Association of polymorphisms of ABCA1 and ROS1 with hypertension in Japanese individuals

Although various environmental factors, such as a high-salt diet, a smoking habit, excessive alcohol intake, and physical inactivity, influence the development of hypertension, genetic variation also contributes to an individual's susceptibility to this condition. The purpose of the present study was to identify gene polymorphisms that confer susceptibility or resistance to hypertension, and thereby contribute to the prediction of the genetic risk for this condition. The study population comprised 2752 unrelated Japanese individuals (1370 men, 1382 women), including 1276 subjects with hypertension (774 men, 502 women) and 1476 controls (596 men, 880 women). The genotypes for 50 polymorphisms of 35 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the Chi-square test and subsequent multivariable logistic regression analysis with adjustment for age, sex, body mass index, smoking status, and the prevalence of diabetes mellitus and hypercholesterolemia revealed that the -14C-->T polymorphism of ABCA1, the C-->G (Ser2229Cys) polymorphism of ROS1, the C-->T (Asn591Asn) polymorphism of LDLR, the 13989A-->G (Ile118Val) polymorphism of CYP3A4, the C-->G and A-->C polymorphisms of ADIPOR1, and the -519A-->G polymorphism of MMP1 were significantly (P<0.05) associated with the prevalence of hypertension. Systolic and diastolic blood pressure differed significantly among genotypes for the -14C-->T polymorphism of ABCA1 and the C-->G (Ser2229Cys) polymorphism of ROS1, with the variant T and G alleles, respectively, being related to increased blood pressure. These results suggest that polymorphisms of ABCA1 and ROS1 are determinants of blood pressure and the development of hypertension in Japanese individuals. Determination of genotypes for ABCA1 and ROS1 may thus prove informative for the prediction of the genetic risk for hypertension.     

Assessment of genetic factors for type 2 diabetes mellitus

The purpose of the present study was to identify gene polymorphisms for reliable assessment of genetic factors for type 2 diabetes mellitus. The study population comprised 4853 unrelated Japanese individuals (2688 men, 2165 women), including 1489 subjects with type 2 diabetes mellitus (969 men, 520 women) and 3364 controls (1719 men, 1645 women). The genotypes for 148 polymorphisms of 124 candidate genes were determined with a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Sixteen polymorphisms were related (p<0.05) to the prevalence of type 2 diabetes mellitus as determined by the chi-square test. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that, among these polymorphisms, the -603A --> G polymorphism of the gene for coagulation factor III (F3) was significantly (p<0.001) associated with the prevalence of type 2 diabetes mellitus, with the -603G allele representing a risk factor for this condition. A stepwise forward selection procedure demonstrated that F3 genotype (GG versus AA + AG) significantly (p<0.001) and independently affected the prevalence of type 2 diabetes mellitus. Genotype for F3 may prove reliable for assessment of genetic factors for type 2 diabetes mellitus. Determination of the genotype for this gene may contribute to personalized prevention of this condition.     

Association of a polymorphism of CYP3A4 with type 2 diabetes mellitus

Although several environmental factors, including a high-calorie diet and physical inactivity, influence the development of type 2 diabetes mellitus, genetic factors have been shown to contribute to individual susceptibility to this condition. The purpose of the present study was to identify gene polymorphisms that confer susceptibility or resistance to type 2 diabetes mellitus, and thereby to contribute to assessment of the genetic risk for this condition. The study population comprised 5259 unrelated Japanese individuals (2980 men, 2279 women), including 1640 subjects with type 2 diabetes mellitus (1071 men, 569 women) and 3619 controls (1909 men, 1710 women). The genotypes for 94 polymorphisms of 67 genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the chi-square test revealed that the 13989-->G (Ile118Val) polymorphism of the cytochrome P450, subfamily IIIA, polypeptide 4 gene (CYP3A4) was significantly (false discovery rate, 0.000009) associated with the prevalence of type 2 diabetes mellitus. Multivariable logistic regression analysis with adjustment for age and sex also revealed that the 13989-->G (Ile118Val) polymorphism of CYP3A4 was significantly (P=0.00002) associated with the prevalence of type 2 diabetes mellitus, with the AG genotype being protective against this condition. Genotyping for CYP3A4 may thus prove informative for assessment of the genetic risk for type 2 diabetes mellitus.     

Genetic risk for atherothrombotic cerebral infarction in individuals stratified by sex or conventional risk factors for atherosclerosis

The aim of the present study was to assess the genetic risk for atherothrombotic cerebral infarction (ACI) in men and women separately as well as in individuals with or without conventional risk factors for atherosclerosis and thereby to contribute to the personalized prevention of ACI. The study population comprised 2705 unrelated Japanese individuals (1244 men, 1461 women), including 636 subjects (372 men, 264 women) with ACI. Subjects with ACI and controls either had or did not have conventional risk factors for atherosclerosis, including hypertension, hypercholesterolemia, and diabetes mellitus. The genotypes for 202 polymorphisms of 152 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis and a stepwise forward selection procedure revealed that 11 different polymorphisms were significantly (P < 0.005) associated with ACI in women or men or in individuals with or without hyper-tension, hypercholesterolemia, or diabetes mellitus: the 584C-->T polymorphism of LIPG, 5665G-->T of EDN1, and G-->A of CCL11 in women; 677C-->T of MTHFR, 1323C-->T of ITGB2, 3932T-->C of APOE, and -231A-->G of EDNRA in men; -572 G -->C of IL6 in hypertensive individuals; -403G-->A of CCL5 and G-->A of COMT in individuals with hypercholesterolemia; and 3932T--> C of APOE and A-->G of TNFSF4 in diabetic individuals. Polymorphisms associated with ACI may thus differ between women and men as well as among individuals with different risk factors. Stratification of subjects on the basis of sex or conventional risk factors for atherosclerosis may therefore be important in order to achieve the personalized prevention of ACI with the use of genetic information.     

Association of genetic variants with atherothrombotic cerebral infarction in Japanese individuals with metabolic syndrome

Metabolic syndrome is a risk factor for cardiovascular disease. The aim of the present study was to identify genetic variants that confer susceptibility to atherothrombotic cerebral infarction among individuals with metabolic syndrome in order to allow prediction of genetic risk for this condition. The study population comprised 1284 unrelated Japanese individuals with metabolic syndrome, including 313 subjects with atherothrombotic cerebral infarction and 971 controls. The genotypes for 296 polymorphisms of 202 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. The Chi-square test, multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of hypertension, hypercholesterolemia, and diabetes mellitus, as well as a stepwise forward selection procedure revealed that the 2445G-->A (Ala54Thr) polymorphism (rs1799883) of FABP2, the -108/3G-->4G polymorphism of IPF1 (S82168), the A-->G (Thr94Ala) polymorphism (rs2241883) of FABP1, the G-->A (Asp2213Asn) polymorphism (rs529038) of ROS1, the -11377C-->G polymorphism (rs266729) of ADIPOQ, the 162A-->C polymorphism (rs4769055) of ALOX5AP, the -786T-->C polymorphism (rs2070744) of NOS3, and the 3279C-->T polymorphism (rs7291467) of LGALS2 were associated (P<0.05) with the prevalence of atherothrombotic cerebral infarction. Among these polymorphisms, the 2445G-->A (Ala54Thr) polymorphism of FABP2 was most significantly associated with this condition. Our results suggest that FABP2, IPF1, FABP1, ROS1, ADIPOQ, ALOX5AP, NOS3, and LGALS2 are susceptibility loci for atherothrombotic cerebral infarction among Japanese individuals with metabolic syndrome. Genotypes for these polymorphisms, especially for the 2445G-->A (Ala54Thr) polymorphism of FABP2, may prove informative for the prediction of genetic risk for atherothrombotic cerebral infarction among such individuals.     

护骨素基因T950C及A163G多态性与老年2型糖尿病患者的骨密度

背景：2型糖尿病患者发生骨质疏松症的比率较高。 目的：观察老年2型糖尿病患者护骨素基因启动子区域T950C、A163G位点多态性与骨密度的关系。 方法：纳入147例老年2型糖尿病患者,男性100例,女性47例,应用多聚酶链反应-限制性片段长度多态性方法测定患者护骨素基因T950C、A163G的基因型;采用双能X线骨密度吸收仪测定患者腰椎、髋部及前臂的骨密度。 结果与结论：在老年女性2型糖尿病患者中,T950C不同基因型在特定部位具不同骨密度,CC基因型的腰椎L2、L4骨密度高于TC或TT型;在老年男性2型糖尿病患者中,未发现T950C不同基因型与骨密度相关。在老年女性2型糖尿病患者中,A163G不同基因型在特定部位具不同骨密度,AA型的股骨大转子、前臂骨密度高于AG或GG型;在老年男性2型糖尿病患者中AA型的腰椎L3、L4骨密度高于AG或GG型。表明护骨素基因启动子区T950C基因多态性与老年女性2型糖尿病患者的骨密度相关,A163G基因多态性与老年男、女性2型糖尿病患者的骨密度皆相关。     

肝脂酶基因启动子-250G/A多态性与2型糖尿病合并冠心病易感性的相关研究

目的 探讨汉族人群肝脂酶(hepatic lipase,HL)基因启动子-250G/A多态性与2型糖尿病(type 2 diabetes mellitus,T2DM)合并冠心病(coronary heart disease,CHD)的相关性.方法 采用聚合酶链反应-限制性片段长度多态性方法(polymerase chain reaction-restricted fragment length polymorphism,PCR-RFLP)检测364例T2DM+CHD组、357例T2DM组患者和356名健康对照者HL基因启动子-250G/A多态性,并分析其对脂类的影响.结果 T2DM组与对照组HL基因启动子-250G/A多态性基因型和等位基因频率差异无统计学意义(P>0.05);T2DM+CHD组GA+AA基因型频率低于对照组(0.431 vs 0.618,P=0.031);等位基因频率差异无统计学意义(P>0.05).调整混杂因素后,Spearman相关及线性回归分析,糖尿病患者(T2DM组和T2DM+CHD组),A等位基因与高密度脂蛋白胆固醇、载脂蛋白A1呈正相关;Logistic回归分析显示,A等位基因是冠心病发生的一个危险因素.结论 HL基因启动子-250G/A多态性与2型糖尿病合并冠心病的发生有关,并影响脂类代谢.     

Association of gene polymorphisms with myocardial infarction in individuals with different lipid profiles

Hyperlipidemia or dyslipidemia is one of the most important risk factors for coronary heart disease. The purpose of the present study was to identify gene polymorphisms for assessment of the genetic risk for myocardial infarction (MI) in individuals with low or high serum concentrations of high- density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, or triglyceride (TG), thereby contributing to the personalized prevention of MI in such individuals. The study population comprised 2682 unrelated Japanese individuals (1796 men, 886 women), including 1113 subjects (869 men, 244 women) with MI and 1569 controls (927 men, 642 women). The genotypes for 164 polymorphisms of 137 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analyses and stepwise forward selection procedures revealed that seven different polymorphisms were significantly (P<0.005) associated with MI in individuals with low or high serum concentrations of HDL- or LDL-cholesterol or of TG: the 190T --> C (Trp64Arg) polymorphism of ADRB3 in individuals with low HDL-cholesterol; the 1018C --> T (Thr145Met) polymorphism of GP1BA, the A --> G (Ile646Val) polymorphism of AKAP10, and the -55C --> T polymorphism of UCP3 in individuals with high HDL-cholesterol; the -603A --> G polymorphism of F3 and the -11377C --> G polymorphism of ADIPOQ in individuals with low LDL-cholesterol; the 1018C --> T polymorphism of GP1BA in individuals with low TG; and the 4G --> 5G polymorphism of PAI1 in individuals with high TG. No polymorphism was associated with MI in individuals with high LDL-cholesterol. These results suggest that polymorphisms associated with MI may differ among individuals with different lipid profiles. Stratification of subjects according to lipid profiles may thus be important for personalized prevention of MI based on genetic information.     

Ⅱ型对氧磷酯酶基因311Cys/Ser多态性与2型糖尿病合并冠心病关系的研究

目的:探讨型对氧磷酯酶(PON2)基因311Cys/Ser遗传多态性与2型糖尿病合并冠心病的关系。方法:应用PCR-RFLP技术,对75例老年2型糖尿病患者,其中39例2型糖尿病者合并冠心病者,36例糖尿病对照者,和38例健康对照者,检测PON2-311Cys/Ser基因多态性,等位基因以C/S表示。结果:2型糖尿病合并冠心病组与健康对照组比较,各基因型分布有显著差异(P<0.05)。S等位基因在2型糖尿病合并冠心病组明显增高;S等位基因是2型糖尿病并发冠心病的危险因素(OR=2.09,95%CI:1.04-4.22,P<0.05)。结论:PON2基因311Cys/Ser遗传多态性与中国北方地区2型糖尿病并发冠心病发病具有相关性。该酶切位点多态性具有明显的种族差异。     

Association of gene polymorphisms with blood pressure and the prevalence of hypertension in community-dwelling Japanese individuals

Hypertension is a complex multifactorial disorder that is thought to result from an interaction between genetic background and environmental factors. Although various loci and genes have been implicated in predisposition to hypertension by genetic linkage analyses and candidate gene association studies, the genes that confer susceptibility to this condition remain to be identified definitively. We examined the relations of nine candidate gene polymorphisms to blood pressure (BP) and the prevalence of hypertension in a population-based study. The 2238 subjects (1110 women, 1128 men) were aged 40 to 79 years and were randomly recruited for a population-based prospective cohort study of aging and age-related diseases in Japan. BP was measured with subjects having rested in a sitting position for at least 15 min. Genotypes for the 160C-->T (Arg54Trp) polymorphism of QPCT, the C-->T (Pro198Leu) polymorphism of GPX1, the 137,346T-->C polymorphism of FYN, the -344C-->T polymorphism of CYP11B2, and the A-->G (Ser49Gly) polymorphism of ADRB1 were determined with a fluorescence-based allele-specific DNA primer assay system; those for the A-->G polymorphism of CNR2, the I/D (22,375delAC) polymorphism of CAV1, and the -1213T-->C polymorphism of ESR2 by melting curve analysis, and that for the (GT)n polymorphism of COL1A2 were determined by DNA fragment analysis. The polymorphism of FYN was associated with systolic and diastolic BP in women. In men, polymorphisms of CNR2, QPCT, GPX1, COL1A2, CYP11B2, and ESR2 were associated with systolic and diastolic BP, those of CAV1 and FYN with systolic BP, and that of ADRB1 with diastolic BP. The polymorphisms of QPCT and CYP11B2 were also associated with the prevalence of hypertension in men. These results suggest that polymorphisms of QPCT and CYP11B2 are determinants of BP and the development of hypertension in Japanese men.     

Genetic factors for lone atrial fibrillation

Atrial fibrillation (AF) may result from an electric conduction disturbance, increased hemodynamic stress, ischemia, inflammation, or remodeling in atria. Although genetic epidemiological studies have identified several genetic variants as risk factors for AF, the genetic determinants of this condition remain largely unknown. The purpose of the present study was to identify gene polymorphisms that confer susceptibility to lone AF. The study population comprised 1069 unrelated Japanese individuals, including 196 subjects with chronic lone AF and 873 controls. The genotypes for 40 polymorphisms of 32 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperchole-sterolemia as well as a stepwise forward selection procedure revealed that the -1306C-->T polymorphism of the matrix metalloproteinase 2 gene (MMP2) and the -592A-->C polymorphism of the interleukin 10 gene (IL10) were significantly (false discovery rate of <0.05) associated with the prevalence of AF. The T allele of the MMP2 polymorphism and the C allele of the IL10 polymorphism were a risk factor for and protective factor against AF, respectively. Determination of the genotypes for these polymorphisms may thus prove informative for assessment of the genetic component of AF.     

The association of adiponectin serum level and ADIPOQ +45 T/G and ADIPOR1 −106 A/G gene polymorphisms with diabetic nephropathy in type 2 DM

Adiponectin encoded by ADIPOQ, gene (adiponectin, C1Q and Collagen Domain-Containing) is an adipocyte-derived protein, plays a major role in mediating insulin sensitivity, and lower plasma adiponectin concentration has been linked to microangiopathies in type 2 diabetes mellitus (DM). It has been hypothesized that blood adiponectin concentration may reflect the extent of kidney damage in diabetic patients. Our aim was to study genetic polymorphisms in adiponectin genes (ADIPOQ +45 T/G and adiponectin receptor 1 (ADIPOR1) ?106 A/G) and the serum level of adiponectin in type 2 DM and to correlate this with the stages of diabetic nephropathy. Forty-eight patients with type 2 DM were recruited from Internal Medicine Department and Nephrology Outpatient Clinic in Kasr El Aini Hospital, Cairo University, from April 2011 until March 2012. They were divided into normoalbuminuric (nonnephropathic), n?=?17; and nephropathic group, n?=?31; who were further subdivided into microalbuminuric, macroalbuminuric, and end-stage renal disease groups. They were compared to ten healthy control subjects. Blood urea, creatinine, HbA1c, and adiponectin were measured. ADIPOQ +45 T/G and ADIPOR1 ?106 A/G gene polymorphisms were analyzed by PCR RFLP. Serum adiponectin was significantly lower in nephropathic group versus nonnephropathic and control group (P?=?0.026) with the lowest level in macroalbuminuric group (P?<?0.001). Serum urea, blood glucose, HbA1c, and duration of diabetes were found to be independent predictors of adiponectin level, r ²?=?0.59. In case of ADIPOQ, most of the cases carried the TT genotype, and there was absence of GG genotype in both cases and control. The ADIPOR1 gene polymorphism was strongly associated with type 2 DM and diabetic nephropathy. The G allele of ADIPOR1 was found to be a risk factor for type 2 DM with OR 3.1 (95 % confidence interval 1.1–8.5), P?=?0.028. This evidence highlights the role of ADIPOR1 in the pathogenesis of diabetic nephropathy and type 2 diabetes (T2D), suggesting AdipoR1 as a promising target for the treatment of T2D patients, particularly those who have microalbuminuria. Also, adiponectin serum level is a biomarker for kidney disease and may be targeted for prevention and treatment.     

Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes

Background: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design. Methods and results: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (p<0.05) associations with 10: ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and THPO. For five of these genes, the polymorphism associated in our study was different from that previously reported, suggesting linkage disequilibrium as an explanation for failure to replicate associations consistently across studies. We found strong linkage disequilibrium between polymorphisms within and between genes, especially on chromosome 1q22-q25, a region containing several candidate genes. Conclusions: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.     

线粒体DNA变异与2型糖尿病易感性的关联研究

目的研究湖北地区2型糖尿病（type 2 diabetes mellitus，T2DM）中线粒体基因突变的发生率及其相关性。方法采用聚合酶链反应一限制性片段长度多态性及DNA测序技术，对184例2型糖尿病患者和210名糖耐量正常的健康对照进行检测，并用mfold和tRNAscan-SE软件对检出的突变位点进行二级结构分析。结果MIND1 3316（G→A）、MIND1 3394（T→C）、D环区16189（T→C）变异率分别为3．26％、2．72％、36．9％，并首次在T2DM中发现4例MTTE14693（A→G）突变（2．17％）；对照组检出3316（G→A）突变2例（0．99％）、16189（T→C）变异56例（26．6％），朱检出3394、14693的点突变；两组间3394（T→C）、14693（A→G）、16189（T→C）变异率差别均有统计学意义（P〈0．05）；且T2DM组中16189（T→C）变异阳性者的胰岛素抵抗指数（HOMA→IR）值较16189（T→C）变异阴性组升高，差异有统计学意义（P=0．028）：多元回归分析显示该变异为参与HOMA→IR的独立变量（R2=0．043，P=0．037）。RNA二级结构预测发现，3394（T→C）和14693（A→G）突变使其相应的二级结构发生变化。结论3394（T→C）、14693（A→G）突变与T2DM的易感性有一定关联，16189（T→C）变异与湖北地区汉族人T2DM胰岛素抵抗相关。     

Genetic risk for coronary artery disease in individuals with or without type 2 diabetes

Given that a substantial proportion of individuals with coronary artery disease (CAD) also have type 2 diabetes, it is important to identify genes that confer susceptibility to CAD independently in subjects with type 2 diabetes and in those without this condition. A large-scale association study was performed to identify genes that confer susceptibility to CAD in either the absence or presence of type 2 diabetes. The study population comprised 5207 unrelated Japanese individuals, including 3085 subjects with CAD and 2122 controls. Among all subjects, 1704 individuals had type 2 diabetes and 3503 individuals did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, hypercholesterolemia, and hyperuricemia revealed that the following polymorphisms were significantly (P < 0.005) associated with CAD: the 1019C -->T of the connexin 37 gene for men with type 2 diabetes; the 2445G -->A in the fatty acid-binding protein 2 gene for women with this condition; the -863C-->A in the tumor necrosis factor-alpha gene, the -219G-->T in the apolipoprotein E gene, the 1019C-->T in the connexin 37 gene for men without type 2 diabetes; and the -482C-->T in the apolipoprotein C-III gene for women without this condition. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for CAD in the absence or presence of type 2 diabetes.     

Association between osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) gene polymorphisms and circulating OPG, soluble RANKL levels, and bone mineral density in Korean postmenopausal women

OBJECTIVE: To investigate the association between osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) gene polymorphisms and circulating OPG, soluble RANKL (sRANKL) levels, and bone mineral density (BMD) in Korean postmenopausal women. DESIGN: The OPG gene A163G, G209A, T245G, and G1181C polymorphisms, the RANK gene C421T and C575T polymorphisms, and the RANKL rs12721445 and rs2277438 polymorphisms were analyzed in 385 Korean postmenopausal women. Levels of serum OPG, soluble RANKL, osteocalcin, C-telopeptide of type I collagen, parathyroid hormone, calcium, and phosphorus and BMD at the lumbar spine and femoral neck were measured. RESULTS: The A163G, G209A, and T245G polymorphisms in the OPG gene were in complete linkage. The RANK C421T and C575T polymorphisms and the RANKL rs12711445 polymorphism were not observed. An association with BMD was found only for the OPG G1181C polymorphism, and BMD at the lumbar spine in women with the CC genotype was significantly higher than in women with the GC or GG genotype, with a C allele dose effect. In itself, the RANKL rs2277438 polymorphism was not related to BMD, but by combining the RANKL genotypes with the GC genotypes of the OPG G1181C polymorphism, the association with BMD at the lumbar spine became significant. No significant differences in the levels of any biochemical marker among genotypes of these polymorphisms were found. CONCLUSIONS: The OPG gene G1181C polymorphism, alone and in combination with the RANKL rs2277438 polymorphism, was identified as a genetic factor associated with BMD of the lumbar spine in Korean women.     

Combined estrogen receptor alpha and estrogen receptor beta genotypes influence the age of menarche

BACKGROUND: Age at menarche has a strong genetic influence. We reported recently an association between the XbaI (351A-->C)and PvuII (397T-->C) polymorphisms of the estrogen receptor (ER)alpha gene with the age of menarche in Greek adolescents. In the present study, we examined whether ERbeta genotypes alone, or in combination with ERalpha genotypes, may also influence onset of menarche. METHODS: We performed genotyping for the single nucleotide polymorphisms 1730A-->G and 1082G-->A of the ERbeta gene and examined their association with the age of menarche in the same cohort of 145 Greek girls. We then looked for a possible effect of combined ERalpha and beta genotypes on the age of menarche. RESULTS: Menarche occurred 7 months later in girls with the AA genotype of the 1730A-->G polymorphism than in girls with the AG genotype (mean +/- SD: 13.23 +/- 1.24 versus 12.66 +/- 1.26 years, respectively; P = 0.005). The 1082G-->A polymorphism was not detected in any of the girls examined. A significant effect of combined ERalpha and beta genotypes was also apparent. Menarche occurred 11 months later in girls bearing the AA/TT,AA (ERalpha, ERbeta) genotypes compared with girls with the CC/CC,AG genotype (13.30 +/- 1.27 nersus 12.41 +/- 1.28 years; P = 0.042). The difference remained significant after adjusting for body mass index (P = 0.034). CONCLUSION: Combined ERalpha and ERbeta polymorphisms may influence the age of menarche.     

妊娠期糖尿病3个候选基因单核苷酸多态性的研究

目的了解孕妇中妊娠期糖尿病（GDM）候选基因肝细胞核因子基因HNF4AP2、肿瘤坏死因子TNFa基因、脂联素基因APM1的单核苷酸多态性（SNP）,为大规模筛查奠定基础。方法随机选择GDM患者,采用PCR及限制性内切酶技术判定基因型并进行Hardy—Weinberg遗传平衡定律检验。结果除HNF4AP2 111T／C位点等位基因频率为0放弃继续检测外,其他位点频率大于5％而且符合Hardy—Weinberg平衡。结论说明该人群具有良好的代表性,可在孕妇中检测以进一步明确与妊娠期糖尿病的关系。     

PON2基因C311S、G148A多态性与脑卒中关系的研究

目的探讨对氧磷酶2（paraoxonase2,PON2）基因多态性与脑卒中的关系。方法用聚合酶链反应-限制性片段长度多态性分析法分别检测PON2基因C311S、G148A多态性在脑出血组（150例）、脑梗死组（180例）和正常对照组（120名）的基因频率。结果发现中国湖南地区人群存在PON2基因C311S、G148A多态性,在正常对照组中等位基因频率分别是S/C0.77/0.23,A/G0.43/0.57。脑出血组、脑梗死组患者PON2基因的等位基因频率与正常对照组相比差异无统计学意义（P〉0.05）。结论PON2基因多态性可能与中国湖南汉族人群脑卒中发病无关,C/S、G/A等位基因可能不是中国湖南地区汉族人群脑卒中发病的独立危险因素。     

No association of SUMO4 M55V with autoimmune diabetes in Asian-Indian patients

Autoimmune diabetes [type 1 diabetes mellitus (T1DM), latent autoimmune diabetes in adults (LADA) and part of malnutrition-related diabetes] has been shown to have genetic predisposition. Studies in IDDM 5 have lead to the discovery of a novel polymorphism 163 A-->G, of SUMO4 (small ubiquitin-related modifier) gene, associated with risk to T1DM in Asians, but not in Caucasians. We studied patients with T1DM (n = 134), patients with LADA (n = 101), patients with malnutrition-modulated diabetes mellitus (n = 66) and patients with fibrocalculous pancreatic diabetes (n = 43) and healthy controls subjects (n = 114) from Cuttack, India. Polymerase chain reaction-sequence-specific primer (PCR-SSP) was used to amplify the 163 A-->G sequences. Restriction fragment length polymorphism (RFLP) was performed using restriction enzyme Taq I (PCR-RFLP). Differences in the allelic frequencies of the A and the G alleles were tested statistically using Fisher's exact test or chi-squared test wherever appropriate. P-values were considered significant when equal to or less than 0.05. No significant association was detected between SUMO4 M55V and T1DM susceptibility in Asian-Indians. Comparison of the A and G alleles with HLA DR3-DR4 did not result in any significant P-values. No significant association was found between SUMO4 M55V and LADA or malnutrition-related diabetes mellitus (MRDM). Our results show that Asian-Indians with T1DM are different from other Asian populations. Asian-Indians show more similarity to Caucasians with respect to the association of SUMO4 M55V variant in T1DM. Association studies on Asian-Indian patients with LADA and MRDM showed no significant difference in the presence of the A and the G alleles when compared to healthy controls.