韩国人calpain-10基因单核苷酸多态性及其组合型的分析

目的分析发现于墨西哥裔美国人群中的2型糖尿病易感基因calpain-10单核苷酸多态性（single nucletide polymorphism。SNP）及其组合型在韩国人群中的分布。方法采用聚合酶链式反应．限制性片段长度多态性技术，分析312名健康韩国人calpain-10基因UCSNP-43、-19、-63位点的基因型及其组合型，计算基因型、等位基因和组合型频率。结果UCSNP-43位点基因型频率为1／1型的是86．2％、1／2型的是13．5％、2／2型的是0．3％，等位基因频率为G的是0．930、A0．070。UCSNP-19位点基因型频率为1／1型的是9．9％、1／2型的是44．6％、2／2型的是45．5％，等位基因频率为D的是0．322、I的是0．678。UCSNP-63位点基因型频率为1／1型的是57．4％、1／2型的是35．9％、2／2型的是6．7％，等位基因频率为C的是0．754、T的是0．246。各基因型分布匀符合Hardy-Weinberg平衡定律。韩国人中上述3个单核苷酸多态性基因型组合类型共见12种，75．6％由3种基因型组合构成。按UCSNP-43，-19，-63排列，分别为GG-DI-CC（单倍型组合111／121）、GG-DI-CT（112／121）、GC-II-CC（121／121），其频率分别为10．6％、28．8％、36．2％。结论韩国人calpain-10基因SNP分布与白人、美籍墨西哥人及美籍Pima印第安人等种族间存在较大差异，与中国和日本人群较为相近，其112／121单倍型组合频率显著高于美籍墨西哥人。     

Calpain-10基因的SNP组合变异与2型糖尿病及其临床代谢性状的关系

目的 观察NIDDM1位点calpain-10基因（CAPN-10）的单核苷酸多态性（SNP）组合与中国人2型糖尿病（type2diabetes,T2DM)及有关临床代谢性状的关系。方法 268名上海地区中国人,其中144人为正常糖耐量（NGT）者,124例为T2DM患者,予口服75g葡萄糖后0、30、60、120及180分钟测血浆葡萄糖（PG）,胰岛素（INS）、C-肽（CP）及游离脂肪酸（FFA）,并估测胰岛β细胞岛素分泌及组织胰岛素敏感性,检测CAPN-10UCSNP44、-43、-19及-63基因型。结果 （1）中国人NGT者4个SNP的优势等位基因在UCSNP44为T（频率91%）、UCSNP43为G（89%）、UCSNP19为Ⅰ（3次32bp序列重复）（67%）及UCSNP63为C（79%）,这些频率与文献报道的其他种群频率间差异有显著性。（2）中国人NGT者中上述4个SNP基因型组合类型共见14种。群体中69%由4种基因型组合构成。按UCSNP44-43-19-63排列,这4种主要组合分别为组合A：TT-GG——DI-CC（单倍型组合1121/1111）（频率为10%）、组合B：TT-GA-Ⅱ-CC（1121/1221）（10%）、组合C：TT-GG-Ⅱ-CC（1121/1121）（26%）及组合D：TT——GG-DI-CT（1121/1112）（22%）。（3）CAPN-10上述单个SNP或4个SNP组合频率在NGT及T2DM者间差异均无显著性。（4）NGT者中主要基因型组合亚组间比较中可见临床代谢变量水平在组间呈从正常逐渐向糖耐量异常代谢情况移行的现象,组合A与组合D比较可见前者在糖兴奋后：（1）PG偏高且高峰后移;（2）FFA下降少且缓慢,后期无回升;（3）胰岛素偏高且高峰后移;（4）有胰岛素敏感性下降倾向,差异有显著性的比较者中半数以上经年龄、性别、体块指数及腰围校正后差异仍然存在。结论 CAPN-10变异与T2DM有关的临床代谢变量水平变异相关,此种相关有赖于CAPN-10基因各变异间形成的单倍型,且有赖于变异单倍型间的组合情况。     

Hidden population substructures in an apparently homogeneous population bias association studies

Linkage- and association-based approaches have been applied to attempt to unravel the genetic predisposition for complex diseases. However, studies often report contradictory results even when similar population backgrounds are investigated. Unrecognized population substructures could possibly explain these inconsistencies. In an apparently homogeneous German sample of 612 patients with type 2 diabetic and end-stage diabetic nephropathy and 214 healthy controls, we tested for hidden population substructures and their possible effects on association. Using a genetic vector space analysis of genotypes of 20 microsatellite markers, we identified four distinct subsets of cases and controls. The significance of these substructures was demonstrated by subsequent association analyses, using three genetic markers (UCSNP-43,-19,-63; intron 3 of the calpain-10 gene). In the undivided sample, we found no association between individual SNPs or any haplogenotypes (ie the genotype combination of two multilocus haplotypes) and type 2 diabetes. In contrast, when analyzing the four groups separately, we found that there was evidence for association of the common C allele of UCSNP-63 with the trait in the largest group (n=547 cases/101 controls; P=0.002). In this subset haplotype 112 was more frequent in controls than in cases (P=0.006; haplogenotype 112/121: odds ratio (OR)=0.27, 95% confidence intervals (CI)=0.13-0.57), indicating a protective effect against the development of type 2 diabetes. Our study demonstrates that unconsidered population substructures (ethnicity-dependent factors) can severely bias association studies.     

Association of the calpain-10 gene with type 2 diabetes mellitus in a Mexican population

Variation in the calpain-10 gene (CAPN10) has been associated with risk of type 2 diabetes in the Mexican American population of Starr County, Texas. We typed five polymorphisms in the calpain-10 gene (SNP-43, -43, -63, and -110 and Indel-19) to test for association with type 2 diabetes in 248 individuals representative of the mestizo population of Mexico City and Orizaba, Mexico including 134 patients with type 2 diabetes and 114 subjects with normal fasting blood glucose levels. We found a significant difference in SNP-44 allele and genotype frequencies between type 2 diabetic and non-diabetic subjects. The rare allele at SNP-44 was associated with increased risk of type 2 diabetes (odds ratio (OR)=2.72, 95% confidence interval (CI)=1.16-6.35, P=0.017). SNP-110, which is in perfect linkage disequilibrium with SNP-44, was also associated with type 2 diabetes. The SNP-43, Indel-19, and SNP-63 haplogenotype 112/121 associated with significantly increased risk (OR=2.16, 95% CI=1.31-3.57) of type 2 diabetes in Mexican Americans was not associated with significantly increased in risk in Mexicans (OR=1.15, 95% CI=0.57-2.34). The results suggest that variation in CAPN10 affects risk of type 2 diabetes in the mestizo population of central Mexico (Mexico City and Orizaba) and in Mexican Americans (Starr County, Texas).     

Obesity is associated with the Arg389Gly ADRB1 but not with the Trp64Arg ADRB3 polymorphism in children from San Luis Potosí and León,México

This research was designed to analyze the possible associations of Arg389Gly ADRB1 and Trp64Arg ADRB3 polymorphisms in children with obesity. A cross-sectional study included 1,046 school-age Mexican participants (6-12 years old) from the cities of San Luis Potosí and León. Children were classified as non-obese or obese according to their body mass index (BMI) percentile; obese children had a BMI≥95th percentile for sex and age. Biochemical data were collected. Polymorphisms were detected using TaqMan qPCR assay. A logistic regression analysis was used to calculate the risk of obesity based on genotypes. Differences were found between groups where obese children had a significant increase in systolic and diastolic blood pressure, fasting plasma glucose, insulin, HOMAIR, LDL-cholesterol, triglycerides, and lower HDL-cholesterol compared with the normal weight group (P < 0.05).The distribution of allele frequency in the population was Arg = 87.4 and Gly = 12.6 (Hardy Weinberg equilibrium c2 = 3.16 , P = 0.07 ); Trp = 81.5 and Arg = 18.5 (Hardy Weinberg equilibrium c2 = 2.2, P = 0.14 ) for ADRB1 and ADRB3, respectively. Even though no different frequencies of Arg389Gly polymorphism between groups were found (P = 0.08), children carriers of one Gly389 ADRB1 allele had a risk for obesity of OR = 1.40 (95%CI, 1.03–1.90, P = 0.03) after adjustment for age and gender. No other association was found for Trp64Arg ADRB3 polymorphism. Only the Arg389Gly ADRB1 polymorphism was associated with risk for obesity in Mexican children.     

Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population

Variation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and 50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis 50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.Naoko Iwasaki, Yukio Horikawa and Takafumi Tsuchiya contributed equally to this work.     

Obesity as a risk factor for non-insulin-dependent diabetes mellitus in Korea

Most Korean patients with non-insulin-dependent diabetes mellitus (NIDDM) have been reported not to be obese, and many of them lost weight significantly during the course of their disease. In this regard, a retrospective cohort study was conducted to determine the relationship between body mass index (BMI, kg/m2) and the risk for NIDDM among Koreans. Subjects who had received a medical examination from 1990 to 1991 and who were available for the detection of NIDDM until September 1999 were included. Subjects who initially had diabetes or were diagnosed as diabetic within 1 yr after enrollment were excluded. We reviewed the medical records of final cohort of 2,531 subjects. Follow-up of this cohort revealed 117 cases with diabetes with an incident of 7.8 per 1,000 person-years. Compared with those with BMI less than 23 kg/m2, the adjusted relative risks for diabetes mellitus for those with BMI of 23-24.9, 25-26.9, and greater than 27 kg/m2 were 0.85 (0.47-1.50), 1.29 (0.72-2.31), and 3.38 (1.22-4.63), respectively, for men (p for trend<0.01) and as for 9.14 (1.99-41.8), 7.36 (1.47-36.8), and 14.5 (3.03-69.2), respectively, for women (p for trend<0.01). These data indicate a direct relationship between obesity and the risk for the development of diabetes, emphasizing the importance of weight control for the prevention of NIDDM in Koreans.     

Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses

We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.     

Adiponectin gene variation associates with the increasing risk of type 2 diabetes in non-diabetic Japanese subjects

Adiponectin is an adipocyte-secreted protein that is known to modulate insulin sensitivity and glucose homeostasis. A number of genetic variations have been studied. Among them, two single-nucleotide polymorphisms (SNP45T>G, SNP276G>T) showed an association with type 2 diabetes in the Japanese population. In this study, we examined the association between these SNPs and risk factors of type 2 diabetes in 194 non-diabetic Japanese subjects. SNP45 was associated with insulin sensitivity (determined by HOMA-IR, p=0.046) and obesity (body mass index; BMI, p=0.043). SNP276 showed a stronger association with HOMA-IR (p=0.018) and BMI (p=0.017). However, neither SNP had an association with insulin secretion (insulinogenic index) and plasma lipid levels. Moreover, a linkage dis-equilibrium was observed between SNP45 and SNP276. Carriers with SNP45G-SNP276G haplotype had higher BMI (p=0.034) and carriers with SNP45T-SNP276T haplotype had lower BMI (p=0.005) and HOMA-IR (p=0.037). Adiponectin gene variations showed an association with obesity and insulin sensitivity, and adiponectin genotypes may predict the increasing risk for type 2 diabetes in non-diabetic subjects.     

Insatiable insecurity: maternal obesity as a risk factor for mother–child attachment and child weight

Childhood obesity has become a rising health problem, and because parental obesity is a basic risk factor for childhood obesity, biological factors have been especially considered in the complex etiology. Aspects of the family interaction, e.g., mother–child attachment, have not been the main focus. Our study tried to fill this gap by investigating whether there is a difference between children of obese and normal weight mothers in terms of mother–child attachment, and whether mother–child attachment predicts child’s weight, in a sample of 31 obese and 31 normal weight mothers with children aged 19 to 58 months. Mother–child attachment was measured with the Attachment Q-Set. We found that (1) children of obese mothers showed a lower quality of mother–child attachment than children of normal weight mothers, which indicates that they are less likely to use their mothers as a secure base; (2) the attachment quality predicted child`s BMI percentile; and (3) the mother–child attachment adds incremental validity to the prediction of child’s BMI beyond biological parameters (child’s BMI birth percentile, BMI of the parents) and mother’s relationship status. Implications of our findings are discussed.     

Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations

The therapeutic effects of cannabinoid receptor blockade on obesity-associated phenotypes underline the importance of the endocannabinoid pathway on the energy balance. Using a staged-approach, we examined the contribution of the endocannabinoid receptor 1 gene (CNR1) on obesity and body mass index (BMI) in the European population. With the input of CNR1 exons and 3' and 5' regions sequencing and HapMap database, we selected and genotyped 26 tagging single-nucleotide polymorphisms (SNPs) in 1932 obese cases and 1173 non-obese controls of French European origin. Variants that showed significant associations (P < 0.05) with obesity after correction for multiple testing were further tested in two additional European cohorts including 2645 individuals. For the identification of the potential causal variant(s), we further genotyped SNPs in high linkage disequilibrium (LD) with the obesity-associated variants. Of the 25 successfully genotyped CNR1 SNPs, 12 showed nominal evidence of association with childhood obesity, class I and II and/or class III adult obesity (1.16 < OR < 1.40, 0.00003 < P < 0.04). Intronic SNPs rs806381 and rs2023239, which resisted correction for multiple testing were further associated with higher BMI in both Swiss obese subjects and Danish individuals. The genotyping of all know variants in partial LD (r(2) > 0.5) with these two SNPs in the initial case-control study, identified two better associated SNPs (rs6454674 and rs10485170). Our study of 5750 subjects shows that CNR1 variations increase the risk for obesity and modulate BMI in our European population. As CB1 is a drug target for obesity, a pharmacogenetic analysis of the endocannabinoid blockade obesity treatment may be of interest to identify best responders.     

Association between obesity and insulin resistance with UCP2-UCP3 gene variants in Spanish children and adolescents

A number of studies have yielded controversial results on the association between polymorphisms in UCP2 and UCP3 genes with obesity and its comorbidities. The discrepancy among studies might be partially explained by the lack of consideration of the effect of adjacent loci in the same haplotype and the exclusion of key lifestyle factors in the statistical analysis. In this study, we have assessed the association between three genetic variants of the UCP2-UCP3 gene cluster, the -866G/A (rs659366) and the 45bp insertion (in position 173247 of the AC019121) of the UCP2 gene, the -55C/T (rs1800849) polymorphism of the UCP3 gene and their estimated haplotypes with childhood obesity and insulin resistance. This research was designed as a case-control study and information about several environmental parameters such as leisure time physical activity and time spent watching television were included. The study sample consisted in 193 obese children and adolescents (cases) and 170 controls aged 6-18. We found that the individual polymorphisms were not associated with obesity, but the (-866G; rs659366)-(Del; 45bp)-(-55T; rs1800849) haplotype was significantly associated with obesity and its presence in the control group increased about nine times the insulin resistance risk. Thus, the (-866A; rs659366)-(Ins; 45bp)-(-55C; rs1800849) haplotype may protect against insulin resistance in the obese population group.     

Endothelial nitric oxide synthase haplotypes are associated with preeclampsia in Maya mestizo women

Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women. A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T→C, intron 4 variants, Glu298Asp of eNOS were determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r^{2}, and haplotype analysis was conducted. Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR =3.01; 95% CI = 1.74-5.23; P =2.9 × 10^{-4}).Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker.     

Variations in the FTO gene are associated with severe obesity in the Japanese

Variations in the fat-mass and obesity-associated gene (FTO) are associated with the obesity phenotype in many Caucasian populations. This association with the obesity phenotype is not clear in the Japanese. To investigate the relationship between the FTO gene and obesity in the Japanese, we genotyped single nucleotide polymorphisms (SNPs) in the FTO genes from severely obese subjects [n = 927, body mass index (BMI) > or = 30 kg/m2] and normal-weight control subjects (n = 1,527, BMI < 25 kg/m2). A case-control association analysis revealed that 15 SNPs, including rs9939609 and rs1121980, in a linkage disequilibrium (LD) block of approximately 50 kb demonstrated significant associations with obesity; rs1558902 was most significantly associated with obesity. P value in additive mode was 0.0000041, and odds ratio (OR) adjusted for age and gender was 1.41 [95% confidential interval (CI) = 1.22-1.62]. Obesity-associated phenotypes, which include the level of plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure were not associated with the rs1558902 genotype. Thus, the SNPs in the FTO gene were found to be associated with obesity, i.e., severe obesity, in the Japanese.     

Methodological issues in the anthropometric assessment of Hmong children in the United States.

The effectiveness of the body mass index (BMI; kg/m2) in assessing overweight/obesity may be diminished in populations of short stature. In a sample (n = 79) of Hmong refugee children in the United States, of age 4-11 years, median z scores for height, BMI, and the triceps skinfold were -1.04z, +0.53z, and +0.18z, respectively. Further, 41.7% of children were above the NHANES 85th percentile for BMI-for-age, categorizing them as overweight/obese. Assessment of obesity by other established criteria for children, such as the triceps skinfold and body fat percentage, produced significantly lower estimates than did BMI. This is consistent with patterns found in other stunted populations, suggesting that BMI be employed in conjunction with other methods when assessing overweight/obesity in these groups. Finally, although stunting and overweight/obesity were both common in this study, at the individual level height z scores were positively correlated to z scores of various measures of adiposity.     

Obesity and upper body fat distribution in Mexican American children from families with a diabetic proband

Upper and centralized body fat distribution is associated with non-insulin dependent diabetes mellitus (NIDDM). Few studies have focused on anthropometric characteristics of preadults from families in which there is a diabetic (NIDDM) proband. This study explores the prevalence of upper and centralized body fatness in Mexican American children from the Diabetes Alert study (1981–1983) in Starr County, Texas. Anthropometric data on 165 males and 224 females 9–19 years include measures of adiposity such as skinfold thicknesses and the body mass index (BMI), a measure of overweight. They show rates of obesity two to three times that of White children of comparable age and sex from National Health Surveys. In comparison with U.S. White subjects, Mexican American adults are shorter, have more adiposity and arm muscle mass and have sitting heights and body breadths at the mean of these dimensions for the U.S. population. Children from Diabetes Alert families show only marginal excess of severe obesity (> 95th percentile of BMI) when compared to the general population of children surveyed in Starr County schools. Girls from these families, but not boys, have excess fatness in the BMI compared to Mexican American children from the Hispanic Health and Nutrition Examination Survey (HHANES); suprailiac skinfold thicknesses are also greater in children of the Diabetes Alert study than in HHANES children. From 1972 through 1982, Mexican American children in South Texas showed an increase in average stature, weight, and the BMI. These data together suggest that excessive obesity exists and may be increasing in children in populations at risk for NIDDM. The prevention of NIDDM in the Mexican American population may be more effective if educational and promotional interventions include the school aged population. © 1993 Wiley-Liss, Inc.     

Leptin and Leptin receptor polymorphisms,plasma Leptin levels and obesity in Tunisian volunteers

Adipose tissue is an important endocrine organ that secretes a number of adipokines, like Leptin (LEP). The aim this study was to investigate the prevalence of single nucleotide polymorphisms in LEP gene (LEP 3′UTR A/C, ?2548 G/A) and LEPR (K109R and Q223R) and their association with Leptin level and obesity. We recruited 169 non‐obese (body mass index [BMI] = 24.51‐3.69 kg/m²) and 160 obese (BMI = 36‐4.78 kg/m²) patients. Genotyping was performed using polymerase chain reaction‐restriction fragment length polymorphism, BMI was calculated, and Leptin level was measured by ELISA. Statistical analyses were performed by spss 19.0. According to LEP 3′UTR A/C polymorphism, AC and CC genotype carriers had higher Leptin levels than AA genotype carriers, respectively, 31[0.05‐148.8] (P = .008) vs 41[0.05‐111.6] (P = .003). The K109R polymorphism was associated with obesity (P = .025) and seems to significantly decrease the LEP levels (P < .001). Concerning LEP G2548A polymorphism, our results showed that the OR of obesity associated with 2548 AA/GG was 1.87[1.106‐2.78] P = .028 vs 1.41[1.035‐1.85] P = .045 for 223AA/GG polymorphism. In our haplotype analysis, one haplotype seems to be the more protective and one other seems to be the highest risk to obesity. LEP 3′UTR A/C and LEPR K109R polymorphisms were associated with Leptin level and obesity.     

Polymorphism R25P in the gene encoding transforming growth factor-beta (TGF-beta1) is a newly identified risk factor for proliferative diabetic retinopathy

Associations of the genetic polymorphisms in the promoter region and the signal peptide sequence of the transforming growth factor-beta (TGF-beta1) gene with proliferative diabetic retinopathy (PDR) in patients with non-insulin-dependent diabetes mellitus (NIDDM) were studied. A total of 245 Caucasian subjects comprised the two groups: NIDDM patients with PDR (n = 73) and NIDDM patients without PDR (n = 172). Allele frequencies of common TGF-beta1 polymorphisms (at positions -988C/A, -800G/A, -509C/T, +869T/C (L10P), and +915G/C (R25P)) were determined by PCR-based methodology. All polymorphisms were in strong linkage disequilibrium (P < 10(-2)). Significantly higher frequencies of both the L allele and the R allele of the signal sequence polymorphisms in PDR subjects were found (after a correction for multiple comparisons, P(corr) < 10(-2) and P(corr) < 10(-4), respectively). Calculated odds ratios (ORs) for the LL and RR genotypes were 2.89 (95% confidence interval (CI), 1.6-5.1) and 19.73 (95% CI, 2.6-146.8), respectively. No significant differences between groups were found for the -800G/A and -509C/T polymorphisms. The -988A allele was not represented in our sample. Multiple logistic regression identified age, diabetes duration, and R25P polymorphism as significant predictors (P = 0.002, P = 0.000003, and P = 0.007, respectively). The frequencies of genotype combinations of the -800G/A, -509C/T, L10P, and R25P TGF-beta(1) polymorphisms were significantly different between the PDR and non-PDR groups (chi(2) = 37.83, df = 20, P < 10(-2)). The frequency of haplotype consisting of majority alleles was found significantly associated with PDR (P < 0.03). The presented data indicate that the R25P polymorphisms in the TGF-beta1 gene could be regarded as a strong genetic risk factor for PDR.     

p.Q223R leptin receptor polymorphism associated with obesity in Brazilian multiethnic subjects.

Several genes play a major role in obese phenotypes, and studies suggest that genetic variations among individuals, as well as their lifestyles, may bring about different body compositions. Among these genes, LEP, which codifies leptin, and the LEPR gene encoding its receptor were extensively studied for variants that could explain the obese phenotype. The LEPR p.Q223R gene polymorphism was analyzed in a sample of obese and nonobese individuals from Brazil to evaluate the role of this polymorphism in the obese phenotype in the population. Two hundred obese patients (60 males, 140 females, body mass index (BMI) >30 kg/m2) were screened, together with 150 lean or normal healthy individuals (63 males, 87 females, BMI <24 kg/m2). Genomic DNA was extracted and amplified by polymerase chain reaction (PCR). PCR products were digested with the restriction of endonuclease MspI, and separated by electrophoresis through an 8% polyacrilamide gel stained with silver nitrate. There was a significant difference in LEPR p.Q223R polymorphism frequency when comparing obese and lean subjects, with an odds ratio of 1.92 and a 95% confidence interval of 1.15-3.22 (P = 0.013). There is a strong association of the LEPR p.Q223R gene polymorphism with obesity in Brazil.