rs12255372

* Type-2 Diabetes Risk Overview: numerous papers report an increase in risk, on the order of 1.5 – 2x for the risk genotypes compared to the non-risk genotype. Key papers include:

• • [Type-2 diabetes in a Finnish sample.
  • rs12255372 Common variants (rs12255372 and rs7903146) in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance
  • [type-2 diabetes with rs7903146 rs12255372 rs10885406.
  • [type-2 diabetes in a study of 500+ Japanese patients plus pooled meta-analysis with 6 previous association studies (also of Japanese).
  • A HuGE review and meta-analysis including over 35,000 type-2 diabetes cases and 39,000 controls concluded that the Bayesian odds ratio for rs12255372(T;T) homozygotes and (G;T) heterozygotes versus (G;G) homozygotes was 1.885 (95% credible interval (CrI): 1.698 – 2.088) and 1.360 (95% CrI: 1.291 – 1.433), respectively. Along with 3 other TCF7L2 SNPs, a multiplicative genetic model was indicated.[PMID 19228405]

* Breast Cancer Risk Overview: some papers report a small increase in risk, around 1.1 to 1.2x for the risk genotypes compared to the non-risk genotype, and other papers report no increased risk. Key papers include:

• • [PMID 17109766] is the paper which links it to Breast cancer. It suggests the T allele as increasing risk.
  • [PMID 26309596] Meta-analysis totaling 4800 breast cancer cases finds a small risk increase (1.07 to 1.17x, depending on genetic model) for T allele
  • [PMID 19732438] Mayo Clinic study of 800 patients found no association between rs12255372 and risk for breast cancer or ovarian cancer
  • [PMID 23085767] A study of 7,700 Hispanic patients did find increased risk for the rs12255372 T allele, however, it was of borderline statistical significance

* Prostate Cancer Risk Overview:

• • [PMID 18302196] In a study of 1,457 prostate cancer cases and 1,351 controls, while there was no association with overall risk, males who were rs12255372(T;T) homozygotes and who had prostate cancer were at elevated relative risk of more aggressive prostate cancer, as defined by high Gleason score (OR = 1.7, CI: 1.0-2.8) or regional/distant stage (OR = 1.7, CI: 1.1-2.6) disease.

Many other papers mention rs12255372, including:

[PMID 18972257] Comparison of genetic risk in three candidate genes (TCF7L2, PPARG, KCNJ11) with traditional risk factors for type 2 diabetes in a population-based study–the HUNT study

[PMID 19183934] TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study

[PMID 20028944] Gene variants of TCF7L2 influence weight loss and body composition during lifestyle intervention in a risk population for type 2 diabetes

[PMID 20361036] Gene-gene interactions lead to higher risk for development of type 2 diabetes in an ashkenazi jewish population

[PMID 20503258] Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City

[PMID 20546291] Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5)

[PMID 21301999] Genetic variations in transcription factor 7-like 2 (TCF7L2) gene: association of TCF7L2 rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico-pathological parameters

[PMID 22052079] Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs

[PMID 22402060] Functional analysis of TCF7L2 genetic variants associated with type 2 diabetes

[PMID 22441719] Stronger Association of Common Variants in TCF7L2 Gene with Nonobese Type 2 Diabetes in the Latvian Population

[PMID 17437080] Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion

[PMID 21399856] Variants of transcription factor 7-like 2 (TCF7L2) gene and incident glucose intolerance in Japanese-Brazilians

[PMID 16855264] TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program.

[PMID 16936216] Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men.

[PMID 16936218] Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance.

[PMID 17003360] Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.

[PMID 17031610] Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort.

[PMID 17093941] Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population.

[PMID 17130514] Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women.

[PMID 17226113] Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys.

[PMID 17245407] TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden.

[PMID 17245589] A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population.

[PMID 17259383] Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans.

[PMID 17317761] Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans.

[PMID 17340123] Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population.

[PMID 17429603] TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels.

[PMID 17463248] A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

[PMID 17470138] Association of TCF7L2 polymorphisms with type 2 diabetes in Mexico City.

[PMID 17503332] Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals.

[PMID 17579206] Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population.

[PMID 17601994] Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy.

[PMID 17618413] Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men.

[PMID 17661009] Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms.

[PMID 17665514] Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women.

[PMID 17668382] Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium.

[PMID 17697858] The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians.

[PMID 17805508] Disparate genetic influences on polycystic ovary syndrome (PCOS) and type 2 diabetes revealed by a lack of association between common variants within the TCF7L2 gene and PCOS.

[PMID 17903298] Genome-wide association with diabetes-related traits in the Framingham Heart Study.

[PMID 17909099] TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3,501 individuals.

[PMID 17934151] A variant of the transcription factor 7-like 2 (TCF7L2) gene and the risk of posttransplantation diabetes mellitus in renal allograft recipients.

[PMID 17972059] TCF7L2 is associated with high serum triacylglycerol and differentially expressed in adipose tissue in families with familial combined hyperlipidaemia.

[PMID 18097733] Association of TCF7L2 polymorphisms with susceptibility to type 2 diabetes in 4,087 Japanese subjects.

[PMID 18248681] Prevalence of common disease-associated variants in Asian Indians.

[PMID 18268068] Variation in TCF7L2 and increased risk of colon cancer: the Atherosclerosis Risk in Communities (ARIC) Study.

[PMID 18282631] Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects.

[PMID 18291022] Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population.

[PMID 18437354] TCF7L2 single nucleotide polymorphisms, cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study.

[PMID 18478343] Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk.

[PMID 18493736] Exon sequencing and association analysis of polymorphisms in TCF7L2 with type 2 diabetes in a Chinese population.

[PMID 18598350] Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk.

[PMID 18650481] TCF7L2 variants associate with CKD progression and renal function in population-based cohorts.

[PMID 18655717] Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population.

[PMID 18706099] TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes.

[PMID 18712344] Association of variants of the TCF7L2 gene with increases in the risk of type 2 diabetes and the proinsulin:insulin ratio in the Spanish population.

[PMID 19002430] Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population.

[PMID 19050058] Single nucleotide transcription factor 7-like 2 (TCF7L2) gene polymorphisms in antiislet autoantibody-negative patients at onset of diabetes.

[PMID 19053027] Loci of TCF7L2, HHEX and IDE on chromosome 10q and the susceptibility of their genetic polymorphisms to type 2 diabetes.

[PMID 19141698] Polyunsaturated fatty acids modulate the effect of TCF7L2 gene variants on postprandial lipemia.

[PMID 19211816] TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women.

[PMID 19279076] Genetic predisposition, Western dietary pattern, and the risk of type 2 diabetes in men.

[PMID 19309528] Specific and complete human genome amplification with improved yield achieved by phi29 DNA polymerase and a novel primer at elevated temperature.

[PMID 19351735] Evidence for association between polycystic ovary syndrome (PCOS) and TCF7L2 and glucose intolerance in women with PCOS and TCF7L2.

[PMID 19369405] Linkage analysis of albuminuria.

[PMID 19455305] No association of multiple type 2 diabetes loci with type 1 diabetes.

[PMID 19482368] Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in East Asian population.

[PMID 19497595] Genetic variation of FTO and TCF7L2 in premature adrenarche.

[PMID 19602480] Tissue-specific alternative splicing of TCF7L2.

[PMID 19789636] Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes.

[PMID 19825152] TCF7L2 polymorphisms and inflammatory markers before and after treatment with fenofibrate.

[PMID 19924244] TCF7L2 polymorphism rs7903146 is associated with coronary artery disease severity and mortality.

[PMID 20075150] Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study.

[PMID 20144327] A genomics study of type 2 diabetes mellitus in U.S. Air Force personnel.

[PMID 20161033] Personalized pharmacotherapy for Type 2 diabetes mellitus.

[PMID 20648057] Potential role of TCF7L2 gene variants on cardiac sympathetic/parasympathetic activity.

[PMID 21159844] Variants and haplotypes of TCF7L2 are associated with beta-cell function in patients with newly diagnosed type 2 diabetes: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 1.

[PMID 21278902] Genetic risk profiling for prediction of type 2 diabetes.

[PMID 21349175] TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes.

[PMID 21423583] Single nucleotide polymorphisms of TCF7L2 are linked to diabetic coronary atherosclerosis.

[PMID 21441683] Screening with OGTT alone or in combination with the Indian diabetes risk score or genotyping of TCF7L2 to detect undiagnosed type 2 diabetes in Asian Indians.

[PMID 21672010] Gestational diabetes mellitus is associated with TCF7L2 gene polymorphisms independent of HLA-DQB1*0602 genotypes and islet cell autoantibodies.

[PMID 21834909] A replication study of the IRS1, CAPN10, TCF7L2, and PPARG gene polymorphisms associated with type 2 diabetes in two different populations of Mexico.

[PMID 21898192] Worldwide distribution of type II diabetes-associated TCF7L2 SNPs: evidence for stratification in Europe.

[PMID 22301903] Association of fibrillin-3 and transcription factor-7-like 2 gene variants with metabolic phenotypes in PCOS.

[PMID 23041303] Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese population

[PMID 23577093] Association of TCF7L2 Gene Polymorphisms with T2DM in the Population of Hyderabad, India

[PMID 23579632] Association of rs12255372 in the TCF7L2 gene with type 2 diabetes mellitus: a meta-analysis

[PMID 23690305] Genetic variants and the risk of gestational diabetes mellitus: a systematic review

[PMID 23188737] TCF7L2 gene polymorphisms and type 2 diabetes risk: a comprehensive and updated meta-analysis involving 121,174 subjects

[PMID 24157263] Polymorphisms of Transcription Factor-7-Like 2 (TCF7L2) gene in Tunisian women with polycystic ovaries syndrome (PCOS)

[PMID 24371822] IRS1, TCF7L2, ADRB1, PPARG, and HHEX Polymorphisms Associated with Atherogenic Risk in Mexican Population

[PMID 22480428] T2D risk haplotypes of the TCF7L2 gene in the Czech population sample: the association with free fatty acids composition.

[PMID 22843023] TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy.

[PMID 23034957] TCF7L2 genetic variants modulate the effect of dietary fat intake on changes in body composition during a weight-loss intervention.

[PMID 23085767] Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study.

[PMID 23107111] Transcription factor-7-like 2 gene variants are strongly associated with type 2 diabetes in Lebanese subjects.

[PMID 23142382] Transcription factor-7-like 2 gene variants are strongly associated with type 2 diabetes in Tunisian Arab subjects.

[PMID 25185411] Association of rs7903146, rs12255372, and rs290487 polymorphisms in TCF7L2 gene with type 2 diabetes in an Iranian Kurdish ethnic group

[PMID 25678248] Association between rs7903146 and rs12255372 polymorphisms of transcription factor 7-like 2 gene and polycystic ovary syndrome: a systematic review and meta-analysis

[PMID 26058934] Association of rs12255372 (TCF7L2) and D76N (PDX-1) Polymorphisms with Type 2 Diabetes in a Population Living in Northeast Iran

[PMID 25299103] Association of the rs7903146 and rs12255372 polymorphisms in the TCF7L2 gene with type 2 diabetes in a population from northeastern Brazil

[PMID 26201011] Design of an allele-specific PCR assay to genotype the rs12255372 SNP in a pilot study of association between common TCF7L2 polymorphisms and type 2 diabetes in Venezuelans

The ''T'' allele showed an association with familial breast cancer risk with borderline significance (OR = 1.19, P = 0.04) [R]. 

Men homozygous for the variant allele ''T''  had an elevated relative risk of more aggressive prostate cancer (OR = 1.7) or regional/distant stage (OR = 1.7) disease [R].

''T'' allele showed a strong associations with type 2 diabetes (T2D) (OR = 1.78, p = 0.002) [R].

A significant increase of GT/TT genotypes was observed in low glutamic acid decarboxylase (GADA) titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and controls (P < or = 0.04 for both comparisons) [R]. 

The TT genotype was significantly associated with an adjusted 2.85-fold risk (p = 0.021) of incident diabetes in the control group, but not in the intervention group [R].

Each copy of the ''T'' allele was associated with a 1.32-fold (P = 0.0002) and 1.53-fold (P < 0.0001) increased type 2 diabetes risk in women and men, respectively. The odds ratios associated with homozygous carriers of the ''T'' allele were 1.86 and 2.15 in women and men, respectively [R].

''T'' allele significantly increases type 2 diabetes risk with an allelic odds ratio (OR) 1.60 (P = 7.6 x 10(-28)) [R]. 

The frequency of the "T" allele was significantly higher in diabetic subjects (23%) compared to that in normal glucose-tolerant subjects (19%; P = .001). Normal glucose-tolerant subjects with the TT genotype had significantly higher 2-hour plasma glucose levels (mean +/- SD, 6.1 +/- 1.4 mmol/L) than those with the GG genotype (5.6 +/- 1.0 mmol/L, P = .011) [R].

Homozygote ''T'' allele carriers had significantly higher (P < 0.05) post-fenofibrate concentrations of MCP-1 in the recessive model [R]. 

TT genotype is associated with lower insulin secretion and higher cardiosympathetic activity [R].

The heterozygous genotypes GT (T is risk for Type 2 diabetes) as well as the homozygous genotypes TT were strongly associated with gestational diabetes (P < 0.0001) [R].

The GT genotype (OR = 2.23, p = 0.005), TT genotype (OR = 4.25, p = 0.046), and the dominant model (OR = 2.2, p = 0.001) of gave a higher risk for type 2 diabetes (T2DM) [R].