Diabetes Metab J.  2021 Jul;45(4):578-593. 10.4093/dmj.2020.0101.

Association of Combined TCF7L2 and KCNQ1 Gene Polymorphisms with Diabetic Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus

• Rattanatham R
• Settasatian N
• Komanasin N
• Kukongviriyapan U
• Sawanyawisuth K
• Intharaphet P
• Senthong V
• Settasatian C

• KMID: 2518900
• DOI: http://doi.org/10.4093/dmj.2020.0101

Abstract

Background
Vascular complications are the major morbid consequences of type 2 diabetes mellitus (T2DM). The transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) are common T2DM susceptibility genes in various populations. However, the associations between polymorphisms in these genes and diabetic complications are controversial. This study aimed to investigate the effects of combined gene-polymorphisms within TCF7L2, KCNQ1, and KCNJ11 on vascular complications in Thai subjects with T2DM.
Methods
We conducted a case-control study comprising 960 T2DM patients and 740 non-diabetes controls. Single nucleotide polymorphisms in TCF7L2, KCNQ1, and KCNJ11 were genotyped and evaluated for their association with diabetic vascular complications.
Results
The gene variants TCF7L2 rs290487-T, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-C were associated with increased risk of T2DM. TCF7L2 rs7903146-C, TCF7L2 rs290487-C, KCNQ1 rs2237892-T, and KCNQ1 rs2237897-T revealed an association with hypertension. The specific combination of risk-alleles that have effects on T2DM and hypertension, TCF7L2 rs7903146-C, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-T, as genetic risk score (GRS), pronounced significant association with coronary artery disease (CAD), cumulative nephropathy and CAD, and cumulative microvascular and macrovascular complications (respective odds ratios [ORs] with 95% confidence interval [95% CI], comparing between GRS 2–3 and GRS 5–6, were 7.31 [2.03 to 26.35], 3.92 [1.75 to 8.76], and 2.33 [1.13 to 4.79]).
Conclusion
This study demonstrated, for the first time, the effect conferred by specific combined genetic variants in TCF7L2 and KCNQ1 on diabetic vascular complications, predominantly with nephropathy and CAD. Such a specific pattern of gene variant combination may implicate in the progression of T2DM and life-threatening vascular complications.

Keyword

Diabetes mellitus, type 2; Diabetic angiopathies; Hypertension; potassium channel; Polymorphism, genetic; Transcription factor 7-like 2 protein

Figure

• 

  Fig. 1. Adjusted odds ratios (ORs) and 95% confidence interval (CI) for the combined effect of KCNQ1 rs2237892 and rs2237897 risk alleles, as genetic risk score (GRS), on vascular complications in type 2 diabetes mellitus patients: (A) diabetic nephropathy (DN), (B) coronary artery disease (CAD), (C) cumulative DN and CAD, and (D) cumulative micro- and macrovascular complications; GRS 0–1 as reference; ORs adjusted for age, sex, hypertension, dyslipidemia, glycated hemoglobin, and body mass index.

• 

  Fig. 2. Adjusted odds ratios (ORs) and 95% confidence interval (CI) for the combined effect of TCF7L2 (rs7903146) and KCNQ1 (rs2237892 and rs2237897) risk alleles, as genetic risk score (GRS), on vascular complications in type 2 diabetes mellitus patients: (A) diabetic nephropathy (DN), (B) coronary artery disease (CAD), (C) cumulative DN and CAD, and (D) cumulative micro- and macrovascular complications; GRS 2–3 as reference; ORs adjusted for age, sex, hypertension, dyslipidemia, glycated hemoglobin, and body mass index.

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