Transferability and Fine Mapping of genome-wide associated loci for lipids in African Americans

Background

Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder. Recently, several genome-wide association studies (GWAS) have identified many novel susceptibility loci for T2DM, and indicated that there are common genetic causes contributing to the susceptibility to T2DM in multiple populations worldwide. In addition, clinical and epidemiological studies have indicated that obesity is a major risk factor for T2DM. However, the prevalence of obesity varies among the various ethnic groups. We aimed to determine the combined effects of these susceptibility loci and obesity/overweight for development of T2DM in the Japanese.

Methods

Single nucleotide polymorphisms (SNPs) in or near 17 susceptibility loci for T2DM, identified through GWAS in Caucasian and Asian populations, were genotyped in 333 cases with T2DM and 417 control subjects.

Results

We confirmed that the cumulative number of risk alleles based on 17 susceptibility loci for T2DM was an important risk factor in the development of T2DM in Japanese population (P < 0.0001), although the effect of each risk allele was relatively small. In addition, the significant association between an increased number of risk alleles and an increased risk of T2DM was observed in the non-obese group (P < 0.0001 for trend), but not in the obese/overweight group (P = 0.88 for trend).

Conclusions

Our findings indicate that there is an etiological heterogeneity of T2DM between obese/overweight and non-obese subjects.     

No evidence of the APC D1822V missense variant's pathogenicity in Tunisian patients with sporadic colorectal cancer

Objectives

Sporadic colorectal cancer is influenced by numerous single nucleotide polymorphisms (SNPs), each with minor effects on the cancer risk. This study seeks to determine whether there is any association of the I1307K, E1317Q and D1822V variants within the Adenomatous polyposis coli gene (APC) and risk to develop colorectal cancer in Tunisian population.

Methods

Direct sequencing was used to investigate three SNPs in the APC in 48 Tunisian sporadic colorectal cancer cases and 63 controls.

Results

There was no statistically significant association between the I1307K, E1317Q and D1822V variants investigated and colorectal cancer risk.

Conclusion

The lack of association may show that these variants selected for this study are not involved in the colorectal carcinogenic process. Otherwise, the eventual biological effect is so little to go undetected, unless increasing the sample size.     

Genome-wide association with diabetes-related traits in the Framingham Heart Study

Background

Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants.

Methods

We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with three diabetes-related quantitative glucose traits (fasting plasma glucose (FPG), hemoglobin A1c, 28-yr time-averaged FPG (tFPG)), three insulin traits (fasting insulin, HOMA-insulin resistance, and 0–120 min insulin sensitivity index); and with risk for diabetes. We used additive generalized estimating equations (GEE) and family-based association test (FBAT) models to test associations of SNP genotypes with sex-age-age²-adjusted residual trait values, and Cox survival models to test incident diabetes.

Results

We found 415 SNPs associated (at p < 0.001) with at least one of the six quantitative traits in GEE, 242 in FBAT (18 overlapped with GEE for 639 non-overlapping SNPs), and 128 associated with incident diabetes (31 overlapped with the 639) giving 736 non-overlapping SNPs. Of these 736 SNPs, 439 were within 60 kb of a known gene. Additionally, 53 SNPs (of which 42 had r² < 0.80 with each other) had p < 0.01 for incident diabetes AND (all 3 glucose traits OR all 3 insulin traits, OR 2 glucose traits and 2 insulin traits); of these, 36 overlapped with the 736 other SNPs. Of 100K SNPs, one (rs7100927) was in moderate LD (r² = 0.50) with TCF7L2 (rs7903146), and was associated with risk of diabetes (Cox p-value 0.007, additive hazard ratio for diabetes = 1.56) and with tFPG (GEE p-value 0.03). There were no common (MAF > 1%) 100K SNPs in LD (r² > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. PPARG P12A (rs1801282) was not significantly associated with diabetes or related traits.

Conclusion

Framingham 100K SNP data is a resource for association tests of known and novel genes with diabetes and related traits posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Framingham 100K data replicate the TCF7L2 association with diabetes.

     

Weak or no association of <Emphasis Type="Italic">TCF7L2</Emphasis> variants with Type 2 diabetes risk in an Arab population

Background  

The rs7903146 and rs12255372 variants of TCF7L2 have been strongly associated with type 2 diabetes (T2D) risk in most populations studied to date. Meta-analysis of 27 different studies has resulted in a global OR of 1.46 [1.42–1.51] (rs7903146 variant). Thus far, despite a high incidence of T2D, the role of this variant in Arabs has not been established.     

Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study

Background

Chromosome 15q14-22.1 has been linked to type 2 diabetes (T2D) and its related traits in Japanese and other populations. The presence of T2D disease susceptibility variant(s) was assessed in the 21.8 Mb region between D15S118 and D15S117 in a Japanese population using a region-wide case-control association test.

Methods

A two-stage association test was performed using Japanese subjects: The discovery panel (Stage 1) used 372 cases and 360 controls, while an independent replication panel (Stage 2) used 532 cases and 530 controls. A total of 1,317 evenly-spaced, common SNP markers with minor allele frequencies > 0.10 were typed for each stage. Captured genetic variation was examined in HapMap JPT SNPs, and a haplotype-based association test was performed.

Results

SNP2140 (rs2412747) (C/T) in intron 33 of the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) gene was selected as a landmark SNP based on repeated significant associations in Stage 1 and Stage 2. However, the marginal p value (p = 0.0043 in the allelic test, OR = 1.26, 95% CI = 1.07–1.48 for combined samples) was weak in a single locus or haplotype-based association test. We failed to find any significant SNPs after correcting for multiple testing.

Conclusion

The two-stage association test did not reveal a strong association between T2D and any common variants on chromosome 15q14-22.1 in 1,794 Japanese subjects. A further association test with a larger sample size and denser SNP markers is required to confirm these observations.     

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project

Background

Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the IL18 gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, IL18R1 and IL18RAP, with the risk of developing CVD.

Methods

Eleven tagging SNPs, 5 in IL18R1 and 6 in IL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD.

Results

We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 IL18 SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful.

Conclusion

Our analysis suggests that the variability of IL18R1 and IL18RAP genes are unlikely to contribute to modulate the risk of CVD.     

A Validation Study of Type 2 Diabetes‐related Variants of the TCF7L2, HHEX,KCNJ11, and ADIPOQ Genes in one Endogamous Ethnic Group of North India

The aim of this study was to validate the single nucleotide polymorphisms (SNPs) of four candidate genes (TCF7L2, HHEX, KCNJ11, and ADIPOQ) related to type 2 diabetes (T2D) in an endogamous population of north India; the Aggarwal population, having 18‐clans. This endogamous population model was heavily supported by recent land mark work and we also verified the homogeneity of this population by clan‐based stratification analysis. Two SNPs (rs4506565; rs7903146) in TCF7L2 were found to be significant (p‐value = 0.00191; p‐value = 0.00179, respectively), and odds ratios of 2.1 (dominant‐model) and 2.0 (recessive‐model) respectively, were obtained for this population. The TTT haplotype in the TCF7L2 gene was significantly associated with T2D. Waist‐Hip ratio (WHR), systolic blood pressure (SBP), and age were significant covariates for increasing risk of T2D. Single‐SNP, combined‐SNPs and haplotype analysis provides clear evidence that the causal mutation is near to or within the significant haplotype (TTT) of the TCF7L2 gene. In spite of a culturally‐learned sedentary lifestyle and fat‐enriched dietary habits, WHR rather than body‐mass‐index emerged as a robust predictor of risk for T2D in this population.     

Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population

Background

The protein tyrosine phosphatase N22 gene (PTPN22) encodes a lymphoid-specific phosphatase (LYP) which is an important downregulator of T cell activation. A PTPN22 polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population.

Methods

A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System.

Results

We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17–2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45–6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed.

Conclusion

Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.     

<Emphasis Type="Italic">TCF7L2</Emphasis> and therapeutic response to sulfonylureas in patients with type 2 diabetes

Background  

Variants in the TCF7L2 have been shown to be associated with an increased risk for type 2 diabetes (T2D). Since the association with diabetes could be explained by effects on insulin secretion, we investigated whether patients with diabetes risk alleles at rs7903146 might have an altered hypoglycaemic response to sulfonylureas (SUs).     

Association of promoter region single nucleotide polymorphisms at positions ?819C/T and ?592C/A of interleukin 10 gene with ischemic heart disease

Objective

Ischemic heart disease (IHD) is a disease characterized by ischemia of the heart muscle, usually due to coronary artery disease. Interleukin-10 (IL10) is a proinflammatory cytokine known to protect endothelial function. In this study, we investigated the association of promoter region polymorphisms of the IL10 gene with IHD.

Methods

We recruited 313 control and 173 IHD patients. The selected SNPs in IL10 were genotyped using pyrosequencing.

Results

SNPs at positions ?592C/A and ?819C/T were statistically associated with IHD (P?=?0.014 and P?=?0.037). Similarly, the mean value of C-reactive protein in the C allele at ?592C/A and ?819C/T was significantly higher than that in the A allele at ?592C/A (P?=?0.026) and T allele at ?819C/T (P?=?0.026). The presence of hypertension in the C allele at ?592C/A and ?819C/T was significantly more frequent than that in the A allele at ?592C/A (P?=?0.044) and T allele at ?819C/T (P?=?0.044). In the haplotype of two SNPs (?592C/A and ?819C/T), one haplotype (CC) presented an association with IHD (P?=?0.012).

Conclusions

These results indicate that the C allele with SNPs at position ?592C/A and ?819C/T of IL10 gene may be associated with IHD in the Korean population.     

<Emphasis Type="Italic">TCF7L2</Emphasis> rs7903146 variant does not associate with smallness for gestational age in the French population

Background  

In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance.     

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies

Background  

An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.     

An update meta-analysis and systematic review of TAP polymorphisms as potential biomarkers for judging cancer risk

Objective

Transporter associated with antigen processing protein (TAP) is a heterodimer protein consist of TAP1 and TAP2, act a pivotal part in the immune surveillance. In recent days, controversial relationships were reported between TAP polymorphisms and cancer risk, thus, a systematic meta-analysis was performed to resolve this discrepancy.

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Lack of association between IL-23R gene polymorphisms and systemic lupus erythematosus in a Chinese population

Objective

The aim to this study was to investigate the association between the single-nucleotide polymorphisms (SNPs) of interleukin (IL)-23 receptor gene and systemic lupus erythematosus (SLE) in a Chinese population.

Methods

A case–control study was performed to investigate the associations of SNPs in IL-23R gene (rs10889677 and rs1884444) with susceptibility to SLE in 521 Chinese SLE patients and 527 normal controls. The chi-square test and unconditional Logistic regression were used to analysis by SPSS 10.1 software.

Results

No significant differences were detected for the distribution of allele and genotype frequencies of these two SNPs between patients and controls as well as SLE patients with nephritis (LN) and those without nephritis.

Conclusion

The findings suggest that the polymorphisms of IL-23R gene might not contribute to the susceptibility of SLE in the Chinese population.     

Association of tumor necrosis factor-�� (TNF-��) promoter polymorphisms with overweight/obesity in a Korean population

Objective

Obesity is characterized by the activation of an inflammatory process leading to an increase in proinflammatory cytokines and adipokines. This study was designed to investigate the genetic association between tumor necrosis factor-?? (TNF-??) polymorphisms and the risk of obesity in the Korean population.

Methods

Three single nucleotide polymorphisms [G-238A (rs361525), C-857T (rs1799724), and C-863A (rs1800630)] in the promoter region of TNF-?? gene were analyzed in 123 control [body mass index (BMI) between 18 and 23] and 208 overweight/obese (BMI????23) subjects.

Results

The mean values of BMI in the control and overweight/obese groups were 21.1?±?1.4 and 25.4?±?1.8, respectively. Of the three SNPs, G-238A presented a significant association with overweight/obesity in the codominant model; the frequency of the G/G genotype in the overweight/obese group was 9.3% higher than that in the control group (P?=?0.0046). When control and overweight/obesity subjects were combined together and analyzed, the level of high-density lipoprotein (HDL) was significantly higher in the C-857T C/C type SNP (P?Conclusions The results of this study suggest that the G allele of G-238A in TNF-?? gene may be a risk factor for overweight/obesity in the Korean population and that the C allele of C-857T may be an protective factor in relation to the HDL level in the general Korean population.