene polymorphism with essential hypertension in the Chinese population, 86 hypertensive and 107 normotensive subjects were enrolled from an epidemiologic survey. Leukocyte DNA was extracted and digested with Hind HI and Bgl I restriction enzymes. Southern hybridization was done with digoxigenin-incorporated renin gene probes generated by polymerase chain reaction. The restriction fragments were detected by anti-digoxigenin antibody and enzyme methods. Two Hind III polymorphysms of the renin gene (8.7kb and 6.2kb) were identified. The allele frequences were 129(75%) and 43(25%), respectively, in hypertensives; they were 139(65%) and 75(35%), respectively, in normotensives (χ²= 4.074, p = 0.044). The genotypes of 8.7/8.7,8.7/6.2 and 6.2/6.2 were significantly different between hypertensives and normotensives, being 45(52%), 39(45%), 2(3%) and 48(45%), 43(40%), and 16(15%), respectively (χ²= 9.002, p = 0.011). The Bgl I polymorphism did not show a difference between hypertensives and normotensives. Thus, we conclude that the renin gene Hind III polymorphysm is associated with hypertension in this Chinese population.     

细胞因子及相关受体基因位点与中国人原发性高血压的连锁分析

目的 在中国汉族人中进行细胞因子及相关受体基因位点与原发性高血压（essential hypertension,EH)的连锁分析，以筛选EH易感基因。方法 在8种细胞因子及相关受体基因附近选择DNA短串联重复序列（short tandem repeat,STR)作为遗传标记，采用荧光标记STR引物及基因分型技术，对上海地区95个汉族EH核心家系，477个成员染色体上7个遗传标记位点进行基因分型，运用GENEHUNTER软件计算最大Lod值、两点非参数连锁分析（non-parametric linkage analysis,NPL)及传递／不平衡检验（transmission/disequilibrium test,TDT)。结果 TDT显示D14S61位点等位基因在EH患病同胞中传递显著不平衡（χ^2=14.29,P=0.00016)最大Lod值为0.72;NPL的Z＝0．78，P＞0．05。其余位点最大Lod值均＜－1，TDT和NPL统计结果未提示这些位点传递不平衡与EH存在连锁（P＞0．05）。结论 D14S61位点在EH患病同胞中存在明显的传递不平衡。已知转化生长因子β3基因距该位点0.1cM，提示这一染色体区域附近基因与EH关系有待进一步研究。     

白细胞介素-1基因多态性与高血压易感性的研究

目的　观察白细胞介素 - 1(interleukin- 1,IL- 1)基因多态性在中国汉族人群中的分布及其与原发性高血压 (essential hypertension,EH)的关系 ,初步分析其基因型与 EH易感性的相关性。方法　应用聚合酶链反应和限制性片段长度多态性的方法 ,检测湖北省汉族 15 2例 EH患者和 16 8名正常对照者的IL- 1基因多态性 ,包括 IL- 1α(- 889C/ T)位点、IL- 1β(- 5 11C/ T)位点、IL- 1β( 395 3C/ T)位点、IL- 1Ra( 80 0 6 T/ C)位点多态性以及 IL- 1Ra第 2内含子可变数串联重复序列多态性。结果　IL- 1α(- 889C/ T)位点、IL- 1β( 395 3C/ T)位点、IL- 1Ra( 80 0 6 T/ C)位点多态性和 IL- 1Ra可变重复序列多态性在 EH组和正常人群中的分布差异无显著性 (P>0 .0 5 ) ,而 IL- 1β(- 5 11C/ T)位点多态性在两组人群中的分布差异存在显著性 (P<0 .0 5 ) ,携带 CT基因型罹患 EH的危险性可增加 2 .5 4倍。结论　 IL- 1β基因启动子区 - 5 11位点 C/ T多态性可能与 EH易感性存在相关关系。     

原发性高血压患者巨细胞病毒感染及与血管并发症关系 …

目的 探讨原发性高血压患者巨细胞病毒感染及与血管并发症之间的关系。方法 应用间接酶联免疫吸附试验（ＥＬＩＳＡ）检测了１０５例原发性高血压患者血清人巨细胞病毒（ＨＣＭＶ）特异性抗体。结论 研究结果提示原发性高血压患者存在较高的活动性巨细胞病毒感染，ＨＣＭＶ活动性感染似与血管并发症有一定关联。     

肠道菌群是高血压干预的新靶点

人体肠道菌群与高血压危险因素(糖脂代谢紊乱、肥胖、动脉粥样硬化)之间有关系;肠道菌群与生物钟紊乱、中枢血压调控等亦有关联。肠道菌群结构改变以及由此伴随的能量吸收异常、肠源性内毒素低水平升高、肠黏膜屏障损伤等因素影响高血压的形成和发展,"菌群-肠-脑"轴可能是其中重要途径之一。结合肠道菌群参与高血压控制的初步探索结果,提出肠道菌群是高血压干预的新靶点。     

云南汉族原发性高血压与HLA-DRB1等位基因的相关性

目的　探讨云南汉族人群 HL A- DRB1等位基因与高血压病的相关性。方法　应用病例 -对照相关分析方法 ,采用 PCR-序列特异性引物基因分型技术对云南汉族 91名健康个体和 83例高血压病患者 (均无血缘关系 )进行 HL A- DRB1位点 17个特异性的等位基因分型 ,并进行遗传相关分析。结果　原发性高血压患者中 DRB1* 15 0 1/ 2的频率为 ( 0 .2 19)显著高于对照组 ( 0 .0 6 0 ) ,χ2 =18.331,P<0 .0 1,相对危险率为 4 .4 6 ,病因分数为 0 .34。 DR9( DRB1* 0 90 1)的频率 ( 0 .0 81)显著低于对照组 ( 0 .192 ) ,χ2 =8.70 4 ,P<0 .0 5。相对危险率 RR为 0 .4 1,预防分数为 0 .19。结论　云南汉族 HL A- DRB1等位基因与高血压病的相关性与北方汉族存在差异 ,HL A- DRB1* 15 0 1/ 2可能与原发性高血压易感相关 ;DRB1* 0 90 1可能在发病中有保护作用。     

The role of mitochondrial genome in essential hypertension in a Chinese Han population

Earlier genetic studies of essential hypertension have focused on nuclear genes or family-based mitochondrial screening in Caucasian and African-American pedigrees. The role of mitochondria in sporadic Chinese hypertensives is unknown. We sequenced mitochondrial genomes in 306 age- and gender-balanced Chinese Han hypertensives and controls. In 153 hypertensives, putative functional changes included 4 changes in rRNA genes, 11 changes in tRNA genes and 25 amino-acid substitutions. The remaining variants were synonymous changes or non-coding regions. In the 153 controls, 2 base changes in the tRNA genes and 13 amino-acid substitutions were found. A8701G in ATP6 gene (belongs to haplogroup M; P=0.0001) and C8414T in ATP8 gene (belongs to haplogroup D; P=0.01) were detected significantly different in the cases and controls. Interestingly, the cases were more likely to have two or more amino-acid changes and RNA variants compared with the controls (57.43 versus 23.81%, P=0.0001). In addition, several variants we found were highly conserved and/or specifically located at the 3′ end adjacent to the anticodon, which may contribute to the stabilization of structure, and thus lead to the decrease of tRNA metabolism. In conclusion, mitochondrial SNPs (mtSNPs) may affect the course of hypertension in sporadic Chinese hypertensives. Some specific mtSNP within mitochondria may have potential role in the Chinese hypertensives due to their function. Synergetic interaction between mitochondrial mtSNPs and/or haplogroups is needed to be investigated in the future.     

Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension

Background

Inositol polyphosphate phosphatase‐like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension.

Objective and methods

To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort.

Results

We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1).

Conclusion

These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically.     

Human renin gene BglI dimorphism associated with hypertension in two independent populations

The renin (REN) gene is a good candidate that could underlie an individual's genetic susceptibility to human essential hypertension (EHT). We describe here a polymerase chain reaction-based assay for detection of a BglI dimorphic site located in the first intron of the REN gene. In this retrospective, case-control, association study, we investigated BglI allele and genotype distributions in 554 subjects (280 hypertensives and 274 normotensives) from the United Arab Emirates (UAE) - a genetically homogeneous ethnic population with no history of smoking or alcohol consumption - and in 485 hypercholesterolemic, US Caucasian subjects (250 hypertensives and 235 normotensives). A statistically significant association was found between alleles on which the BglI site is present [BglI(+)] and clinical diagnosis of EHT in the UAE sample group (odds ratio = 2.69, p = 0.0006), and a similar trend was observed in the US group (odds ratio = 1.97, p = 0.01). BglI(+) homozygous status was also investigated in the US group and found to be associated with elevated systolic and diastolic blood pressure values (respectively, 144.8+/-26.1 vs. 134.1+/-23.0 mm Hg, p = 0.04; and 91.0+/-12.5 vs. 82.2+/-12.7 mm Hg, p = 0.009). In conclusion, variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with the REN BglI(+) marker could play a role in contributing to an increased individual's genetic susceptibility to EHT in the UAE population and amongst US hypercholesterolemic Caucasians. Such a genetic influence, which seems to show a recessive mode of inheritance, could also be implicated in raising both systolic and diastolic blood pressures.     

醛固酮合酶和Y染色体基因多态性与原发性高血压的相关性

目的探讨醛固酮合酶基因CYP11B2-344C／T、Y染色体Hind Ⅲ酶切位点多态性与原发性高血压的关系。方法对原发性高血压患者654例，正常人386名提取白细胞DNA，聚合酶链反应结合限制性内切酶（Hae Ⅲ、HindⅢ）方法检测醛因酮合酶和Y染色体基因多态性。结果 Hind Ⅲ多态性各基因型差异有统计学意义（P=0．03），Hind Ⅲ（＋）基因型收缩压、舒张压均明显降低（P=0．01，P=0．03）。CYP11B2 CC、CT基因型与Hind Ⅲ（-）基因型组合时，发生高血压的危险增加1．998倍（P=0．01）。结论Y染色体Hind Ⅲ酶切位点多态性与原发性高血压相关，CYP11B2-344C／T多态性与Y染色体胁Hind Ⅲ酶切位点多态性可能具有联合作用。     

Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension

In a study of the genetic basis of essential hypertension (HT), we tested four variants in three candidate genes not previously investigated in HT. These encoded the endothelin receptor type A (EDNRA), which transduces most of the vasoconstrictive properties of endothelin-1, protein kinase lysine deficient 4 (WNK4) whose gene resides in a HT linkage region on chromosome 17, and FK506-binding protein 1B (FKBP1B), which can reduce blood pressure by increasing nitric oxide. The variants were: for EDNRA , a G→A in the 5'-UTR and C→T in exon 8; for WNK4 , a tetranucleotide repeat in intron 10; and for FKBP1B , a T→C in exon 4. Subjects were Anglo-Celtic white Australians and included 155 HTs with two HT parents and 245 normotensives (NTs) whose parents were both NT. For EDNRA , we found a weak association of the exon 8 variant with HT (p = 0.019) and association of the 5'-UTR variant with elevation in systolic and diastolic blood pressure (BP) (p = 0.038 and 0.0031, respectively). The WNK4 intron 10 variant and the FKP1B exon 4 variant showed no association with HT, but tracking with BP was seen for the latter (p = 0.015 and 0.0011 for systolic and diastolic BP, respectively). Our study thus suggests possible involvement of EDNRA in essential HT.     

Deletion polymorphism in the angiotensin-converting enzyme gene is not associated with hypertension in a Gulf Arab population

We have studied an insertion/deletion dimorphism in the human angiotensin-converting enzyme gene amongst UAE nationals from the Abu Dhabi Emirate. Our findings show lack of association between the I/D allele marker system and clinical diagnosis of essential hypertension, suggesting that variations of the angiotensin-converting enzyme gene do not play a major role in the determination of elevated blood pressure in this Arab population. This agrees with results reported on other ethnic groups.     

Evidence for an asthma risk locus on chromosome Xp: a replication linkage study

Background:  Asthma is a complex genetic disorder characterized by chronic inflammation in the airways. Identification of genetic risk factors for asthma has been complicated due to genetic heterogeneity and influence from environmental risk factors. Despite the fact that multiple genetic linkage studies have been carried out the results are still conflicting and call for replication experiments. A Danish genome-wide scan has prior reported evidence for candidate regions for asthma susceptibility genes on chromosomes 1p, 5q, 6p, 12q and Xp. Linkage to chromosome 12q was later confirmed in the same replication sample as used in the present study. The aim of the study was to replicate linkage to candidate regions for asthma in an independent Danish sample.
Methods:  We performed a replication study investigating linkage to candidate regions for asthma on chromosomes 1p36.31-p36.21, 5q15-q23.2, 6p24.3-p22.3, and Xp22.31-p11.4 using additional markers in an independent set of 136 Danish asthmatic sib pair families.
Results:  Nonparametric multipoint linkage analyses yielded suggestive evidence for linkage to asthma to chromosome Xp21.2 (MLS 2.92) but failed to replicate linkage to chromosomes 1p36.31-p36.21, 5q15-q23.2 and 6p24.3-p22.3.
Conclusions:  The replication results provide evidence for chromosome Xp21 to harbour a susceptibility gene for asthma in the Danish population. To our knowledge, the study is the first to replicate evidence for linkage to chromosome X. A susceptibility gene for asthma on chromosome X could potentially explain observed gender differences in asthma prevalence.     

Association analysis of CA repeat polymorphism of the endothelial nitric oxide synthase gene with essential hypertension in Japanese

The nitric oxide synthase (NOS) gene is thought to be associated with essential hypertension (EH), because NO is implicated in endothelium-mediated vasodilation. We investigated the possible association between the alleles of simple tandem repeat DNA polymorphism of the endothelial constitutive NOS (cNOS) gene and EH in Japanese subjects. In all, 100 patients with EH and 123 subjects with normal blood pressure were studied. Polymerase chain reaction was used to amplify the CA repeat site in the endothelial cNOS gene and alleles based on the CA repeat number were determined. The allele frequencies in the hypertensive group and normotensive group were then compared. Twenty-three alleles were identified in this study of Japanese subjects. The overall distributions of allele frequencies in the two groups were not significantly different. However, comparing the allele frequencies in the EH group without left ventricular hypertrophy (LVH) and the normotensive group, the overall distributions were significantly different (p = 0.019). The 33-repeat allele was found more frequently in the EH group without LVH than in the normotensive group (p = 0.000047, Odds ratio = 3.71). In conclusion, the 33-repeat allele of the endothelial cNOS gene is associated with EH without LVH, and may be a genetic marker of EH in Japanese subjects.