Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review

This evidence review addresses whether type 2 diabetes genomic risk panels improve health outcomes (e.g., reduce rates of developing type 2 diabetes) in low- or high-risk adults; two clinical scenarios promulgated by commercial companies offering such testing. Evidence for the analytic validity of available genomic profiles was inadequate. Clinical validity ranged from inadequate to convincing for 30 variants identified on five type 2 diabetes genomic panels and by genome-wide association studies. Eight common variants were identified for general population use; evidence credibility based on published criteria was strong for two variants, moderate for two variants, and weak for four variants. TCF7L2 had the largest per-allele odds ratio of 1.39 (95% confidence interval 1.33–1.46). Models combining the best four, best eight, and all 30 variants used summary effect sizes, reported genotype frequencies, and assumed independent effects. Areas under the curve were 0.547, 0.551, and 0.570, respectively. In high-risk populations, per-allele odds ratios for TCF7L2 alone were similar to those of the general population. TCF7L2, in combination with other variants, yielded minimal improvement in risk reclassification. Evidence on TCF7L2 clinical validity was adequate. Three studies addressed the clinical utility of intervention effectiveness, stratified by TCF7L2 genotype; none found significant interactions. Clinical utility evidence was inadequate. In addition to analytic validity and clinical utility knowledge gaps, additional gaps were identified regarding how to inform, produce, and evaluate models combining multiple variants.Genet Med 2013:15(8):600–611     

Genome-wide association scan allowing for epistasis in type 2 diabetes

In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two‐dimensional genome‐wide association (GWA) scan using joint two‐locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two‐locus association at 79 SNP‐pairs at a Bonferroni‐corrected P‐value = 0.05 (uncorrected P‐value = 2.14 × 10^?11). The 79 pair‐wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single‐locus association signals (P‐value = 5 × 10^?4). Analyses conditional on the single‐locus effects at TCF7L2 established that the joint two‐locus results could be attributed to single‐locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP‐pairs with case‐control and case‐only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single‐locus association can underlie and obscure multilocus findings.     

过氧化物酶增殖体激活受体-γ2基因Pro12Ala变异与2型糖尿病的关系

目的 探讨过氧化物酶增殖体激活受体－γ2(peroxisome proliferator-activated receptor-γ2,PPAR-γ2）基因外显子B的Pro12Ala变异与2型糖尿病（type 2 diabetes mellitus,DM)及临床特征的关系。方法 应用聚合酶链反应－限制性片段长度多态性测定了无亲缘关系的401名华南地区汉族人PPAR－γ2基因外显子B的Pro12Ala变异（包括180名糖耐量正常者及221例2型糖尿病患者）。结果 PPAR－γ2基因P等位基因和A等位基因在2型糖尿病组和对照组的分布频率分别为96．15％、96．11％和3．85％、3．89％；PP基因型频率为92．77％、92．22％,PA基因频率为6．78％、7．78％，AA基因频率为0．45％、0。两组人群的基因型和等位基因频率差异无显著性。在2型糖尿病组PPAR－γ基因外显子B的Pro12Ala变异与腰围及腰臂比相关（P＝0．037，P＝0．012）。提示我国人群PPAR－γ2基因外显子B的Pro12Ala变异与2型糖尿病发病无明显关联，但与2型糖尿病患者的腹型肥胖有关；PPAR－γ2基因的Pro12Ala多态性具有明显的种族差异。     

TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis

TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29-1.89] (p = 2.9 x 10(-6)) and 1.52 [1.29-1.78] (p = 3.0 x 10(-7)) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (chi (2) = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: chi (2) = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel-Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42-1.51] (p = 5.4 x 10(-140)). No publication bias was detected, using the conservative Egger's regression asymmetry test (t = -1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2.     

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.     

The TCF7L2 Diabetes Risk Variant is Associated with HbA1C Levels: a Genome‐Wide Association Meta‐Analysis

Genome‐wide association (GWA) studies have identified around 20 common genetic variants influencing the risk of type 2 diabetes (T2D). Likewise, a number of variants have been associated with diabetes‐related quantitative glycaemic traits, but to date the overlap between these genes and variants has been low. The majority of genetic studies have focused on fasting plasma glucose levels; however, this measure is highly variable. We have conducted a GWA meta‐analysis of glycated haemoglobin (HbA_1C) levels within three healthy nondiabetic populations. This phenotype provides an estimate of mean glucose levels over 2–3 months and is a more stable predictor of future diabetes risk. Participants were from three isolated populations: the Orkney Isles in the north of Scotland, the Dalmatian islands of Vis, and Kor?ula in Croatia (total of 1782 nondiabetic subjects). Association was tested in each population and results combined by meta‐analysis. The strongest association was with the TCF7L2 gene (rs7903146, P= 1.48 × 10^?7). This is also the strongest common genetic risk factor for T2D but it has not been identified in previous genome‐wide studies of glycated haemoglobin.     

Replication of genetic variants from genome-wide association studies with metabolic traits in an island population of the Adriatic coast of Croatia

Twenty-two single-nucleotide polymorphisms (SNPs) in 10 gene regions previously identified in obesity and type 2 diabetes (T2D) genome-wide association studies (GWAS) were evaluated for association with metabolic traits in a sample from an island population of European descent. We performed a population-based study using 18 anthropometric and biochemical traits considered as continuous variables in a sample of 843 unrelated subjects (360 men and 483 women) aged 18-80 years old from the island of Hvar on the eastern Adriatic coast of Croatia. All eight GWAS SNPs in FTO were significantly associated with weight, body mass index, waist circumference and hip circumference; 20 of the 32 nominal P-values remained significant after permutation testing for multiple corrections. The strongest associations were found between the two TCF7L2 GWAS SNPs with fasting plasma glucose and HbA1c levels, all four P-values remained significant after permutation tests. Nominally significant associations were found between several SNPs and other metabolic traits; however, the significance did not hold after permutation tests. Although the sample size was modest, our study strongly replicated the association of FTO variants with obesity-related measures and TCF7L2 variants with T2D-related traits. The estimated effect sizes of these variants were larger or comparable to published studies. This is likely attributable to the homogenous genetic background of the relatively isolated study population.     

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.     

神经源分化因子基因多态性与2型糖尿病的关联性研究

目的　探讨神经源分化因子 (neurogenic differentiation factor 1,Neuro D)基因多态性与 2型糖尿病发生的关联性。方法　运用错配聚合酶链反应 -限制性片段长度多态性方法检测了中国湖北地区汉族 32 4例 2型糖尿病 (其中以发病年龄 40岁为界 ,分为早发及晚发两组 )及 12 4名正常对照者 ,Neuro D基因第 45位密码子碱基变异 (GCC→ ACC)。结果　 Neuro D基因在所测人群中未发现有纯合变异者。在早发 2型糖尿病组 ,其 AT基因型频率为 2 6 .8% ,与正常对照组 (10 .5 % )及晚发 2型糖尿病组 (11.6 % )比较 ,差异有显著性 (分别为χ2 =7.85 ,P=0 .0 0 5 ;χ2 =8.81,P=0 .0 0 3) ;Thr45等位基因频率在早发 2型糖尿病组及正常对照组、晚发 2型糖尿病组分别为 13.4%、5 .2 %和 5 .8% ,差异亦有显著性 (χ2 =7.15 ,P=0 .0 0 8;χ2 =8.13,P=0 .0 0 4) ;晚发 2型糖尿病组与正常对照组比较 ,Ala45 Thr基因型频率 (11.6 % vs10 .5 % ,P>0 .0 5 )及等位基因频率 (5 .8% vs 5 .2 % ,P>0 .0 5 )差异不明显 ,Thr45等位基因与早发 2型糖尿病发生相关 (OR=2 .5 2 ,95 % CI:1.42～ 4.49) ;基因型为 AT型的 2型糖尿病患者其空腹血浆 C肽水平较 AA型患者低 ,差异有显著性 (P<0 .0 5 )。结论　 Neuro D基因多态性与早发 2型糖尿