The Association between the Polymorphisms in a Sodium Channel Gene SCN7A and Essential Hypertension: A Case‐Control Study in the Northern Han Chinese

Na_x, an α‐subunit of the sodium channel encoded by the SCN7A gene, has been deemed to be a sensor of the concentration of sodium in the brain and may be involved in salt intake behavior. We inferred that Na_x/SCN7A may participate in the regulation of blood pressure and the pathogenesis of essential hypertension (EH). The present case‐control study involving 615 hypertensives and 617 normotensives was performed to investigate the association between SCN7A polymorphisms and EH in the Northern Han Chinese population. The three common single nucleotide polymorphisms (SNPs) (rs3791251, rs6738031, rs7565062) in the exons of SCN7A were genotyped with the TaqMan assay. Significant association between SNP rs7565062 and EH was found under the addictive and dominant genetic models (P = 0.024, OR = 1.283, 95%CI [1.033–1.592]; P = 0.013, OR = 1.203, 95%CI [1.040–1.392]; respectively). The three SNPs were in close pair‐wise linkage disequilibrium with each other and the haplotype analyses indicated that haplotype G–A–T was significantly associated with increased risk of EH (P = 0.023, OR = 1.290). In conclusion, our data showed that SNP rs7565062 of SCN7A was significantly associated with EH and the allele T of rs7565062 or the related haplotype G–A–T will be a genetic risk factor for EH in the Northern Han Chinese population.     

Association between the Interleukin‐6 Gene −572 C/G Polymorphism and the Risk of Type 2 Diabetes Mellitus: A Meta‐Analysis of 11,681 Subjects

The association between the interleukin‐6 (IL‐6) gene ?572 C/G (rs1800796) polymorphism and type 2 diabetes mellitus (T2DM) risk remains controversial. Thus, we performed this meta‐analysis by searching PubMed, Embase, Web of Science, CBMdisc and CNKI databases until January 30, 2012. In addition, hand searching of the references of identified articles was performed. A total of 10 case–control studies including 11,681 subjects were selected to evaluate the possible association. Our results showed evidence for significant association between the IL‐6 gene ?572 C/G polymorphism and T2DM risk (for G allele vs. C allele: odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09–1.52, P = 0.002, P = 0.008 after Bonferroni testing; for G/G vs. C/C: OR = 1.89, 95% CI = 1.51–2.37, P < 0.00001, P < 0.00004 after Bonferroni testing; for GG vs. G/C + C/C: OR = 1.75, 95% CI = 1.20–2.56, P = 0.004, P = 0.016 after Bonferroni testing; for G/G + G/C vs. C/C: OR = 1.32, 95% CI = 1.11–1.57, P = 0.001, P = 0.004 after Bonferroni testing). In addition, similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta‐analysis suggests a significant association between the IL‐6 gene ?572 G allele and increased risk of T2DM.     

Ethnicity‐Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma: A Meta‐Analysis

Pseudoexfoliation (PEX) is an age‐related disorder of the extracellular matrix; it is strongly associated with glaucoma, the leading cause of irreversible blindness worldwide. We conducted an ethnic‐based meta‐analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG). Association studies were retrieved systematically from PubMed, EMBASE, and Web of Knowledge. Allelic and genotype frequencies of rs3825942, rs1048661, and rs2165241 were compared between PEX/PEXG and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Overall, 39 independent cohorts were included. Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06–0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02–0.06) and Koreans (OR = 0.10, 95%CI:0.05–0.22). These associations we‐re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22–17.41) and Koreans (OR = 6.63, 95%CI:2.60–16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups.     

Erratum: Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population

Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medical disorders with stress and genetic components. Dysregulation of the stress response of the hypothalamic–pituitary–adrenal axis, including the corticotrophin‐releasing hormone (CRH) signaling via primary receptors (CRHR1 and CRHR2), is considered to play a major role for onset and recurrence in MDD and PD. To confirm the association of CRHR1 and CRHR2 with MDD and PD, we investigated 12 single nucleotide polymorphisms (SNPs) (rs4076452, rs7209436, rs110402, rs242924, rs242940, and rs173365 for CRHR1 and rs4722999, rs3779250, rs2267710, rs1076292, rs2284217, and rs226771 for CRHR2) in MDD patients (n = 173), PD patients (n = 180), and healthy controls (n = 285). The SNP rs110402 and rs242924 in the CRHR1 gene and the rs3779250 in the CRHR2 gene were associated with MDD. The SNP rs242924 in the CRHR1 gene was also associated with PD. The T–A–T–G–G haplotype consisting of rs7209436 and rs173365 in CRHR1 was positively associated with MDD. The T–A haplotype consisting of rs7209436 and rs110402 in CRHR1 was positively associated with MDD. The C–C haplotype consisting of rs4722999 and rs3779250 in CRHR2 was associated with PD. These results provide support for an association of CRHR1 and CRHR2 with MDD and PD. © 2012 Wiley Periodicals, Inc.     

Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Here, we report on a case–control association study of 178 SLE patients and 899 control subjects, using genome-wide gene-based single nucleotide polymorphism (SNP) markers. An SNP, rs3130342, in a 5’ flanking region of the TNXB gene revealed a significant association with SLE [P = 0.000000930, odds ratio (OR) 3.11, with 95% confidence interval (95%CI) of 1.89–5.28] in a Japanese population. This association was replicated independently with 203 cases and 294 controls (P = 0.0440, OR 1.52, with 95%CI of 1.01–2.78). Although a copy number variation (CNV) of the C4 gene adjacent to the TNXB gene was reported to be associated with SLE, our analysis on this CNV revealed that the association of CNV of the C4 gene was weaker than the SNP in the TNXB gene and likely to reflect the linkage disequilibrium between C4 CNV and this particular SNP. Stratified analysis also revealed that the association of SNP rs3130342 with SLE was independent of the HLA-DRB1*1501 allele that has been shown to be associated with SLE. Our findings strongly imply that the TNXB gene is a candidate gene susceptible to SLE in the Japanese population. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association of the Vascular Endothelial Growth Factor Gene Polymorphisms (–460C/T, +405G/C and +936T/C) with Endometriosis: A Meta‐Analysis

Published data on the association between the vascular endothelial growth factor (VEGF) gene –460C/T (rs833061), +405G/C (rs2010963), +936T/C (rs3025039) polymorphisms and endometriosis risk are inconclusive. Eleven eligible case‐control studies including 2690 cases and 2803 controls were included in this meta‐analysis through searching the databases of PubMed and CBMdisc (up to August 1, 2011). In the overall analysis, no significant association between the –460C/T and +405G/C polymorphisms and risk of endometriosis was observed. However, significant associations were observed between endometriosis risk and VEGF+936T polymorphism with summarized odds ratio of 1.19 (95%CI, 1.02–1.37), 1.18 (95%CI, 1.03–1.37), 1.15 (95%CI, 1.01–1.30) for CT versus CC genotype, dominant mode (CT/TT vs. CC) and allele comparison (T vs. C), respectively. Furthermore, stratified analysis showed that significantly strong association between +936T/C polymorphism and endometriosis was present only in stage III–IV (OR = 1.32 for dominant mode; OR = 1.30 for T vs. C), but not in stage I–II. However, no significantly increased risk of endometriosis was found in any of the genetic models in Asians or in Caucasians. This meta‐analysis supports that VEGF+936T/C polymorphism is capable of causing endometriosis susceptibility.     

A Tryptophan Hydroxylase 2 Gene Polymorphism is Associated with Panic Disorder

Panic disorder (PD) is a complex and heterogeneous psychiatric condition. Dysfunction within the serotonergic system has been hypothesized to play an important role in PD. The novel brain-specific serotonin synthesizing enzyme, tryptophan hydroxylase 2 (TPH2), which represents the rate-limiting enzyme of serotonin production in the brain, may therefore be of particular importance in PD. We investigated the TPH2 703G/T SNP for association with PD. Patients with PD (n = 108), and control subjects (n = 247), were genotyped for rs4570625 (TPH2 703G/T). Male and female subjects were analyzed separately. The severity of their symptoms was measured using the Spielberger state-trait anxiety inventory (STAI), panic disorder severity scale (PDSS), anxiety sensitivity index (ASI), acute panic inventory (API), and Hamilton’s rating scale for depression (HAMD). The genotype and allele frequencies of the PD patients and controls were analyzed using χ ² statistics. There was a significant difference in the allele frequency in rs4570625 between the PD patients and normal controls. The T allele was significantly less frequent in the PD patients. We also found a significant association with rs4570625 in the female subgroup. There was no difference in symptom severity among the genotypes of this polymorphism. This result suggests that rs4570625 polymorphism may play a significant role in the pathogenesis of PD. Moreover, rs4570625 may have a gender-dependent effect on susceptibility to PD. Further studies are needed to replicate the association that we observed. Edited by Tatiana Foroud.     

Association analysis between functional polymorphism of the rs4606 SNP in the RGS2 gene and antipsychotic-induced Parkinsonism in Japanese patients with schizophrenia: Results from the Juntendo University Schizophrenia Projects (JUSP)

Antipsychotic-induced extrapyramidal symptoms (AIEPSs) are commonly recognized side effects of typical 1st generation antipsychotics, and considerable variability is seen in the susceptibility of individual patients to AIEPSs. Regulator of G-protein signaling 2 (RGS2) proteins regulate intracellular signaling and second messenger activation of molecules including dopamine, serotonin, and acetylcholine receptors, all of which appear to be involved in the pathophysiology of AIEPSs. Previous studies have shown an association between AIEPSs in schizophrenia and RGS2, especially the minor G allele of single nucleotide polymorphism (SNP) rs4606 (+2971C > G) in RGS2, and have suggested a possible protective effect by the G allele on AIEPSs. In this study, we investigated whether the rs4606 SNP in RGS2 alone also showed an effect on AIEPSs by utilizing the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) in 103 Japanese patients with schizophrenia. In the assumed G allele recessive model, sialorrhea and total Parkinsonism scores were significantly higher in subjects with the GG genotype than in subjects with other genotypes. Other clinical variables were not significantly different among the various genotype groups. Controlling for clinical variables as covariates, a one-way analysis of covariance found no association between rs4606 genotypes and DIEPSS scores. Taken together, these results, although preliminary, suggest that rs4606 does not affect AIEPSs in Japanese subjects.     

Associations of the 5‐hydroxytryptamine (serotonin) Receptor 1B gene (HTR1B) with alcohol,cocaine, and heroin abuse

Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5‐hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5‐HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta‐analysis based on the available genotype data from individual candidate gene‐based association studies. Evidence of association was found between the functional SNP ?161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio (OR) = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP ?261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non‐Europeans (e.g., P = 0.0018 with OR = 1.42 (1.14, 1.76) and P = 0.01 with ORs = 0.5 (0.3, 0.85), respectively). This meta‐analysis supports the associations of HTR1B ?261T>G and ?161A>T with alcohol and drug abuse and further investigations are warranted in larger samples. © 2013 Wiley Periodicals, Inc.     

Genome‐Wide Association Study Confirms SNPs in SNCA and the MAPT Region as Common Risk Factors for Parkinson Disease

Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome‐wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome‐wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p‐value = 6.7 × 10^?8; genome‐wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17–1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p‐value = 5.6 × 10^?8; genome‐wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62–0.79] T vs. C allele, PAR%= 8%) were genome‐wide significant. No other SNPs were genome‐wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.     

Single nucleotide polymorphisms rs911160 in AURKA and rs2289590 in AURKB mitotic checkpoint genes contribute to gastric cancer susceptibility

Background: Single nucleotide polymorphisms (SNPs) in mitotic checkpoint genes could confer increased susceptibility to gastric cancer (GC). We investigated the association of Aurora kinase A (AURKA), Aurora kinase B (AURKB), Aurora kinase C (AURKC), Polo‐like kinase 1 (PLK1) and Budding uninhibited by benzimidazol 3, yeast (BUB3) gene polymorphisms with GC risk. Materials and methods: Genotyping of 6 SNPs in AURKA (rs911160 and rs8173), AURKB (rs2289590), AURKC (rs11084490), PLK1 (rs42873), and BUB3 (rs7897156) was performed using TaqMan genotyping assays. Results: Our study demonstrated that rs911160 (AURKA) heterozygous genotype was associated with an increased GC risk (OR = 1.50, 95% CI = 1.01‐2.22, P = 0.043). Analysis of rs911160 (AURKA) showed significant association with an increased risk for intestinal type GC (OR = 1.80, 95%CI = 1.01–3.21, P = 0.040) and the risk was significantly higher in women than men (OR = 2.65, 95%CI = 1.02–6.87, P = 0.033). SNP rs2289590 in AURKB might contribute to susceptibility for the development of gastric cancer, particularly in women (OR = 2.08, 95% CI = 1.05–4.09, P = 0.032). Conclusion: Our findings suggested that AURKA (rs911160) and AURKB (rs2289590) polymorphisms could affect GC risk. Further validation studies in larger and multi‐ethnical populations are needed to elucidate their functional impact on the development of GC. Environ. Mol. Mutagen. 58:701–711, 2017. © 2017 Wiley Periodicals, Inc.     

Potential Positive Association between Cytochrome P450 1A1 Gene Polymorphisms and Recurrent Pregnancy Loss: a Meta‐Analysis

In order to discover the potential genetic risks associated with recurrent pregnancy loss (RPL), this meta‐analysis was conducted to assess the association between CYP1A1 gene polymorphism and RPL. Studies were retrieved from the databases PubMed, Embase, HuGENet, and CNKI. Four models were then applied. Seven studies, including three datasets for the rs1048943 and five for the rs4646903 single‐nucleotide polymorphism (SNP), were included in this analysis, involving 613 cases and 398 controls for the rs1048943; and 864 cases and 842 controls for the rs4646903 SNP. After comprehensive analysis, we found that rs4646903 was significantly associated with RPL [recessive (OR = 1.72, 95%CI: 1.13–2.61); codominant (CC vs TT; OR = 1.74, 95%CI: 1.12–2.71), (CC vs CT; OR = 1.67, 95%CI: 1.07–2.62) and allele analysis (OR = 1.27, 95%CI: 1.07–1.50)]. In the following subgroup analysis, a positive association was also discovered among people of Asian descent, especially South Asians. However, there was no obvious association between rs1048943 and RPL. In summary, our results suggest that CYP1A1 gene polymorphism (particularly for rs4646903) might be associated with RPL risk, especially among South Asians. Further studies are required to confirm this association.     

Single nucleotide polymorphisms of ataxia telangiectasia mutated and the risk of papillary thyroid carcinoma

Genetic factors associated with susceptibility to papillary thyroid carcinoma (PTC) are not well known. We evaluated the association between single nucleotide polymorphisms (SNPs) of ataxia telangiectasia mutated (ATM) and the risk of PTC. A total of 437 histologically confirmed PTC cases and 184 cancer‐free controls without thyroid nodules were recruited. Genotypes with respect to five ATM SNPs (rs189037, rs664677, rs373759, rs664143, and rs4585) were determined by the TaqMan assay, and odds ratios and 95% confidence intervals were obtained by logistic regression analysis. Linkage disequilibria and haplotypes were examined from the genotype data. When evaluated separately the genotype distributions of the five ATM SNPs were similar in the PTC cases and controls. Three ATM SNPs (rs373759, rs664143, and rs4585) were found to be in strong linkage disequilibrium (D′ = 1.00, P < 0.001). When the three haplotypes (C‐A‐G), (T‐G‐T), and (C‐G‐T) of these three ATM SNP sites were analyzed, ATM haplotype (C‐G‐T) +/? was associated with a lower risk of PTC than ATM haplotype (C‐G‐T) ?/? (P = 0.03) after adjusting for age and gender. Our results suggest that genetic polymorphisms of ATM may play an important role in the development of thyroid cancer in the Korean population. Environ. Mol. Mutagen. 56:70–76, 2015. © 2014 Wiley Periodicals, Inc.     

Ficolin Gene Polymorphisms in Systemic Lupus Erythematosus and Rheumatoid Arthritis

Systemic lupus erythemathosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases characterized by an immune balance breakdown and by chronic inflammation. Several findings link SLE and RA development with the complement system and ficolin components have emerged as candidates for disease development. Since genetic association studies with ficolin genes in SLE and RA have not yet been conducted in a Brazilian population, the aim of this study was to determine whether polymorphisms of ficolin‐1(FCN1) and ficolin‐2 (FCN2) genes are associated with SLE and RA susceptibility as well as disease manifestation. Two SNPs within FCN1 (rs2989727 and 1071583) and three in FCN2 (rs17514136, rs3124954, and rs7851696) were studied in 208 SLE and184 RA patients as well as 264 healthy individuals in a Southeast Brazilian population. For SLE patients, the FCN2 rs17514136 SNP was associated with a more severe disease (SLICC) (p = 0.0067). Furthermore, an association between the occurrence of nephritis and the T/T genotype for FCN2 rs3124954 SNP (p = 0.047, OR = 3.17, 95%CI = 1.34–7.5) was observed. No association was observed between the studied polymorphisms and RA development. Thus, our data support involvement of the FCN2 gene in the SLE phenotype.     

Association of CC chemokine ligand 5 genotype with urinary albumin excretion in the non-diabetic Japanese general population: the Takahata study

Albuminuria is an early marker of vascular damage, and its development in diabetic nephropathy is associated with genotype of inflammatory CC chemokine ligand 5 (CCL5). This study investigated whether the association of CCL5 and albuminuria is a general phenomenon. We characterized a Japanese population consisting of 2,749 non-diabetic individuals over 40 years in Takahata, Japan. The urine albumin-creatinine ratio (UACR) was obtained from morning spot urine. We genotyped SNPs within the CCL5 gene that displayed frequent minor allele frequencies in Japanese (i.e., rs2107538, rs2280789, rs3817655 and rs9909416). Assessment of possible association and linkage disequilibrium (LD) revealed that all four SNP genotypes are correlated significantly with UACR (P = 0.004–0.005), and these four SNPs variations showed an obvious consistency of genotypes by detecting almost complete linkage disequilibrium (D′ = 1 and r ² > 0.95). We found two exclusive haplotypes in the CCL5 gene (haplotype1: rs2107538G/rs2280789T/rs3817655T/rs9909416G, frequency 0.64 and haplotype2: rs2107538A/rs2280789C/rs3817655A/rs9909416A, frequency 0.35) among the population. A significant association with elevated UACR was identified with haplotype1 (P = 0.002). Homozygotes for haplotype1 displayed strikingly-elevated UACR (48.5 ± 6.6 mg/g, n = 1,116) compared to the rest (28.6 ± 1.6 mg/g, n = 1,530) (P = 0.001). In conclusion, these results suggested that genetic variation of CCL5 might be an important risk factor for albuminuria in the non-diabetic Japanese general population. Sources of support: A grant-in-aid from the 21st Century Center of Excellence (COE) Program of the Japan Society for the Promotion of Science and a grant-in-aid for Scientific Research (no. 14770546) from the Ministry of Education, Science, Sports and Culture, Japan.     

Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer

Objectives: The aims of this study are to (1) study the influence of polymorphisms in adiponectin gene on adiponectin levels and potential associations with breast, prostate and colon cancer; (2) investigate the associations of adiponectin levels with other adipokines and breast, prostate and colon cancers. Subjects: We measured fasting adiponectin, leptin, insulin, Sex steroids in 132 (66 females, 66 males) cancer patients and 68 age and sex matched apparently healthy subjects. Body Mass Index (BMI) and waist circumference were used as indices of obesity. Insulin Resistance was assessed using Homeostasis Model Assessment (HOMA). Three single nucleotide polymorphisms (SNP rs182052 (G-10066-A), SNP rs1501299 (276G > T), SNP rs224176 (45T > G) in adiponectin gene were studied using Real Time Polymerase Chain Reaction. Results: GG genotype of SNP rs1501299 was significantly associated with higher levels of adiponectin (OR=1.2, 95%CI(1.03–1.3), p = 0.02); breast (OR=8.6, 95%CI(1.03–71), p = 0.04), colon cancers (OR= 12, 95%CI(1.2–115), p = 0.03). GT genotype was also associated significantly with colon cancer (OR=2.6, 95%CI (1.1–6), p = 0.03). However SNP rs224176 was associated with only breast cancer. Conclusion: Our results demonstrate that adiponectin gene SNP rs1501299 and SNP rs224176 may be the predisposing factors in some cancers but our results differ from what has been reported in other populations suggesting a complex relationship between genetic variations and phenotypic adiponectin levels.     

Genetic Variation in the Peroxisome Proliferator‐Activated Receptor (PPAR) and Peroxisome Proliferator‐Activated Receptor Gamma Co‐activator 1 (PGC1) Gene Families and Type 2 Diabetes

We used a two‐stage study design to evaluate whether variations in the peroxisome proliferator‐activated receptors (PPAR) and the PPAR gamma co‐activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with type 2 diabetes (T2D) risk. Stage I used data from a genome‐wide association study (GWAS) from Shanghai, China (1019 T2D cases and 1709 controls) and from a meta‐analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN‐T2D). Criteria for selection of single nucleotide polymorphisms (SNPs) for stage II were: (1) P < 0.05 in single marker analysis in Shanghai GWAS and P < 0.05 in the meta‐analysis or (2) P < 10^?3 in the meta‐analysis alone and (3) minor allele frequency ≥ 0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle‐aged men and women from Shanghai with 1700 T2D cases and 1647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR = 0.87; 95% CI: 0.77–0.99). Gene‐body mass index (BMI) and gene–exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2719 cases and 3356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed.     

Association of Cytokine Gene Polymorphisms in Patients with Tuberculosis and Their Household Contacts

Cytokine gene polymorphisms are known to be associated with functional differences in cytokine regulation and may affect host susceptibility to tuberculosis (TB). Contacts are important group in developing tuberculosis infection and are 10–60 times more likely to develop TB than general population. The present study was carried out in patients with TB (N = 176), their household contacts (HHC; N = 155) from Free Chest TB Clinic PPM DOTS (1TU) covering 500,000 population at Mahavir Hospital and Research Centre, Hyderabad, and healthy controls (HC; N = 170) also included. The association of single‐nucleotide polymorphisms (SNPs) in the promoter region of TNF‐α (?308G/A), IL‐2 (?330T/G), IL‐4 (?589C/T) and in exon region of TGF‐β1 (+869T/C) genes was assessed by ARMS & PCR‐RFLP using specific primers in the above‐mentioned subjects. The differences in allelic or genotypic frequencies of TNF‐α (?308G/A) between patients, their HHC and HC were not statistically significant (P > 0.05). IL‐2 (?330T/G) TG genotype was significantly different between patients, HHC compared to HC (P < 0.002, OR‐1.997, 95%CI‐1.260‐3.168, P < 0.03, OR‐1.602, 955CI‐1.003‐2.561).IL‐4 (?589C/T) CC genotype was significantly different between patients and HC (P < 0.03, OR‐1.791, 95%CI‐1.009‐3.189) as well as between HHC and HC at P < 0.0001, OR‐2.56, 95%CI‐1.448‐4.545. In addition, the TGF‐β 1 (+869T/C) TC genotype was significantly associated with susceptibility to tuberculosis in patients when compared against HC(P < 0.0001, OR‐3.416, 95%CI‐2.063‐5.670) and HHC (P < 0.0001, OR‐2.357, 95%CI‐1.439‐3.868), respectively.MDR analysis indicated that TT genotype of TGF‐β1 with TT and CT genotypes of IL‐4 showed high risk with GA, TT genotypes of TNF‐α, IL‐2, respectively. Our results suggest that IL‐2 (‐330T/G), IL‐4 (‐589 C/T) and TGF‐β1 (+869T/C) gene polymorphisms may be associated with TB susceptibility.     

SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians

Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5′ region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P = 0.01, OR = 1.25 95%CI 1.05–1.48, and P = 0.02, OR = 1.17 95%CI 1.02–1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N = 243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P = 0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P = 0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity.     

Two Rare Variants Explain Association with Acute Myocardial Infarction in an Extended Genomic Region Including the Apolipoprotein(A) Gene

Relatively low numbers of kringle 4 type 2 repeats in apolipoprotein(a) and specific haplotypes of the SLC22A3‐LPAL2‐LPA region on chromosome 6 are associated with an increased risk of coronary disease. We examined the possibility that rs3798220 and rs10455872, short variations located in LPA [the apolipoprotein(a) gene], and related to the number of kringle 4 type 2 repeats, may serve as markers for the association between haplotypes and acute myocardial infarction. Genotypes were determined with TaqMan assays in a sample of 2136 cases and 1211 controls. The minor alleles of rs3798220 and rs10455872 were associated with increased risks (rs3798220‐C: adjusted OR 2.14, 95% CI, 1.37–3.33, P = 0.00080; rs10455872‐G: adjusted OR 1.74, 95% CI 1.36–2.24, P < 0.00001). After adjustments were made for potential confounders, none of nine polymorphisms included in a haplotype analysis were singly related to disease. Two risk haplotypes were identified; one (CCTTGTGTG; OR 1.25, 95% CI 1.08–1.45, P = 0.0022) was correlated with rs3798220‐C and the other (CCCTGGATC; OR 1.65, 95% CI 1.14–2.38, P = 0.0074) with rs10455872‐G. Thus, the findings allowed for a more precise definition of risk‐associated markers: specific nucleotides in LPA instead of standard haplotypes defined by noneffective variants from the extensive SLC22A3‐LPAL2‐LPA region.