Abstract 54: Genome-Wide Association Analysis of Gene-Sodium Interactions on Blood Pressure Phenotypes: The GenSalt Study

Background: Elevated blood pressure (BP) is a major public health challenge. Although the heritability of BP has been long established, current findings can explain only a small proportion of the BP variability attributed to genetic factors. Recent studies indicate that gene-environmental interactions may help to identify novel BP loci. Hence, the current study aimed to identify genetic variants influencing BP regulation by conducting genome-wide gene-sodium interaction analyses among 1,906 participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods: GenSalt recruited 1,906 Chinese participants from 633 families. At baseline, one 24-hour and two 8-hour urine specimens were collected to measure urinary sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 868,158 autosomal single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genomewide Human SNP array 6.0 (Affymetrix, Inc, Santa Clara, CA). Mixed effects models were used to test genome-wide SNP-sodium interactions on BP, adjusting for age, gender, and body mass index. Promising findings (interaction term P <1.00х10 -6 ) from GenSalt were further evaluated for replication among Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with available data from the database of genotypes and phenotypes (dbGaP). SNP effects in GenSalt and MESA were meta-analyzed using inverse-variance weighted fixed effect models. Results: The meta-analyses identified 3 novel loci that significantly interacted with sodium to influence BP phenotypes. SNP-sodium interactions on systolic BP were identified for NEK2 variant rs10494938 at 1q32.3 (GenSalt P =2.19х10 -6 , MESA P =4.35х10 -4 , and Meta-analysis P = 3.93х10 -8 ). In addition, CASP4 variant rs1944900 at 11q22.3 interacted with sodium to influence both systolic BP (GenSalt P =1.24х10 -9 , MESA P =4.22х10 -2 , and Meta-analysis P = 1.14х10 -10 ) and mean arterial pressure (GenSalt P =1.68х10 -9 , MESA P =4.27х10 -2 , and Meta-analysis P = 1.91х10 -10 ). Furthermore, C9orf3 variant rs17679141 at 9q22.32 interacted with sodium to influence diastolic BP (GenSalt P =2.85х10 -8 , MESA P =4.55х10 -2 , and Meta-analysis P =4.61х10 -9 ). The 3 variants all physically mapped to the intronic regions of their corresponding genes. Conclusion: The current study identified 3 novel loci which may interact with dietary sodium intake to influence BP phenotypes.

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Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

Scientific Reports ◽

10.1038/s41598-020-79931-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jaakko Laaksonen ◽

Pashupati P. Mishra ◽

Ilkka Seppälä ◽

Leo-Pekka Lyytikäinen ◽

Emma Raitoharju ◽

...

Keyword(s):

Blood Pressure ◽

Mitochondrial Dna ◽

Genome Wide Association Study ◽

Rare Variants ◽

Meta Analysis ◽

Noncommunicable Diseases ◽

Nucleotide Polymorphisms ◽

Genetic Determinants ◽

Genome Wide ◽

Mitochondrial Dna Variants

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

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Abstract P276: A High Sodium Diet Reduces Cutaneous Microvascular Function In Normotensive Individuals With Salt Sensitive Blood Pressure

Hypertension ◽

10.1161/hyp.78.suppl_1.p276 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Jordan C Patik ◽

Joseph M Stock ◽

Nathan T Romberger ◽

Shannon L Lennon ◽

William B Farquhar ◽

...

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Sodium Intake ◽

Local Heating ◽

Urinary Sodium Excretion ◽

Microvascular Function ◽

Dietary Sodium ◽

Heating Unit ◽

Doppler Flowmetry ◽

High Sodium

Impaired vascular function likely contributes to the association between dietary sodium intake and the development of cardiovascular disease. Using the cutaneous microvasculature as a model, we have previously shown that a high sodium (HS) diet blunts local heating-induced vasodilation in normotensive individuals with salt resistant (SR) blood pressure (BP). However, the effect of a HS diet on the cutaneous microvasculature in normotensive salt sensitive (SS) individuals remains unclear. Therefore, we tested the hypothesis that cutaneous microvascular function is reduced by a HS diet to a greater degree in SS compared to SR individuals. After each 7-day controlled feeding diet (low sodium (LS) = 20 mmol/day; HS = 300 mmol/day), an intradermal microdialysis fiber was inserted in the ventral forearm and perfused with Ringer’s solution. Skin blood flow (SkBF) was continuously monitored via laser Doppler flowmetry and a local heating unit was placed over the fiber and heated to 42°C until SkBF reached a stable plateau. Site-specific maximal SkBF was determined by perfusing 28mM sodium nitroprusside and heating to 43°C. Mean arterial pressure (MAP) was assessed at regular intervals on the contralateral arm and was used to calculate cutaneous vascular conductance (CVC = SkBF / MAP). Subjects wore a 24-hr ambulatory BP monitor and collected their urine on the final day of each diet. Fourteen subjects (9W / 5M, 42 ± 14 yr) whose MAP increased >5 mmHg (Δ8 ± 1 mmHg) on the HS diet were defined as SS and were compared to 14 age- (43± 14 yr) and sex-matched SR subjects (Δ1 ± 3 mmHg). SS and SR had similar MAP at baseline (88 ± 9 vs. 90 ± 8 mmHg, P = 0.88) and urinary sodium excretion was increased similarly across groups by the HS diet (Δ239 ± 104 vs. Δ220 ± 66 mmol / 24 hr, P = 0.20). Cutaneous vasodilation in response to local heating was decreased on the HS diet relative to the LS diet in both SS (Δ-9 ± 9 %CVCmax, P = 0.005) and SR (Δ-9 ± 9 %CVCmax, P=0.005); however, there was not a group x diet interaction (P = 0.99). In contrast to our hypothesis, these results suggest that the deleterious effects of high sodium diets on cutaneous microvascular function are similar in normotensive salt sensitive and salt resistant individuals.

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High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.736001 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ruilian You ◽

Lanlan Chen ◽

Lubin Xu ◽

Dingding Zhang ◽

Haitao Li ◽

...

Keyword(s):

Blood Pressure ◽

Causal Relationship ◽

Mendelian Randomization ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Inverse Variance ◽

The Uk ◽

High Level

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

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Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials

BMJ ◽

10.1136/bmj.m315 ◽

2020 ◽

pp. m315 ◽

Cited By ~ 21

Author(s):

Liping Huang ◽

Kathy Trieu ◽

Sohei Yoshimura ◽

Bruce Neal ◽

Mark Woodward ◽

...

Keyword(s):

Systematic Review ◽

Blood Pressure ◽

Dose Response ◽

Sodium Excretion ◽

Meta Analysis ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Dietary Sodium ◽

Sodium Reduction ◽

Randomised Trials

AbstractObjectiveTo examine the dose-response relation between reduction in dietary sodium and blood pressure change and to explore the impact of intervention duration.DesignSystematic review and meta-analysis following PRISMA guidelines.Data sourcesOvid MEDLINE(R), EMBASE, and Cochrane Central Register of Controlled Trials (Wiley) and reference lists of relevant articles up to 21 January 2019.Inclusion criteriaRandomised trials comparing different levels of sodium intake undertaken among adult populations with estimates of intake made using 24 hour urinary sodium excretion.Data extraction and analysisTwo of three reviewers screened the records independently for eligibility. One reviewer extracted all data and the other two reviewed the data for accuracy. Reviewers performed random effects meta-analyses, subgroup analyses, and meta-regression.Results133 studies with 12 197 participants were included. The mean reductions (reduced sodium v usual sodium) of 24 hour urinary sodium, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were 130 mmol (95% confidence interval 115 to 145, P<0.001), 4.26 mm Hg (3.62 to 4.89, P<0.001), and 2.07 mm Hg (1.67 to 2.48, P<0.001), respectively. Each 50 mmol reduction in 24 hour sodium excretion was associated with a 1.10 mm Hg (0.66 to 1.54; P<0.001) reduction in SBP and a 0.33 mm Hg (0.04 to 0.63; P=0.03) reduction in DBP. Reductions in blood pressure were observed in diverse population subsets examined, including hypertensive and non-hypertensive individuals. For the same reduction in 24 hour urinary sodium there was greater SBP reduction in older people, non-white populations, and those with higher baseline SBP levels. In trials of less than 15 days’ duration, each 50 mmol reduction in 24 hour urinary sodium excretion was associated with a 1.05 mm Hg (0.40 to 1.70; P=0.002) SBP fall, less than half the effect observed in studies of longer duration (2.13 mm Hg; 0.85 to 3.40; P=0.002). Otherwise, there was no association between trial duration and SBP reduction.ConclusionsThe magnitude of blood pressure lowering achieved with sodium reduction showed a dose-response relation and was greater for older populations, non-white populations, and those with higher blood pressure. Short term studies underestimate the effect of sodium reduction on blood pressure.Systematic review registrationPROSPERO CRD42019140812.

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Dietary Sodium Restriction in the Management of Chronic Kidney Disease: A Systematic Review and Meta-Analysis of RCTs

10.21203/rs.3.rs-806377/v1 ◽

2021 ◽

Author(s):

Sai Sidharth Manikandan ◽

Murali Dhar

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Salt Intake ◽

Sodium Intake ◽

Meta Analysis ◽

Cost Effective ◽

Mean Difference ◽

Dietary Sodium ◽

High Sodium

Abstract Background: Non-pharmacological strategies such as lowering sodium intake aim to protect renal function and delay the initiation of renal replacement therapy. It might also be a cost-effective method to improve chronic kidney disease (CKD) prognosis. We decided to perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of low versus high sodium intake in adults with CKD. Results:Our search strategy yielded seven studies from six countries with 465 participants. The overall effect on restricted sodium intake favored reduction in systolic blood pressure with an overall mean difference of -6.14(95% CI: -9.52, -2.76) and reduction in diastolic blood pressure with a mean difference of -3.08 (95% CI: -4.62, -1.55). There was lowering of estimated glomerular filtration rate (eGFR), however the same was not statistically significant.Conclusion:The study found that restricted salt intake could significantly reduce systolic and diastolic BP. Further, multi-center RCTs for longer durations across different stages of CKD could effectively assess the effects of restricted sodium intake on vital parameters. Such study designs could also help clinicians identify the optimal intake of dietary sodium to achieve better renal and cardio vascular outcomes.

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Dietary Sodium Restriction in the Management of Chronic Kidney Disease: A Meta-Analysis of RCTs

Austin Journal of Nephrology and Hypertension ◽

10.26420/austinjnephrolhypertens.2021.1098 ◽

2021 ◽

Vol 8 (2) ◽

Author(s):

Sai Sidharth M ◽

◽

Dhar M ◽

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Salt Intake ◽

Sodium Intake ◽

Meta Analysis ◽

Mean Difference ◽

Dietary Sodium ◽

Cochrane Library ◽

High Sodium

Introduction: Non-pharmacological strategies such as lowering sodium intake aim to protect renal function and delay the initiation of renal replacement therapy. It might also be a cost-effective method to improve Chronic Kidney Disease (CKD) prognosis. We decided to perform a meta-analysis of Randomized Controlled Trials (RCTs) to evaluate the effects of low versus high sodium intake in adults with CKD. Methodology: We searched the online databases – PUBMED, Cochrane Kidney and Transplant Specialized Register, Cochrane Library and Google Scholar to 31st December 2020 for RCTs to be included in the study. Meta- Analysis was performed for the intervention groups for each arm against the control. Inverse variance methods were applied for analysis using random effects models due to the high heterogeneity among the studies. Results: Our search strategy yielded seven studies from six countries with 465 participants. The overall effect on restricted sodium intake favored reduction in systolic blood pressure with an overall mean difference of -6.14(95% CI: -9.52, -2.76) and reduction in diastolic blood pressure with a mean difference of -3.08 (95% CI: -4.62, -1.55). There was lowering of estimated Glomerular Filtration Rate (eGFR), however the same was not statistically significant. Conclusion: The study found that restricted salt intake could significantly reduce systolic and diastolic BP. Further, multi-center RCTs for longer durations across different stages of CKD could effectively assess the effects of restricted sodium intake on vital parameters. Such study designs could also help clinicians identify the optimal intake of dietary sodium to achieve better renal and cardio vascular outcomes.

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Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Frontiers in Genetics ◽

10.3389/fgene.2021.693933 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ye Lu ◽

Chiara Corradi ◽

Manuel Gentiluomo ◽

Evangelina López de Maturana ◽

George E. Theodoropoulos ◽

...

Keyword(s):

Pancreatic Cancer ◽

Target Genes ◽

Meta Analysis ◽

Micro Rna ◽

Cancer Case ◽

Nucleotide Polymorphisms ◽

Genetic Heritability ◽

Genome Wide ◽

Association Data ◽

Meta Analyses

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case–Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07–1.17, p = 3.03 × 10−6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

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Association between 24-h urinary sodium and potassium excretion and blood pressure among Chinese adults aged 18–69 years

Scientific Reports ◽

10.1038/s41598-021-83049-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaofu Du ◽

Le Fang ◽

Jianwei Xu ◽

Xiangyu Chen ◽

Yamin Bai ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Excretion ◽

Sodium Intake ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Inverse Association ◽

Potassium Excretion ◽

Chinese Adults ◽

Potassium Intake ◽

Sodium And Potassium

AbstractThe direction and magnitude of the association between sodium and potassium excretion and blood pressure (BP) may differ depending on the characteristics of the study participant or the intake assessment method. Our objective was to assess the relationship between BP, hypertension and 24-h urinary sodium and potassium excretion among Chinese adults. A total of 1424 provincially representative Chinese residents aged 18 to 69 years participated in a cross-sectional survey in 2017 that included demographic data, physical measurements and 24-h urine collection. In this study, the average 24-h urinary sodium and potassium excretion and sodium-to-potassium ratio were 3811.4 mg/day, 1449.3 mg/day, and 4.9, respectively. After multivariable adjustment, each 1000 mg difference in 24-h urinary sodium excretion was significantly associated with systolic BP (0.64 mm Hg; 95% confidence interval [CI] 0.05–1.24) and diastolic BP (0.45 mm Hg; 95% CI 0.08–0.81), and each 1000 mg difference in 24-h urinary potassium excretion was inversely associated with systolic BP (− 3.07 mm Hg; 95% CI − 4.57 to − 1.57) and diastolic BP (− 0.94 mm Hg; 95% CI − 1.87 to − 0.02). The sodium-to-potassium ratio was significantly associated with systolic BP (0.78 mm Hg; 95% CI 0.42–1.13) and diastolic BP (0.31 mm Hg; 95% CI 0.10–0.53) per 1-unit increase. These associations were mainly driven by the hypertensive group. Those with a sodium intake above about 4900 mg/24 h or with a potassium intake below about 1000 mg/24 h had a higher risk of hypertension. At higher but not lower levels of 24-h urinary sodium excretion, potassium can better blunt the sodium-BP relationship. The adjusted odds ratios (ORs) of hypertension in the highest quartile compared with the lowest quartile of excretion were 0.54 (95% CI 0.35–0.84) for potassium and 1.71 (95% CI 1.16–2.51) for the sodium-to-potassium ratio, while the corresponding OR for sodium was not significant (OR, 1.28; 95% CI 0.83–1.98). Our results showed that the sodium intake was significantly associated with BP among hypertensive patients and the inverse association between potassium intake and BP was stronger and involved a larger fraction of the population, especially those with a potassium intake below 1000 mg/24 h should probably increase their potassium intake.

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The Effects of Short-Term Changes in Sodium Intake on Plasma Marinobufagenin Levels in Patients with Primary Salt-Sensitive and Salt-Insensitive Hypertension

Nutrients ◽

10.3390/nu13051502 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1502

Author(s):

Katarzyna Łabno-Kirszniok ◽

Agata Kujawa-Szewieczek ◽

Andrzej Wiecek ◽

Grzegorz Piecha

Keyword(s):

Blood Pressure ◽

Diastolic Blood Pressure ◽

Sodium Intake ◽

Left Ventricular ◽

Primary Hypertension ◽

Dietary Sodium ◽

Sodium Restriction ◽

Short Term ◽

Salt Loading ◽

Dietary Sodium Restriction

Increased marinobufagenin (MBG) synthesis has been suggested in response to high dietary salt intake. The aim of this study was to determine the effects of short-term changes in sodium intake on plasma MBG levels in patients with primary salt-sensitive and salt-insensitive hypertension. In total, 51 patients with primary hypertension were evaluated during acute sodium restriction and sodium loading. Plasma or serum concentrations of MBG, natriuretic pro-peptides, aldosterone, sodium, potassium, as well as hematocrit (Hct) value, plasma renin activity (PRA) and urinary sodium and potassium excretion were measured. Ambulatory blood pressure monitoring (ABPM) and echocardiography were performed at baseline. In salt-sensitive patients with primary hypertension plasma MBG correlated positively with diastolic blood pressure (ABPM) and serum NT-proANP concentration at baseline and with serum NT-proANP concentration after dietary sodium restriction. In this subgroup plasma MBG concentration decreased during sodium restriction, and a parallel increase of PRA was observed. Acute salt loading further decreased plasma MBG concentration in salt-sensitive subjects in contrast to salt insensitive patients. No correlation was found between plasma MBG concentration and left ventricular mass index. In conclusion, in salt-sensitive hypertensive patients plasma MBG concentration correlates with 24-h diastolic blood pressure and dietary sodium restriction reduces plasma MBG levels. Decreased MBG secretion in response to acute salt loading may play an important role in the pathogenesis of salt sensitivity.

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Genetic Polymorphisms and the Risk of Diabetic Foot: A Systematic Review and Meta-Analyses

The International Journal of Lower Extremity Wounds ◽

10.1177/1534734620977599 ◽

2020 ◽

pp. 153473462097759

Author(s):

Jun Zhao ◽

Le-Xuan Zhang ◽

Yu-Ting Wang ◽

Yang Li ◽

Hong-Lin Chen, MD

Keyword(s):

Genetic Polymorphisms ◽

Diabetic Foot ◽

Protective Factor ◽

Meta Analysis ◽

Nucleotide Polymorphisms ◽

Asian Populations ◽

Tnf Α ◽

Newcastle Ottawa Scale ◽

Meta Analyses ◽

Relationship Of

Background Diabetic foot (DF) is a dangerous complication of diabetes. The aim of the study was to synthesize all the published single nucleotide polymorphisms (SNPs) of DF to objectively evaluate the relationship of SNPs and DF risks. Methods The HuGE database and CNKI were searched for eligible publications on genetic polymorphisms and the risk of DF systematically. The quality of literatures was evaluated by the Newcastle-Ottawa scale. Pooled odds ratios with a 95% confidence interval for SNPs were evaluated through 3 genetic models. Results Citing 29 different polymorphisms from 24 articles and the study met our selection criteria. There were 24 polymorphisms summarized systematically, and 5 merged polymorphisms for a meta-analysis: 9 positively associated with DF: HIF-1α rs11549465, TNF-α rs1800629, TLR-9 rs5743836, FIB rs6056, HSP70-2437C/T, VDR rs2228570, LOX rs1800449, ITLN1 rs2274907, and OPG rs2073617, but OPG rs3134069 was not a risk factor in DF; 6 negatively associated with DF: VEGF rs833061 and rs2010963, MCP-1 rs1024611, SDF-1 rs1801157, SIRT1 rs12778366, and OPG rs2073617. In addition, 13 polymorphisms were not associated with DF: MMP-9 rs3918242, eNOS rs1799983, VEGF rs3025039, -7C/T, rs1570360, rs13207351, and rs699947, IL-6 rs1800795, HIF-1α rs11549467, TNF-α rs361525, TLR-2 rs3804100, SIRT1 rs3758391, and TIMP-1 rs2070584. Conclusions The study provided some evidence for SNPs to the development of diabetic foot. The meta-analysis showed that rs1024611 of MCP-1 may be regarded as a protective factor, especially in Asian populations. Other loci indicated inconsistent results.

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