Evaluation of a SNP map of 6q24–27 confirms diabetic nephropathy loci and identifies novel associations in type 2 diabetes patients with nephropathy from an African-American population

Previously, we performed a genome scan for type 2 diabetes (T2DM) using 638 African-American (AA) affected sibling pairs from 247 families; non-parametric linkage analysis suggested evidence of linkage at 6q24–27 (LOD 2.26). To comprehensively evaluate this region, we performed a two-stage association study by first constructing a SNP map of 754 SNPs selected from HapMap on the basis of linkage disequilibrium (LD) in 300 AAT2DM end-stage renal disease (ESRD) subjects, 311 AA controls, 43 European American controls and 45 Yoruba Nigerian samples (Set 1). Replication analyses were conducted in an independent population of 283 AA T2DM-ESRD subjects and 282 AA controls (Set 2). In addition, we adjusted for the impact of admixture on association results by using ancestry informative markers (AIMs). In Stage 1, 137 (18.2%) SNPs showed nominal evidence of association (P < 0.05) in one or more of tests of association: allelic (n = 33), dominant (n = 36), additive (n = 29), or recessive (n = 34) genotypic models, and 2- (n = 47) and 3-SNP (n = 43) haplotypic analyses. These SNPs were selected for follow-up genotyping. Stage 2 analyses confirmed association with a predicted 2-SNP “risk” haplotype in the PARK2 gene. Also, two intergenic SNPs showed consistent genotypic association with T2DM-ESRD: rs12197043 and rs4897081. Combined analysis of all subjects from both stages revealed nominal associations with 17 SNPs within genes, including suggestive associations in ESR1 and PARK2. This study confirms known diabetic nephropathy loci and identifies potentially novel susceptibility variants located within 6q24–27 in AA. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans

Four genome wide linkage scans for diabetic nephropathy have mapped susceptibility loci to chromosome 18q22.3-23 in the region of the carnosinase genes, CNDP1 and CNDP2. CNDP1 has been associated with diabetic nephropathy in Europeans and European Americans, but not African-Americans. Individuals homozygous for a five tri-nucleotide repeat allele (5L; D18S880) are protected from diabetic nephropathy. We identified 64 variants after sequencing the exons, promoter, and 3′ UTR of CNDP1 and CNDP2 in African-American and European American DNA samples. After scanning 44 of these variants, extensive genotyping of 12 SNPs and D18S880 was performed in 1,025 African-American cases with type 2 diabetes (DM)-associated end-stage renal disease (ESRD) and 1,064 African-American non-diabetic non-nephropathy controls to assess whether the carnosinase genes influence risk for DM-ESRD in African-Americans. Evidence of association with DM-ESRD was seen with 2 SNPs: rs6566810 and rs4892247; 3 two-marker haplotypes: rs6566810 and rs17089362, rs17089362 and rs890336, and rs890334 and rs12717111 (global empirical P = 0.0034, 0.0275, and 0.0002, respectively) and 3 three-marker haplotypes: rs6566810, rs17089362, and rs890336; rs890335, rs890334, and rs12717111; and rs890334, rs12717111, and D18S880 (global empirical P = 0.0074, 1.5E-05, and 0.0032, respectively). The risk haplotypes (rs6566810, rs17089362 [A,T] and rs6566810, rs17089362, rs890336 [A,T,C]) were most strongly associated with DM-ESRD among African-Americans in the non 5L–5L group. Variants in the carnosinase genes appear to contribute to diabetic nephropathy susceptibility in African-Americans. Protection from diabetic nephropathy afforded by 5L–5L homozygosity in CNDP1 may be masked by the effects of additional risk haplotypes in CNDP1 and CNDP2. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Comprehensive evaluation of the estrogen receptor α gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population

We previously investigated the estrogen receptor α gene (ESR1) as a positional candidate for type 2 diabetes (T2DM), and found evidence for association between the intron 1-intron 2 region of this gene and T2DM and/or nephropathy in an African American (AA) population. Our objective was to comprehensively evaluate variants across the entire ESR1 gene for association in AA with T2DM and end stage renal disease (T2DM–ESRD). One hundred fifty SNPs in ESR1, spanning 476 kb, were genotyped in 577 AA individuals with T2DM–ESRD and 596 AA controls. Genotypic association tests for dominant, additive, and recessive models, and haplotypic association, were calculated using a χ² statistic and corresponding P value. Thirty-one SNPs showed nominal evidence for association (P < 0.05) with T2DM–ESRD in one or more genotypic model. After correcting for multiple tests, promoter SNP rs11964281 (nominal P = 0.000291, adjusted P = 0.0289), and intron 4 SNPs rs1569788 (nominal P = 0.000754, adjusted P = 0.0278) and rs9340969 (nominal P = 0.00109, adjusted P = 0.0467) remained significant at experimentwise error rate (EER) P ≤ 0.05 for the dominant class of tests. Twenty-three of the thirty-one associated SNPs cluster within the intron 4–intron 6 regions. Gender stratification revealed nominal evidence for association with 35 SNPs in females (352 cases; 306 controls) and seven SNPs in males (225 cases; 290 controls). We have identified a novel region of the ESR1 gene that may contain important functional polymorphisms in relation to susceptibility to T2DM and/or diabetic nephropathy. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Implication of genetic variants near TMEM18, BCDIN3D/FAIM2, and MC4R with coronary artery disease and obesity in Chinese: a angiography-based study

Coronary artery disease (CAD) is multifactorial disease which occurs as a result of the interaction of genetic and environmental factors. Obesity is an independent risk factor for cardiovascular disease. Recent genome-wide association studies have identified several genes associated with obesity in Europeans. We wondered whether these genetic variants were associated with CAD. Three single nucleotide polymorphisms (SNPs) rs7561317 near TMEM18, rs7138803 near BCDIN3D/FAIM2 and rs12970134 near MC4R were examined in 930 Han Chinese subjects based on coronary angiography, using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. There were no significant differences in genotypes and allele distributions of three SNPs between CAD and CAD-free groups. The AA genotype of SNP rs12970134 near MC4R was associated to obesity both in CAD group and CAD-free group in Han Chinese population (P < 0.001, OR = 2.96, 95% CI 2.01–3.73; and P = 0.003, OR = 2.59, 95% CI 1.86–3.19, respectively). Our observations suggest that the polymorphism rs12970134 near MC4R may be associated to the risk of obesity in Han Chinese population.     

Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease

Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM–ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r ² = 0.101; P = 0.019) and in the combined set (r ² = 0.131; P = 3.57 × 10⁻⁵). The absolute difference between frequencies in parental populations, absolute δ, was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. An erratum to this article can be found at     

Association of GSTM1T1 genes with COPD and prostate cancer in north Indian population

The glutathione S-transferase (GST) family of enzymes is known to play a pivotal role in phase II of biotransformation of xenobiotics, environmental carcinogens and pharmacological drugs. The objective of the present study was to investigate the role of GSTM1 and GSTT1 null genotypes as risk factors for chronic obstructive pulmonary disease (COPD) and prostate cancer. The subjects appraised were 200 COPD cases, 150 prostate cancer cases, 150 benign prostatic hyperplasia (BPH) cases, 200 age matched controls for COPD and 172 age matched controls for prostate cancer. GSTM1 and GSTT1 null genotype was found to confer 2.5 (OR 2.45; 95% CI 1.56–3.82; P value = 0.00008) and 2.4-fold (OR 2.39; 95% CI 1.36–4.20; P value = 0.002) significant higher risk for prostate cancer. Smoking imparted a 2.2-fold significant risk of prostate cancer cases (OR 2.23; 95% CI 1.36–3.65 P value = 0.001) and twofold risk in BPH (OR 2.09; 95% CI 1.26–3.46; P value = 0.005). In case of COPD only null genotype of GSTT1 has shown 2.1-fold (OR 2.11; 95% CI 1.22–3.62; P value = 0.007) significant increased risk.     

Genome-wide association analysis with selective genotyping identifies candidate loci for adult height at 8q21.13 and 15q22.33-q23 in Mongolians

We performed a genome-wide association study with 23,465 microsatellite markers to identify genes related to adult height. Selective genotyping was applied to extremely tall and extremely short individuals from the Khalkh-Mongolian population. Two loci, 8q21.13 and 15q22.33, which showed the strongest association with microsatellites were subjected to further analyses of SNPs in 782 tall and 773 short individuals. The most significant association was observed with SNP rs2220456 at 8q21.13 (P = 0.000016). In the LD block at 15q22.32, SNP rs8038652 located in intron 1 of IQCH was strongly associated (P = 0.0003), especially the AA genotype of the SNP under a recessive model was strongly associated with adult height (P = 0.000046).     

<Emphasis Type="Italic">IGFBP3</Emphasis> polymorphisms and risk of cancer: a meta-analysis

Until now, there were several studies evaluating the association between the polymorphisms in the IGFBP3 gene and cancer risk in diverse populations and in multiple types of cancer, but their outcomes have been contradictory and need to be investigated further. Here, we performed a meta-analysis from all eligible case–control studies to address the association of IGFBP3 A-202C and Gly32Ala polymorphisms to cancer. 20 articles including 41 studies for A-202C variant including 28,322 cancer patients and 36,772 healthy controls and six articles for Gly32Ala variant including 4,477 cases and 5,443 controls were selected in our analysis. Overall, A-202C polymorphism was appeared to be a risk factor of cancer (OR = 0.98, P = 0.05). A allele of IGFBP3 A-202C SNP was significantly less common in the cancer patients than in controls and AA genotype significantly decreased the cancer risk in additive genetic model when comparing to CC genotype (OR = 0.93, P = 0.004). Another SNP, Gly32Ala, seemed to be in linkage equilibrium with A-202C SNP. However, no significance was found when we analyzed the relation of cancer risk and Gly32Ala polymorphism (OR = 0.93, P = 0.36). Further, we compared the distributions of A-202C SNP in different types of cancer, significant association was found in additive genetic model in breast cancer (OR = 0.93, P = 0.01) and prostate cancer (OR = 0.88, P = 0.05). In the analysis of the variants in different population, A-202C variant was significantly associated with cancer risk in Africans (OR = 0.90, P = 0.05), but not in Caucasians (OR = 0.98, P = 0.12) or in Asians (OR = 1.03, P = 0.61). These results indicated that polymorphisms of IGFBP3 might have different effect in different types of cancer and different population. Further large study combining both IGFBP3 A-202C and Gly32Ala SNPs on different types of cancer in different populations were needed to validate former results.     

15-Lipoxygenase gene variants are associated with carotid plaque but not carotid intima-media thickness

The major underlying cause of CHD is atherosclerosis, and oxidised LDL is known to play an important role in its development. We examined the role of three single nucleotide polymorphisms (SNPs) in the 15-lipoxygenase gene (ALOX15), in atherosclerosis. We genotyped three SNPs in the ALOX15 promoter in two Western Australian samples—1,111 community-based individuals and 556 with CHD. SNPs and haplotypes were tested for an association with carotid plaque, intima-media thickness and risk of CHD. The −611GG genotype was associated with increased likelihood of carotid plaque in CHD patients (OR = 4.01, 95%CI = 1.39–11.53, P = 0.005) and the C alleles of the G-220C and G-189C SNPs were associated with decreased likelihood of plaque among cases (OR = 0.66, 95%CI = 0.43–0.99, P = 0.05 and OR = 0.51, 95%CI = 0.34–0.78, P = 0.002 respectively). The GGG haplotype was associated with increased risk of carotid plaque in CHD patients (OR = 5.77, 95%CI = 1.82–18.29, P = 0.0007) and in community-based individuals under 53 years (OR = 4.15, 95%CI = 1.23–14.08, P = 0.02). No association was observed between ALOX15 SNPs or haplotypes and intima-media thickness. This study is novel as it is the first to examine the association between 15-lipoxygenase polymorphisms and atherosclerotic indicators. These findings suggest a possible role of ALOX15 polymorphisms in focal plaque formation.     

Genetic diversity of the sulfotransferase-like gene and one nonsynonymous SNP associated with growth traits of clam, Meretrix meretrix

The sulfotransferase (SULT) is an important factor in phase II metabolism. Three single nucleotide polymorphisms (SNPs; MmeSUl-696, MmeSUl-714 and MmeSUl-806) were discovered in a SULT-like gene of Meretrix meretrix. A modified allele-specific PCR detection assay was developed to perform polymorphism analysis of the three SNPs in two families and two populations of M. meretrix. Results showed that the genotype of the three SNPs is accordance to the expected Mendelian segregation ratios and conforms to Hardy–Weinberg Equilibrium (HWE) in families and populations, respectively. Moreover, sampled clams (n = 151) from the two populations were tested for the associations between SNPs and growth traits. The single SNP association analysis indicated MmeSUl-806 significantly (P < 0.05) correlated with growth traits of M. meretrix. A further haplotype-trait association analysis confirmed that the three SNPs were in linkage disequilibrium and showed that the haplotype TTG and TCG associated with low growth in the two populations, respectively, which supported that MmeSUl-806 was a growth related marker. This study suggested SULT gene might be a candidate gene related to growth in bivalves and MmeSUl-806 could be a gene marker in linkage map construction and breeding programs of M. meretrix.     

Associations between matrilin-1 gene polymorphisms and adolescent idiopathic scoliosis curve patterns in a Korean population

Adolescent idiopathic scoliosis (AIS) is a complex disorder with an unclear etiology and pathogenesis. In previous studies, genome-wide linkage and genetic association analyses have been carried out to find genetic factors linked with AIS. In this study, we examined whether the susceptibility to AIS is associated with MATN1 gene polymorphisms in a Korean population, which included 166 individuals with AIS and 126 controls. We found that there were no statistically significant associations between any of the MATN1-linked allele or genotype frequencies between AIS and controls. However, statistically significant associations were found at single nucleotide polymorphism (SNP) rs1065755 when comparing the curve patterns of AIS with the controls. The A allele of SNP rs1065755 was associated with a higher risk of AIS than the allele G in the genotype–phenotype (curve pattern) analysis (P = 0.029). In addition, the frequency of the A allele of SNP rs1065755 in AIS with double major curves was higher than in controls (P = 0.021, ORs = 2.56 within 95% CI = 1.12–5.83). Additionally, among the predicted common haplotypes, the frequency of the haplotype GATT (31.3%) in AIS with double major curves was higher than in controls (15.2%) (P = 0.024, ORs = 2.54 within 95% CI = 1.11–5.84). We conclude that the A allele of SNP rs1065755 in the MATN1 gene is associated with AIS.     

Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population

The potent tumor suppressors P16 and RB1 are the key regulators of cell cycle machinery in eukaryotes. Polymorphisms in these genes play an important role in the outcome of various diseases including cancer. In the present study, we evaluated the association of p16 and RB1 polymorphisms with cervical cancer susceptibility in Indian population. We screened 150 histologically confirmed cervical cancer cases along with equal number of healthy controls with normal cervical cytology. PCR-RFLP method was employed for genotyping of SNPs in p16 C540G (rs11515), C580T (rs3088440) in the 3′-UTR of exon 3 and RB1 A153104G (rs4151580) located in the intron 18 and confirmed by direct sequencing. Both patients and controls were screened for HPV infection. In this case–control study 84.67% (127/150) of cases were found to be positive for HPV DNA sequence. Women carrying p16 C540G carrier genotypes 540 (CG/GG) may have protective effect for the development of cervical cancer (P = 0.0001, OR = 0.31, 95% CI = 0.17–0.56). And SNP at C580T of p16 gene was found to be negatively associated with the risk of cervical cancer (P = 0.0004, OR = 0.04, 95% CI = 0.002–0.63). p16 (540C/580T) has emerged as a major risk haplotype (P = 0.033, OR = 1.47, 95% CI = 1.05–2.07) whereas p16 (540G/580T) as a chief protective haplotype (P = 0.014, OR = 0.39, 95% CI = 0.18–0.83) for the development of cervical cancer among Indian women. Contrary to this, SNP at A153104G of RB1 gene showed statistically significant association (P = 0.035, OR = 1.69, 95% CI = 1.06–2.68) with increased susceptibility for the development of cervical cancer. Our results suggest that single nucleotide polymorphisms in p16, RB1 genes may affect the susceptibility to cervical cancer collectively.     

<Emphasis Type="Italic">FAS</Emphasis> −1,377 G/A polymorphism is associated with cancer susceptibility: evidence from 10,564 cases and 12,075 controls

Published data on the association between FAS −1,377 G/A polymorphism and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 17 studies including 10,564 cases and 12,075 controls were involved in this meta-analysis. Overall, significantly elevated cancer risk was associated with AA variant genotype when all the eligible studies were pooled into the meta-analysis (for AA vs GG: OR = 1.19; 95% CI = 1.01–1.40; P _{heterogeneity} = 0.05; for recessive model: OR = 1.21; 95% CI = 1.04–1.41; P _{heterogeneity} = 0.05). In the subgroup analysis by ethnicity, borderline statistically significantly increased risks were found among Asians for recessive model (OR = 1.20; 95% CI = 1.00–1.45; P _{heterogeneity} = 0.01). In the subgroup analysis by population-based controls or hospital-based controls, statistically significantly increased risks were found among groups with population-based controls for AA versus GG (OR = 1.27; 95% CI = 1.02–1.58; P _{heterogeneity} = 0.05) and recessive model (OR = 1.25; 95% CI = 1.00–1.59; P _{heterogeneity} = 0.01). For breast cancer, borderline statistically significantly increased risks were found for AA versus GG (OR = 1.29; 95% CI = 1.00–1.67; P _{heterogeneity} = 0.41). In summary, this meta-analysis suggests that the FAS −1,377 G/A polymorphism is associated with cancer susceptibility. L. X. Qiu, J. Shi and H. Yuan contributed equally to this work and should be considered as co-first authors.     

A novel association of a polymorphism in the first intron of adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia in Asian Indians

Adiponectin is an adipose tissue specific protein that is decreased in subjects with obesity and type 2 diabetes. The objective of the present study was to examine whether variants in the regulatory regions of the adiponectin gene contribute to type 2 diabetes in Asian Indians. The study comprised of 2,000 normal glucose tolerant (NGT) and 2,000 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. We identified two proximal promoter SNPs (−11377C→G and −11282T→C), one intronic SNP (+10211T→G) and one exonic SNP (+45T→G) by SSCP and direct sequencing in a pilot study (n = 500). The +10211T→G SNP alone was genotyped using PCR-RFLP in 4,000 study subjects. Logistic regression analysis revealed that subjects with TG genotype of +10211T→G had significantly higher risk for diabetes compared to TT genotype [Odds ratio 1.28; 95% Confidence Interval (CI) 1.07–1.54; P = 0.008]. However, no association with diabetes was observed with GG genotype (P = 0.22). Stratification of the study subjects based on BMI showed that the odds ratio for obesity for the TG genotype was 1.53 (95%CI 1.3–1.8; P < 10⁻⁷) and that for GG genotype, 2.10 (95% CI 1.3–3.3; P = 0.002). Among NGT subjects, the mean serum adiponectin levels were significantly lower among the GG (P = 0.007) and TG (P = 0.001) genotypes compared to TT genotype. Among Asian Indians there is an association of +10211T→G polymorphism in the first intron of the adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia.     

Association of +45(T/G) and +276(G/T) polymorphisms in the adiponectin gene with coronary artery disease in a population of Iranian patients with type 2 diabetes

The relation of Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T/G and +276G/T) with coronary artery disease (CAD) is controversial. The aim of the present study was to evaluate the genetic influence of the adiponectin gene polymorphisms in the development of CAD among patients with Type 2 diabetes (T2D). The adiponectin genotypes were detected by polymerase chain reaction and restriction analysis (PCR-RFLP) in our patients. Two adiponectin gene (ADIPOQ) SNPs (i.e. SNPs +45T>G and +276G>T) were genotyped in 114 Type 2 diabetic subjects with CAD, and 127 Type 2 diabetic patients without CAD. Demographic and anthropometric data along with plasma biochemistry including lipids, glycemic indices, and adiponectin were collected. There was a significant difference in the distribution of genotypes of +45T/G and +276G/T between CAD and non-CAD individuals (P < 0.05). Based on our results SNP+276G>T is associated with decreased risk of CAD after adjustment for potential confounding factors [adjusted OR = 0.39 (95%CI: 0.22–0.68); P = 0.001]. Similar findings were not observed for the +45T>G SNP. Two haplotypes 45T-276T and 45G-276T were associated with a decreased risk of CAD [adjusted OR = 0.47 (95% CI: 0.32–0.94); P = 0.03 and adjusted OR = 0.33 (95% CI: 0.13–0.83); P = 0.02 respectively]. No significant difference was observed between HOMA-IR, BMI, waist circumference, history of hypertension, HbA1C, and lipid concentrations regarding the two SNPs. In conclusion, these findings suggest that T allele of +276G>T SNP is significantly associated with decreased risk of CAD in T2D Patients. Also Haplotype analysis showed that two haplotypes 45T-276T and 45G-276T were associated with a decreased risk of CAD.     

IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05–1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.     

Polymorphisms in the 3′ UTR in the neurocalcin δ gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin δ (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3′ UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27–1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of α smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07–3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association of thrombospondin 1 gene with schizophrenia in Korean population

Thrombospondin 1 (THBS1), a multi-domain glycoprotein, is secreted from astrocytes and promotes synaptogenesis. Increasing evidence has suggested that not only various markers for synaptic pathology, but also astrocytes are affected in schizophrenia. In this study, we investigated whether coding region single nucleotide polymorphisms (cSNPs) of the THBS1 gene were associated with schizophrenia and with the clinical symptoms of schizophrenia patients. We genotyped two cSNPs [rs2228261 (Asn470Asn) and rs2292305 (Thr523Ala)] using direct sequencing in 220 schizophrenia patients and 376 control subjects. In this study, rs2228261 revealed significant association with schizophrenia in both codominant (TT vs. CC, P = 0.009, OR = 2.10, 95% CI = 1.23–3.59) and recessive models (TT vs. CC/CT, P = 0.0012, OR = 2.28, 95% CI = 1.38–3.77). Also, rs2292305 was associated with schizophrenia in the recessive model (GG vs. AA/AG, P = 0.0052, OR = 2.05, 95% CI = 1.24–3.38). Additionally, in the analysis of the haplotype, the CA and TG haplotypes consisting of rs2228261 and rs2292305 were associated with schizophrenia in the dominant (P = 0.019, OR = 1.79, 95% CI = 1.10–2.90) and recessive models, respectively (P = 0.0086, OR = 0.51, 95% CI = 0.31–0.84). In further analysis according to the clinical symptoms, rs2292305 showed a weak association with the poor concentration symptoms of schizophrenia patients in the dominant model (AG/GG vs. AA, P = 0.024, OR = 2.04, 95% CI = 1.09–3.83). The results suggest that the THBS1 gene may contribute to the susceptibility of schizophrenia.     

A common variant in the adiponectin gene and polycystic ovary syndrome risk

In this study, we explored whether polymorphisms in insulin receptor (INSR), adiponectin (ADIPOQ), parathyroid hormone (PTH), and vitamin D receptor (VDR) genes are associated with polycystic ovary syndrome (PCOS). A total of 362 subjects, including 181 women with PCOS and 181 controls were enrolled in this case-control study. Two SNPs (rs2059806 and rs1799817) in the INSR gene, two SNPs (rs2241766 and rs1501299) in the ADIPOQ gene, one SNP (rs6256) in the PTH gene, and one SNP (rs757343) in the VDR gene were analyzed using PCR-RFLP method. We observed no significant difference in genotype and allele frequencies between the women with PCOS and controls for the rs2059806, rs1799817, rs1501299, rs6256, and rs757343 polymorphisms either before or after adjustment for confounding factors including age and BMI. However, the ADIPOQ rs2241766 “TT” genotype compared with “TG and GG” genotypes was associated with a 1.93-fold increased risk for PCOS (P = 0.006, OR = 1.93, 95% CI = 1.20–3.11), and the differences remained significant after adjustment for age and BMI (P = 0.039, OR = 1.72, 95% CI = 1.03–2.86). Furthermore, the ADIPOQ rs2241766 “T” allele was significantly overrepresented in women with PCOS than controls (P = 0.006; OR = 1.80, 95% CI = 1.18–2.70), and the difference remained significant after Bonferroni correction. Our findings suggest that the ADIPOQ rs2241766 “TT” genotype is a marker of increased PCOS susceptibility. This study also indicates for the first time that there are no significant association between INSR rs2059806, PTH rs6256, and VDR rs757343 gene polymorphisms and PCOS risk. However, these data remain to be confirmed in larger studies and in other populations.     

Genetic variants in the 8q24 locus and risk of testicular germ cell tumors

Much evidence supports the premise that population genetic variation contributes significantly to the risk of testicular germ-cell tumor (TGCT). However, investigations of the association between genomic markers and TGCT susceptibility are scarce. Single nucleotide polymorphisms (SNPs) at the locus 8q24 have recently been found to be associated with prostate, colorectal and breast cancer. The US Servicemen’s testicular tumor environmental and endocrine determinants (STEED) study was used to investigate the association of 15 specific 8q24 SNPs with TGCT and its two main histologic groups of seminoma and nonseminoma. Conditional and unconditional logistic regression models, adjusted for the matching variables of year of birth, race/ethnicity and serum date, were utilized to produce odds ratios (OR) and 95% confidence intervals (95%CI). The analysis included 680 controls and 568 TGCT cases. In the TGCT analysis, no SNP was associated with risk in both heterozygotes and variant homozygotes. When stratified by histology the seminoma analysis also showed no association with the 8q24 SNPs. Conversely, the analysis of nonseminomas had three tentative associations (rs6470494, OR_{genotype AG} = 1.15, 95%CI: 0.86–1.54; OR_{genotype GG} = 1.68, 95%CI: 1.04–2.73; p for trend = 0.04) (rs13254738, OR_{genotype GT} = 1.04, 95%CI: 0.77–1.40; OR_{genotype TT} = 1.62, 95%CI: 1.06–2.49; p for trend = 0.07) (rs10505476, OR_{genotype CT} = 0.67, 95%CI: 0.50, 0.91; OR_{genotype TT} = 0.81, 95%CI: 0.47–1.39; p for trend = 0.04). There was no linkage disequilibrium between any of the 8q24 SNPs analyzed in this population. In conclusion, this study has found little evidence for an association between the reported 8q24 SNPs and TGCTs, although the findings for nonseminoma may be worth further investigation.