rs12255372

Associated with slight increase in risks for T2D, breast and prostate cancers.

plus

Geno	Mag	Summary
(G;G)	0	normal
(G;T)	2	1.3x increased type-2 diabetes risk
(T;T)	2.2	slight increases (~1.5x) in risk for type-2 diabetes and possibly breast cancer and aggressive prostate cancer

Reference

GRCh38 38.1/141

Chromosome

10

Position

113049143

Gene

TCF7L2

is a	snp
is	mentioned by
dbSNP	rs12255372
dbSNP (classic)	rs12255372
ClinGen	rs12255372
ebi	rs12255372
HLI	rs12255372
Exac	rs12255372
Gnomad	rs12255372
Varsome	rs12255372
LitVar	rs12255372
Map	rs12255372
PheGenI	rs12255372
Biobank	rs12255372
1000 genomes	rs12255372
hgdp	rs12255372
ensembl	rs12255372
geneview	rs12255372
scholar	rs12255372
google	rs12255372
pharmgkb	rs12255372
gwascentral	rs12255372
openSNP	rs12255372
23andMe	rs12255372
SNPshot	rs12255372
SNPdbe	rs12255372
MSV3d	rs12255372
GWAS Ctlg	rs12255372

GMAF

0.2029

Max Magnitude

2.2

?

(G;G) (G;T) (T;T)

28

rs12255372, also known as IVS4G>T and c.483+9017G>T, is a well-studied SNP in the TCF7L2 gene on chromosome 10. In some studies, it has been linked to slight increases in risk for type-2 diabetes, breast cancer and aggressive prostate cancer.

* 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:

- [PMID 16936217] reports the association of rs12255372 and rs7903146 with 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
- [PMID 17671651 ] Considered for type-2 diabetes with rs7903146 rs12255372 rs10885406.
- [PMID 17971425 ] Associated in a study of ~1000 Hispanic-Americans with reduced insulin secretion as measured by acute insulin response and adjusted for the degree of insulin sensitivity (p = 0.036).
- [PMID 19033397 ] This SNP was confirmed to be associated with 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

OMIM	602228
Desc	TRANSCRIPTION FACTOR 7-LIKE 2; TCF7L2
Variant
Related	also

[PMID 19732438 ] No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer

[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

OMIM	602228
Desc
Variant	0002
Related	also

[PMID 21109996 ] Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth

[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

ClinVar
Risk	rs12255372(A;A) Rs12255372(T;T)
Alt	rs12255372(A;A) Rs12255372(T;T)
Reference	Rs12255372(G;G)
Significance	Other
Disease	Diabetes mellitus type 2
Variation	info
Gene	TCF7L2
CLNDBN	Diabetes mellitus type 2
Reversed	0
HGVS	NC_000010.10:g.114808902G>T
CLNSRC	OMIM Allelic Variant
CLNACC	RCV000007839.2,

[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

[PMID 27605886 ] TCF7L2 rs7903146 polymorphism is associated with gastric cancer: A case-control study in the Venezuelan population.

[PMID 28101933] Associations of common variants in the SLC16A11, TCF7L2, and ABCA1 genes with pediatric-onset type 2 diabetes and related glycemic traits in families: A case-control and case-parent trio study.

[PMID 28277135] TCF7L2, CAPN10 polymorphisms are associated with gestational diabetes mellitus (GDM) risks: a meta-analysis.

[PMID 28352326 ] Genetic variants in KCNJ11, TCF7L2 and HNF4A are associated with type 2 diabetes, BMI and dyslipidemia in families of Northeastern Mexico: A pilot study.

[PMID 30858716 ] Interaction between dietary patterns and TCF7L2 polymorphisms on type 2 diabetes mellitus among Uyghur adults in Xinjiang Province, China.

[PMID 32445548] Association between type 2 diabetes mellitus & TCF7L2 gene variants in the Emirati population: Genetics of diabetes in the United Arab Emirates.