Single Nucleotide Polymorphisms Rs7903146 Research Articles

Genetic variations in IL6 and IL12B decreasing the risk for psoriasis

BackgroundPsoriasis is a chronic inflammatory skin disorder. Recent studies associated a number of genetic variants to this immune-mediated pathology. ObjectiveThis study aims to assess whether the association between the non-susceptibility allelic variants of IL12B single-nucleotide polymorphism (SNPs) rs3212227 and rs6887695, IL23R SNPs rs11209026 and rs7530511, IL6 SNP rs1800795 and HLA-Cw6 could be correlated with decreased risk for psoriasis. Material and methodsWe genotyped 67 psoriasis patients and 69 healthy subjects for polymorphisms of IL12B rs3212227 and rs6887695, IL23R rs11209026 and rs7530511, IL6 rs1800795 and for the presence of HLA-Cw6. The patients and controls were recruited from Dermatology Department, part of “Tor Vergata” Clinic, Rome. Demographic data of the control group matched those of psoriasis patients, with a female:male ratio of 2.55 and mean age of 45.5±12.2 years for patients and 44.8±11.7 years for controls. ResultsThe following genotypes were less frequent in patients: IL12B SNP rs6887695 CC (OR, 0.179; CI95% 0.046–0.699; p=0.01), IL6 SNP rs1800795 CG (OR, 0.367; CI95% 0.179–0.753; p=0.006) and IL6 SNP rs1800795 CC (OR, 0.069; CI95% 0.008–0.586; p=0.01). Also the HLA-Cw6 allele was rarely found in controls (OR, 0.459; CI95% 0.230–0.916; p=0.02). The multivariate analysis showed that the existence of at least one C allele in both IL12B SNP rs6887695 and IL6 SNP rs1800795 or the absence of HLA-Cw6 allele and at least one C allele in IL12B SNP rs6887695 or IL6 SNP rs1800795 is associated with a lower risk of psoriasis (OR, 0.185; CI95% 0.037–0.929; p=0.04). The presence of at least one C allele in both IL12B SNP rs6887695 and IL6 SNP rs1800795 and the absence of HLA-Cw6 allele decreased even further the risk of psoriasis (OR, 0.038; CI95% 0.006–0.244; p=0.001). ConclusionWe report carriers of variations in the IL6, IL12B and absence of HLA-Cw6 as having decreased risk for psoriasis.

VDR Gene Polymorphisms, Interaction with Smoking and Risk of Periodontal Disease in Japanese Women: the Kyushu Okinawa Maternal and Child Health Study

Epidemiological evidence on the relationship between vitamin D receptor (VDR) polymorphisms and periodontal disease is inconsistent. We investigated associations between four VDR single-nucleotide polymorphisms (SNPs) including rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI) and rs2228570 (FokI), and the risk of periodontal disease among young Japanese women. Cases included 131 women who had at least one tooth with a probing depth of 3.5mm or deeper. Controls included 1019 women without periodontal disease. Adjustment was made for age, region of residence, education, toothbrushing frequency and use of an interdental brush. Compared with the AA genotype of SNP rs731236, the GG genotype had a significantly increased risk of periodontal disease: the adjusted OR was 3.68 (95% confidence interval: 1.06-12.78). There were no significant relationships between SNPs rs7975232, rs1544410 or rs2228570 and periodontal disease. None of the haplotypes were significantly related to periodontal disease. Compared with subjects with the AA or AG genotype of SNP rs731236 who had never smoked, those with the GG genotype who had ever smoked had a significantly increased risk of periodontal disease; nevertheless, neither multiplicative nor additive interaction was significant. The additive interaction between SNP rs7975232 and smoking was significant, although the multiplicative interaction was not statistically significant. No multiplicative or additive interactions were observed between the other SNPs and smoking. Our results indicated that VDR SNP rs731236 might be associated with periodontal disease. In addition, we present new evidence for a biological interaction between VDR SNP rs7975232 and smoking that affects periodontal disease.

FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients

Obesity is a major health problem worldwide. Associations of obesity with common variants of the fat mass- and obesity-associated gene (FTO) and insulin-induced gene 2 (INSIG2) have been reported in various studies. We aimed to further investigate the association of 2 single nucleotide polymorphisms (SNPs), rs9939609 in FTO and rs7566605 in INSIG2, with body mass index (BMI) and other anthropometric and metabolic parameters in subjects with morbid obesity (BMI ≥40). SNPs rs9939609 and rs7566605 were genotyped in 124 unrelated morbidly obese patients (mean BMI = 50, range 40.1-77.1) from Mainz, Germany, and in 253 normal controls without a history of morbid obesity. Metabolic and anthropometric parameters were analyzed in 109 of the 124 patients, and associations with the genotype data were examined. The high-risk AA genotype for FTO rs9939609 was observed in 32.3% of patients versus 15.8% of controls (p = 0.0004) and was associated with an increased obesity risk [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.53-4.21]. The intermediate-risk AT genotype was found in patients and controls at similar frequencies (48.4 vs. 48.6%, OR = 0.99). The low-risk TT genotype for rs9939609 was found in 19.4% of patients (35.5% of controls; p = 0.0013) and was associated with a decreased risk for morbid obesity (OR = 0.43, CI = 0.26-0.73). In contrast, INSIG2 rs7566605 showed no association with obesity in our patients. Evaluation of metabolic data indicated associations between the high-risk FTO genotype (rs9939609_AA) and increased levels of serum glutamic oxaloacetic transaminase (GOT) and between the high-risk INSIG2 genotype (rs7566605_CC) and lower waist-to-hip ratio and lower hemoglobin A1c (HbA1c) levels. Our results confirm an association of the FTO SNP with extreme obesity. However, we found no association of the potential obesity risk allele of INSIG2 in our sample and thus cannot confirm an association of the INSIG2 CC genotype with obesity. We identified an association between the high-risk FTO genotype (rs9939609_AA) and higher GOT levels, which could possibly reflect the increased frequency of nonalcoholic steatohepatitis with obesity. We also detected associations of the high-risk INSIG2 genotype (rs7566605_CC) with lower waist-to-hip ratios and lower HbA1c levels, which may indicate amelioration of impaired glucose tolerance and type 2 diabetes for patients with this genotype after bariatric surgery.

Association between 9p21.3 genomic markers and coronary artery disease in East Asians: a meta-analysis involving 9,813 cases and 10,710 controls

Recently, genome-wide association studies on Coronary Artery Disease (CAD) identified a series of associated Single-Nucleotide Polymorphisms (SNPs) in an intergenic region of chromosome 9p21.3, near the CDKN2A and CDKN2B genes. We investigated the association of this locus with CAD in 12 case–control studies of East Asians and undertook a meta-analysis for effect size, heterogeneity, publication bias, and strength of evidence. English and Chinese language articles were tested for 9p21.3 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an Odds Ratio (OR). Articles were excluded if reporting other outcomes (e.g., stroke). Thirty-five articles were initially identified and 12 were included. Independent extraction was performed by two reviewers and consensus was reached. SNP rs1333049, rs2383206 and rs10757278 representing the 9p21.3 locus, were genotyped in 12 case–control studies involving a total of 9,813 patients and 10,710 controls. For rs1333049 (8 data sets), using a fixed-effects model, the summary OR was 1.29 (95% CI, 1.23–1.36, P = 0.001). For rs2383206 (6 data sets), using a fixed-effects model, the summary OR was 1.24 (95% CI, 1.18–1.31, P = 0.001). For rs10757278 (6 data sets), using a random-effects model, the summary OR was 1.34 (95% CI, 1.21–1.50, P = 0.001). In addition, we defined the haploblock structure of SNPs within the region of 9p21.3 in China population in one study. This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD in East Asians.

Association of adiponectin promoter variants with traits and clusters of metabolic syndrome in Arabs: Family-based study

Plasma levels of adiponectin are decreased in type 2 diabetes, obesity and hypertension. Our aim was to use a family-based analysis to identify the genetic variants of the adiponectin (ADIPOQ) gene that are associated with obesity, insulin resistance, dyslipidemia and hypertension, among Arabs. We screened 328 Arabs in one large extended family for single nucleotide polymorphisms (SNPs) in the promoter region of the ADIPOQ gene. Two common SNPs were detected: rs17300539 and rs266729. Evidences of association between traits related to the metabolic syndrome and the SNPs were studied by implementing quantitative genetic association analysis. Results showed that SNP rs266729 was significantly associated with body weight (p-value=0.001), waist circumference (p-value=0.037), BMI (p-value=0.015) and percentage of total body fat (p-value=0.003). Up to 4.1% of heritability of obesity traits was explained by the rs266729 locus. Further cross-sectional analysis showed that carriers of the G allele had significantly higher values of waist circumference, BMI and percentage of total body fat (p-values 0.014, 0.004 and 0.032, respectively). No association was detected between SNP rs266729 and other clusters of metabolic syndrome or their traits except for HOMA-IR and fasting plasma insulin levels, p-values 0.035 and 0.004, respectively. In contrast, both measured genotype and cross-sectional analysis failed to detect an association between the SNP rs17300539 with traits and clusters of metabolic syndrome. In conclusion, we showed family-based evidence of association of SNP rs266729 at ADIPOQ gene with traits defining obesity in Arab population. This is important for future prediction and prevention of obesity in population where obesity is in an increasing trend.

Polymorphisms in FTO and MAF Genes and Birth Weight, BMI, Ponderal Index, Weight Gain in a Large Cohort of Infants with a Birth Weight below 1500 Grams

BackgroundThe FTO gene, located on chromosome 16q12.2, and the MAF gene, located on chromosome 16q22-23, were identified as genes harboring common variants with an impact on obesity predisposition. We studied the association of common variants with birth weight, gain of body weight, body mass index (BMI), Ponderal index and relevant neonatal outcomes in a large German cohort of infants with a birth weight below 1500 grams.MethodsThe single nucleotide polymorphisms rs9939609 (FTO gene) and rs1424233 (MAF gene) were genotyped using allelic discrimination assays in a prospective multicenter cohort study conducted in 15 neonatal intensive care units in Germany from September 2003 until January 2008. DNA samples were extracted from buccal swabs according to standard protocols.Results1946 infants were successfully genotyped at FTO and 2149 infants at MAF. Allele frequencies were not significantly different from other European cohorts. The polymorphisms were in Hardy-Weinberg equilibrium. The polymorphisms did not show associations with birth weight, BMI and Ponderal Index at discharge, and weight gain, neither testing for a dominant, additive nor for a recessive model.DiscussionSince an association of the polymorphisms with weight gain has been demonstrated in multiple populations, the lack of association in a population of preterm infants with regular tube feeding after birth and highly controlled feeding volumes provides evidence for the hypothesis that these polymorphisms affect food intake behavior and hunger rather than metabolism and energy consumption.

Association of arterial stiffness with single nucleotide polymorphism rs1333049 and metabolic risk factors

BackgroundIncreased arterial stiffness is a cardiovascular outcome of metabolic syndrome (MetS). The chromosome 9p21 locus has been identified as a major locus for risk of coronary artery disease (CAD). The single nucleotide polymorphism (SNP), rs1333049 on chromosome 9p21.3 has been strongly associated with CAD and myocardial infarction. Increased arterial stiffness could be the link between the 9p21 polymorphism and increased cardiovascular risk. Since the impact of a genetic polymorphism on arterial stiffness especially in Asian populations has not been well defined, we aimed to investigate the association of arterial stiffness with rs 1333049 variant on chromosome 9p21.3 in Thai subjects with and without MetS risk factors.MethodsA total of 208 Thai subjects, aged 35–75 years, 135 with and 73 without MetS, according to IDF and NCEP-ATPIII criteria, were included in this study. Aortic-femoral pulse wave velocity (afPWV), brachial-ankle pulse wave velocity (baPWV) and aortic ankle pulse wave velocity (aaPWV) were measured and used as markers of arterial stiffness. The chromosome 9p21.3 locus, represented by the rs 1333049 variant and blood biochemistry were evaluated.ResultsArterial stiffness was elevated in subjects with MetS when compared with nonMetS subjects. PWV, especially afPWV increased progressively with increasing number of MetS risk factors (r = 0.322, P <0.001). We also found that the frequency distribution of the rs1333049 genotypes is significantly associated with the afPWV (P <0.05). In multivariate analyses, there was an association between homozygous C allele and afPWV (Odds ratio (OR), 8.16; 95% confidence interval (CI), 1.91 to 34.90; P = 0.005), while the GC genotype was not related to afPWV (OR, 1.79; 95% CI, 0.84 to 3.77; P = 0.129) when compared with the GG genotype.ConclusionsOur findings demonstrate for the first time that arterial stiffness is associated with genetic polymorphism in 9p21 and metabolic risk factors in a Thai population.

SAT0007 Fine-mapping of the 5Q31 psoriatic arthritis susceptibility LOCI in a british population

BackgroundPsoriatic Arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis which manifests as a heterogeneous disease with a wide spectrum of disease severity. PsA is a complex disease whereby...

Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis

BackgroundBecause of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB.ResultsWe reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies.For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 – 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity.ConclusionsIL6 SNP rs1800795 genotype CC is protective against PTB in women of European descent. It is not significant in other heterogeneous or admixed populations, or in fetal genotype analysis.Population structure is an important confounding factor that should be controlled for in studies of PTB.

Common variants in adiponectin gene are associated with coronary artery disease and angiographical severity of coronary atherosclerosis in type 2 diabetes

BackgroundAdiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common single nucleotide polymorphisms (SNPs) in the adiponectin gene influenced plasma adiponectin level and whether they were associated with the risk of coronary artery disease (CAD) and its angiographical severity in type 2 diabetes in Chinese population.Methods11 tagging SNPs were genotyped in 1110 subjects with or without CAD in type 2 diabetes. Variants of adiponectin gene were determined by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by sandwich enzyme-linked immunosorbent assay. The severity and extent of coronary atherosclerosis were assessed using the angiographic Gensini score and Sullivan Extent score.ResultsAmong the 11 SNPs, the minor G allele of SNP rs266729 was significantly associated with higher odds of CAD (odds ratio (95% CI) = 1.49 (1.10 - 2.16), P = 0.022) after adjusting for covariates. In stepwise multivariate logistic regression, SNP rs266729 was a significant independent factor of CAD. Multivariate linear regression analysis revealed that rs266729 (β = −0.101, P < 0.0001), rs182052 (β = −0.044, P = 0.0035), and rs1501299 (β = 0.073, P < 0.0001) were significantly associated with adiponectin level, and also indicated that the minor G allele of SNP rs266729 had higher Gensini score (β = 0.139, P < 0.001) and Sullivan Extent score (β = 0.107, P < 0.001). Haplotypes analysis revealed different haplotype distributions in case and control subjects (P = 0.0003), with two common haplotypes GGG and GAG of the rs266729, rs182052, and rs1501299 being associated in heterozygotes with a greater than threefold increase in cardiovascular risk (odds ratio (95% CI)=3.39 (1.83 - 6.30), P = 0.0001).ConclusionsIn our population, genetic variants in the adiponectin gene influence plasma adiponectin levels, and one of them is a strong determinant of CAD susceptibility and its angiographical severity in type 2 diabetes. This study has provided further evidence for a role of adiponectin in the development of CAD.

Genetic variants of the genes encoding zinc finger protein 313 and interleukin-13 confer a risk for psoriasis in a Chinese Uygur population

Recent work using genome–wide association studies (GWAS) in Chinese Han and white populations have discovered several novel psoriasis susceptibility genes. To examine whether the risk loci for psoriasis identified in previous GWAS in a white population are also associated with psoriasis in a Chinese Uygur population in Xinjiang. Genotyping analysis of eight single-nucleotide polymorphisms (SNPs) associated with psoriasis was performed for 539 patients with psoriasis and 749 controls, all of Chinese Uygur descent, using a commercial assay. Two SNPs had an association with psoriasis in this Chinese Uygur population: SNP rs495337 in the gene encoding for zinc finger protein 313 (P < 0.001; OR = 0.80) and SNP rs20541 of the gene encoding for interleukin-13 (P < 0.001; OR = 0.82). In subgroup analyses, the two SNPs were significantly associated (P < 0.05) with type I psoriasis, Rs495337 showed statistically difference between positive family history of psoriasis patients and controls whereas rs20541 might preferentially associated with negative family history psoriasis patients. Interestingly, using multifactor dimensionality reduction, a significant two-locus interaction was seen between rs495337 and rs20541, with a crossvalidation consistency of 4/5 and average balanced prediction (accuracy 55.5%, P < 0.001). ZNF313 and IL-13 are associated with risk for psoriasis in a Chinese Uygur population, and there is an effect of interaction between the two genes on this risk.

TCF7L2 gene polymorphisms and type 2 diabetes risk: a comprehensive and updated meta-analysis involving 121 174 subjects

Recently, many new loci associated with type 2 diabetes have been uncovered by genetic association studies and genome-wide association studies. As more reports are made, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each major racial group. In addition, some reports have claimed ethnic-specific associations with alternative single-nucleotide polymorphisms (SNPs), and to that end there has been a degree of confusion. We conducted a meta-analysis using an additive genetic model. Eight polymorphisms in 155 studies with 121174 subjects (53385 cases and 67789 controls) were addressed in this meta-analysis. Significant associations were found between type 2 diabetes and rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565, with summary odds ratios (ORs) (95% confidence interval) of 1.39 (1.34-1.45), 1.33 (1.27-1.40), 1.20 (1.14-1.26), 1.32 (1.25-1.39), 1.21 (1.13-1.29) and 1.39 (1.29-1.49), respectively. In addition, no significant associations were found between the two polymorphisms (rs290487 and rs11196218) and type 2 diabetes. The summary ORs for the six statistically significant associations (P < 0.05) were further evaluated by estimating the false-positive report probability, with results indicating that all of the six significant associations were considered noteworthy, and may plausibly be true associations. Significant associations were found between the six polymorphisms (rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565) in the TCF7L2 gene and type 2 diabetes risk, and the other two polymorphisms (rs11196218 and rs290487) were not found to be significantly associated with type 2 diabetes. Subgroups analyses show that significant associations are not found between the six SNPs (rs7903146, rs12255372, rs11196205, rs7901695, rs7895340, and rs4506565) and the type 2 diabetes in some ethnic populations.

Association of ANRIL polymorphism (rs1333049:C>G) with myocardial infarction and its pharmacogenomic role in hypercholesterolemia

Single nucleotide polymorphisms (SNPs) of non-coding RNA in the INK4 locus (ANRIL) have been found to be associated with myocardial infarction (MI). However, the effect of rs1333049:C>G in INK4 locus in familial hypercholesterolemia patients and on lipid profile of the patients has not been studied in Pakistan. We therefore investigated the association of SNP rs1333049:C>G with MI as well as familial hypercholesterolemia patients and also determined the effect of genotype on lipid levels in a northern Pakistani population. A case–control association study was performed in which 611 individuals (294 patients, 290 healthy controls and 27 patients from hypercholesterolemia families) were genotyped for rs1333049:C>G, using an Allele specific polymerase chain reaction. We found a significant association of rs1333049:C>G with MI (χ2=22.3, p<0.001). The frequency of risk genotype CC was significantly different from the healthy controls (p<0.001, χ2=22.3). The risk allele C was at a higher frequency in the MI patients as compared to the controls (odds ratio [OR]=1.55 (95% confidence interval [CI]=1.22–1.96), p<0.001). The logistic regression analysis for the genotype distribution resulted in strong association of risk allele C with MI under recessive model (OR=3.17 (95% CI=1.85–5.44) p<0.001). When the data were further analyzed along the lines of gender, a significant association with both males and females was observed.The pleiotropic role of rs1333049 was revealed further when CC genotype hypercholesterolemic individuals on statins were found to have a significantly lower TC, LDL-C and Tg levels as compared to the CG and GG individuals (p<0.05). The current study demonstrates a strong association of the ANRIL SNP (rs1333049) with MI as well as familial hypercholesterolemia patients in a northern Pakistani population and could be used as a useful genetic marker for the screening of MI in the general Pakistani population.

Aerobic Fitness Does Not Modify the Effect of FTO Variation on Body Composition Traits

PurposePoor physical fitness and obesity are risk factors for all cause morbidity and mortality. We aimed to clarify whether common genetic variants of key energy intake determinants in leptin (LEP), leptin receptor (LEPR), and fat mass and obesity-associated (FTO) are associated with aerobic and neuromuscular performance, and whether aerobic fitness can alter the effect of these genotypes on body composition.Methods846 healthy Finnish males of Caucasian origin were genotyped for FTO (rs8050136), LEP (rs7799039) and LEPR (rs8179183 and rs1137101) single nucleotide polymorphisms (SNPs), and studied for associations with maximal oxygen consumption, body fat percent, serum leptin levels, waist circumference and maximal force of leg extensor muscles.ResultsGenotype AA of the FTO SNP rs8050136 associated with higher BMI and greater waist circumference compared to the genotype CC. In general linear model, no significant interaction for FTO genotype-relative VO2max (mL·kg−1·min−1) or FTO genotype-absolute VO2max (L·min−1) on BMI or waist circumference was found. Main effects of aerobic performance on body composition traits were significant (p<0.001). Logistic regression modelling found no significant interaction between aerobic fitness and FTO genotype. LEP SNP rs7799039, LEPR SNPs rs8179183 and rs1137101 did not associate with any of the measured variables, and no significant interactions of LEP or LEPR genotype with aerobic fitness were observed. In addition, none of the studied SNPs associated with aerobic or neuromuscular performance.ConclusionsAerobic fitness may not modify the effect of FTO variation on body composition traits. However, relative aerobic capacity associates with lower BMI and waist circumference regardless of the FTO genotype. FTO, LEP and LEPR genotypes unlikely associate with physical performance.

Association between 9p21.3 genomic markers and coronary artery disease in East Asians: a meta-analysis involving 9,813 cases and 10,710 controls

Recently, genome-wide association studies on coronary artery disease (CAD) identified a series of associated single-nucleotide polymorphisms (SNPs) in an intergenic region of chromosome 9p21.3, near the CDKN2A and CDKN2B genes. We investigated the association of this locus with CAD in 12 case-control studies of East Asians and undertook a meta-analysis for effect size, heterogeneity, publication bias, and strength of evidence. English and Chinese language articles were tested for 9p21.3 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an odds ratio (OR). Articles were excluded if reporting other outcomes (e.g., stroke). Thirty-five articles were initially identified and 12 were included. Independent extraction was performed by two reviewers and consensus was reached. SNP rs1333049, rs2383206 and rs10757278 representing the 9p21.3 locus, were genotyped in 12 case-control studies involving a total of 9,813 patients and 10,710 controls. For rs1333049 (8 data sets), using a fixed-effects model, the summary OR was 1.29 (95 % CI, 1.23-1.36, P = 0.001). For rs2383206 (6 data sets), using a fixed-effects model, the summary OR was 1.24 (95 % CI, 1.18-1.31, P = 0.001). For rs10757278 (6 data sets), using a random-effects model, the summary OR was 1.34 (95 % CI, 1.21-1.50, P = 0.001). In addition, we defined the haploblock structure of SNPs within the region of 9p21.3 in China population in one study. This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD in East Asians.

Fat mass and obesity-associated gene polymorphisms do not affect metabolic response to hormone therapy in healthy postmenopausal women

To determine whether fat mass and obesity-associated gene polymorphisms rs9939609 T>A and rs8050136 A>C or their haplotypes influence anthropometric and metabolic variables in recently postmenopausal women receiving hormone therapy. In this randomized crossover study carried out in a university clinic, 86 postmenopausal women consulting for symptoms of estrogen deficiency were genotyped by real-time polymerase chain reaction for single nucleotide polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated gene. Haplotypes were constructed from the combination of polymorphisms rs9939609 and rs8050136, and their frequencies were inferred using the PHASE 2.1.1 program. Participants were clinically evaluated before and after 6 months of hormone therapy to determine body mass index (current kg/m(2)) and waist circumference, blood pressure, lipid profile (total cholesterol, HDL cholesterol and triglycerides) plasma glucose (oral glucose tolerance test), and insulin. Blood samples were also drawn for ultra sensitive C reactive protein. The lipid accumulation product index was calculated as (waist [cm] - 58) × triglyceride concentration (mmol/L). Non-normally distributed parameters were log10 transformed before statistical analysis. Measurements at baseline and at follow-up were compared with ANOVA for repeated measures. Data were considered significant at P<0.05. In women with the homozygous polymorphic AA genotype of the single nucleotide polymorphisms rs9939609 and the wild AA genotype of the single nucleotide polymorphisms rs8050136, lipid accumulation product index and ultra sensitive C reactive protein were higher before hormone therapy in comparison with women with other genotypes from the same single nucleotide polymorphisms group. There was no worsening of any of the anthropometric or metabolic variables, and lipid accumulation product index improved slightly after hormone therapy in SNP rs9939609 (P=0.03) and haplotype AAAA. No changes were observed after hormone therapy in SNP rs8050136. The presence of fat mass and obesity-associated gene risk variants in healthy early postmenopausal women does not adversely affect their response to hormone therapy.

Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis

Aims/hypothesis FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS.MethodsA systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis.ResultsA total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10−11) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10−10). This translated into an approximately 3.3 kg/m2 increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations.Conclusions/interpretationThe effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

BackgroundCytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated.MethodologyIn a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs.Principal findings/resultsIn a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses.Conclusions/significanceThese findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.

Stronger Association of Common Variants in TCF7L2 Gene with Nonobese Type 2 Diabetes in the Latvian Population

Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the strongest common genetic risk factors for type 2 diabetes (T2D) across multiple ethnicities. This study was conducted to evaluate an association between TCF7L2 variants and diabetes susceptibility in the population of Latvia. We genotyped 4 single nucleotide polymorphisms (SNP) rs7901695, rs7903146, rs11196205 and rs12255372 in 1 093 controls and 1 043 diabetic subjects. Association with T2D was found for 3 SNPs rs7901695, rs7903146 and rs12255372 in the whole sample (under an additive genetic model, the adjusted odds ratios (OR) were 1.26, 95% CI [1.08-1.48], P=0.003; OR=1.32, 95% CI [1.12-1.55], P=0.001 and OR=1.35, 95% CI [1.15-1.60], P=0.0004 respectively). In addition observed effects on T2D susceptibility for analysed SNPs were higher among subjects with BMI under 30 kg/m². The impact of TCF7L2 variation on T2D risk in Latvian population is compatible with that demonstrated by a range of studies conducted in various ethnic groups.

Environmental tobacco smoke and male sex modify the influence of IL‐13 genetic variants on cord blood IgE levels

Elevated cord blood IgE (cIgE) levels enhance the risk of childhood atopic diseases. However, genetic determinants of cIgE elevation and their potential modifiers remain inconclusive. We aimed to investigate the associations of single-nucleotide polymorphisms (SNPs) in the IL-13 gene (IL-13) with cIgE elevation and their interactions with prenatal environmental tobacco smoke (ETS) and neonatal sex. A structured questionnaire regarding prenatal environmental exposures was completed during pregnancy. Birth information was extracted from the medical records. Cord blood from 794 term neonates was genotyped for three SNPs (rs1800925, rs20541, and rs848) of IL-13 and measured for cIgE levels. SNP rs20541 and a 3-SNP haplotype containing rs1800925, rs20541, and rs848 (denoted as h011) were significantly associated with cIgE elevation (p = 0.04 and 0.003, respectively). Two-way interaction analysis revealed that the associations of IL-13 rs20541 and h011 with cIgE elevation were synergistically enhanced by prenatal ETS (p for interaction = 0.03 and 0.03, respectively), but not by male sex. If the association analyses were stratified by prenatal ETS and neonatal sex simultaneously, IL-13 rs20541 and h011 had the highest risks for cIgE elevation in male babies prenatally exposed to ETS, with adjusted odds ratios (95% confidence interval) being 3.03 (1.56-5.88) and 2.81 (1.54-5.15), respectively. When three-way interactions were examined, both IL-13 rs20541 and h011 exhibited significant interactions with male sex and ETS (p for interaction = 0.03 and 0.007, respectively). In conclusion, the influence of IL-13 genetic variants on cIgE elevation was modified by male sex and prenatal ETS.