Arg913Gln of SLC12A3 gene promotes development and progression of end-stage renal disease in Chinese type 2 diabetes mellitus

Zhang, Rong; Zhuang, Langen; Li, Ming; Zhang, Juan; Zhao, Wenxue; Ge, Xin; Chen, Yating; Wang, Feng; Wang, Niansong; Bao, Yuqian; Liu, Limei; Liu, Yanjun; Jia, Weiping

doi:10.1007/s11010-017-3120-z

Cited by 17 publications

(19 citation statements)

References 33 publications

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“…It regulates the reabsorption of sodium ions and chloride ions and is a pivotal point of maintaining electrolyte homeostasis and regulating arterial blood pressure [76]. A loss of NCC function is responsible for Gitelman syndrome, an autosomal recessive disorder characterized by low blood pressure, hypocalciuria, hypokalemic metabolic alkalosis, and hypomagnesemia.…”

Section: Other Susceptibility Genesmentioning

confidence: 99%

“…Additionally, in a Korean population, SNPs and haplotypes of the SLC12A3 gene, especially Arg913Gln, were significantly associated with ESRD caused by DN [79]. A recent case-control study suggested that Arg913Gln was associated with a high risk of DN-ESRD in Chinese T2DM patients undergoing hemodialysis and that the GA+AA genotype may be related to increased blood pressure and urinary albumin excretion rate [76]. However, genetic variation at the SLC12A3 locus does not explain the risk of advanced DN among Caucasians and North Indian populations with T2D [80].…”

Section: Other Susceptibility Genesmentioning

confidence: 99%

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The Susceptibility Genes in Diabetic Nephropathy

Wei

Xiao

et al. 2018

Kidney Dis

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Background: Diabetes mellitus (DM) poses a severe threat to global public health. Diabetic nephropathy (DN) is one of the most common complications of diabetes and the leading cause of end-stage renal disease (ESRD). Approximately 30–40% of DM patients in the world progress to ESRD, which emphasizes the effect of genetic factors on DN. Family clustering also supports the important role of hereditary factors in DN and ESRD. Therefore, a large number of genetic studies have been carried out to identify susceptibility genes in different diabetic cohorts. Extensive susceptibility genes of DN and ESRD have not been identified until recently. Summary and Key Messages: Some of these associated genes function as pivotal regulators in the pathogenesis of DN, such as those related to glycometabolism and lipid metabolism. However, the functions of most of these genes remain unclear. In this article, we review several susceptibility genes according to their genetic functions to make it easier to determine their exact effect on DN and to provide a better understanding of the advancements from genetic studies. However, several challenges associated with investigating the genetic factors of DN still exist. For instance, it is difficult to determine whether these variants affect the expression of the protein they encode or other cytokines. More efforts should be made to determine how these genes influence the progression of DN. In addition, many results could not be replicated among races, suggesting that the association between genetic polymorphisms and DN is race-specific. Therefore, large, well-designed studies involving more relevant variables and ethnic groups and more relevant functional studies are urgently needed. These studies may be beneficial and retard the progression of DN by early intervention, especially for patients who carry certain risk alleles or genotypes.

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Section: Other Susceptibility Genesmentioning

confidence: 99%

Section: Other Susceptibility Genesmentioning

confidence: 99%

The Susceptibility Genes in Diabetic Nephropathy

Wei

Xiao

et al. 2018

Kidney Dis

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“…[ 29 ] Mutation p.N359K is not the only SLC12A3 mutation associated with T2DM; mutation Arg913Gln of SLC12A3 has also been known to predict the development and progression of end-stage renal disease in Chinese T2DM patients. [ 30 ]…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes mellitus caused by Gitelman syndrome-related hypokalemia

He¹,

Gang²,

Sun³

et al. 2020

Medicine

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Introduction: Gitelman syndrome (GS) is an autosomal-recessive disease caused by SLC12A3 gene mutations. It is characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Recently, patients with GS are found at an increased risk for developing type 2 diabetes mellitus (T2DM). However, diagnosis of hyperglycemia in GS patients has not been thoroughly investigated, and family studies on SLC12A3 mutations and glucose metabolism are rare. Whether treatment including potassium and magnesium supplements, and spironolactone can ameliorate impaired glucose tolerance in GS patients, also needs to be investigated. Patient concerns: We examined a 55-year-old Chinese male with intermittent fatigue and persistent hypokalemia for 17 years. Diagnoses: Based on the results of the clinical data, including electrolytes, oral glucose tolerance test (OGTT), and genetic analysis of the SLC12A3 gene, GS and T2DM were newly diagnosed in the patient. Two mutations of the SLC12A3 gene were found in the patient, one was a missense mutation p.N359K in exon 8, and the other was a novel insert mutation p.I262delinsIIGVVSV in exon 6. SLC12A3 genetic analysis and OGTT of 9 other family members within 3 generations were also performed. Older brother, youngest sister, and son of the patient carried the p.N359K mutation in exon 8. The older brother and the youngest sister were diagnosed with T2DM and impaired glucose tolerance by OGTT, respectively. Interventions: The patient was prescribed potassium and magnesium (potassium magnesium aspartate, potassium chloride) oral supplements and spironolactone. The patient was also suggested to maintain a high potassium diet. Acarbose was used to maintain the blood glucose levels. Outcomes: The electrolyte imbalance including hypokalemia and hypomagnesemia, and hyperglycemia were improved with a remission of the clinical manifestations. Conclusion: GS is one of the causes for manifestation of hypokalemia. SLC12A3 genetic analysis plays an important role in diagnosis of GS. Chinese male GS patients characterized with heterozygous SLC12A3 mutation should be careful toward occurrence of T2DM. Moreover, the patients with only 1 SLC12A3 mutant allele should pay regular attention to blood potassium and glucose levels. GS treatment with potassium and magnesium supplements, and spironolactone can improve impaired glucose metabolism.

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“…Hypertensive patients are often accompanied by abnormal lipid metabolism; therefore, hypertension and dyslipidemia are closely associated with each other and can affect each other’s morbidity. The second possibility is that recent studies have shown that in addition to hypertension and hyperlipidemia, SLC12A3 is also associated with type II diabetes [ 24 ] and obesity [ 25 ]. Several epidemiologic studies have shown that the co-existence of hypertension, and diabetes or obesity is due to common genetic and environmental factors such as diet, physical activity and age [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population

Liang

Zhang

et al. 2018

Lipids Health Dis

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BackgroundThe serum lipid profile, including LDL-C level, is associated with hypertension which is the major cause of cerebrovascular disease (CVD) amounting 30% of global death rate. Previous work also demonstrated important roles of genetic variants of SLC12A3 gene on human CVD, hypertension and other diseases in Mongolian population. However, the relationship between SLC12A3 gene polymorphisms on individuals’ lipid profile is still unknown.MethodsA panel of 15 SNPs of SLC12A3 gene was genotyped within a 424 Mongolians pedigree cohort. The associations between SLC12A3 polymorphisms and four lipid profiles were analyzed by family-based association test (FBAT) and confirmed with haplotype analysis.ResultsFrom both single site and haplotype analyses, the results demonstrated a close relationship between SLC12A3 polymorphisms and LDL-C level. Two SNPs, rs5803 and rs711746 showed significant associations with individuals’ serum LDL-C level (z = − 2.08, P-e = 0.038; z = 2.09, P-e = 0.023, respectively), and distribution of haplotypes constructed by two SNPs also associated with participants’ serum LDL-C level, significantly (Global Chi2 = 9.06 df = 3, P = 0.028).ConclusionOur results demonstrated the importance of SLC12A3 polymorphisms in individuals’ difference about their serum lipid profiles, thereby providing evidence that the genetic variants may contribute to CVD development via modulating person’s LDL-C level and blood pressure, in certain contexts.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0737-1) contains supplementary material, which is available to authorized users.

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Arg913Gln of SLC12A3 gene promotes development and progression of end-stage renal disease in Chinese type 2 diabetes mellitus

Cited by 17 publications

References 33 publications

The Susceptibility Genes in Diabetic Nephropathy

The Susceptibility Genes in Diabetic Nephropathy

Type 2 diabetes mellitus caused by Gitelman syndrome-related hypokalemia

Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population

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