Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case-control study

<p>Abstract</p> <p>Background</p> <p>Candidate gene and genome-wide association studies have both reproducibly identified several common Single Nucleotide Polymorphisms (SNPs) that confer type 2 diabetes (T2D) risk in European populations. Our aim was to evaluate the contribution to T2D of five of these established T2D-associated loci in the Arabic population from Tunisia.</p> <p>Methods</p> <p>A case-control design comprising 884 type 2 diabetic patients and 513 control subjects living in the East-Center of Tunisia was used to analyze the contribution to T2D of the following SNPs: E23K in <it>KCNJ11/Kir6.2</it>, K121Q in <it>ENPP1</it>, the -30G/A variant in the pancreatic β-cell specific promoter of Glucokinase, rs7903146 in <it>TCF7L2 </it>encoding transcription factor 7-like2, and rs7923837 in <it>HHEX </it>encoding the homeobox, hematopoietically expressed transcription factor.</p> <p>Results</p> <p><it>TCF7L2</it>-rs7903146 T allele increased susceptibility to T2D (OR = 1.25 [1.06–1.47], <it>P </it>= 0.006) in our study population. This risk was 56% higher among subjects carrying the TT genotype in comparison to those carrying the CC genotype (OR = 1.56 [1.13–2.16], <it>P </it>= 0.002). No allelic or genotypic association with T2D was detected for the other studied polymorphisms.</p> <p>Conclusion</p> <p>In the Tunisian population, <it>TCF7L2</it>-rs7903146 T allele confers an increased risk of developing T2D as previously reported in the European population and many other ethnic groups. In contrast, none of the other tested SNPs that influence T2D risk in the European population was associated with T2D in the Tunisian Arabic population. An insufficient power to detect minor allelic contributions or genetic heterogeneity of T2D between different ethnic groups can explain these findings.</p

Renin–angiotensin–aldosterone system genotypes and haplotypes affect the susceptibility to nephropathy in type 2 diabetes patients

Background: The association between renin C-4063T and angiotensinogen (AGT) T174M, M235T, and A-6G polymorphisms with diabetic nephropathy (DN) was investigated in Tunisian type 2 diabetes (T2DM) patients. Methods: Study subjects comprised 917 T2DM patients (405 normoalbuminuric, 329 microalbuminuric and 185 macroalbuminuric). Genotyping was done by PCR-RFLP. Results: Renin C-4063T allele and genotype frequencies were comparable between DN cases and normoalbuminuric controls. Although AGT 235T and -6G allele, and 235T/T and -6G/G genotype frequencies were higher in DN compared to normoalbuminuric patients, they were comparable between microalbuminuric or macroalbuminuric patients. Three-locus AGT haplotype analysis (A-6G/T174M/M235T) identified DN-protective (ATM, AMM, GTM) and DN-susceptible (GTM, ATT, GMT and AMT) haplotypes, and demonstrated enrichment of GTT haplotype in macroalbuminuric compared to microalbuminuric or normoalbuminuric patients. Regression analysis confirmed negative (AMM) and positive (GTM, ATT, GMT, AMT) association of AGT haplotypes with microalbuminuria, and negative (AMM) and positive (GTM and ATT) association of AGT haplotypes with macroalbuminuria. None of the AGT haplotypes was associated with DN severity. Conclusions: Genetic variation at the AGT gene influences the risk of nephropathy in T2DM patients but not extent of DN severity, and thus represents a potential DN genetic susceptibility locus worthy of replication. </jats:p

Exploring the Association of Biochemical Characterization and Genetic Determinants of TNF-&alpha;, CXCR2, and CCR5 Delta 32 Mutation with Predisposition to Polycystic Ovary Syndrome

PCOS is a heterogeneous, multifactorial endocrine disorder with a complex pathophysiology. It is a globally rising infertility disorder that affects a large percentage of women of reproductive age, with a relatively high prevalence of 8&ndash;13%. Genome-wide association studies have revealed associations of genetic variations with many diseases, including PCOS. The cellular activity of IL8 is mediated by the receptor CXCR2, and transcription of IL8 is controlled by TNF-&alpha;. Therefore, this study aimed to investigate the association of TNF-&alpha;, CCR5-delta32, and CXCR2 gene variations with PCOS. Methodology: In this case control study, we used amplification-refractory mutation system (ARMS)-PCR to detect and determine the presence of the polymorphic variants TNF-&alpha;, CCR5-delta32, and CXCR2 in the study subjects. These gene polymorphs may serve as critical candidate gene variants in PCOS pathogenesis and therapeutics. Results: The case&ndash;control study&rsquo;s findings revealed that the majority of the biochemical and endocrine serum biomarkers examined in the investigation&mdash;including lipids (LDL, HDL, and cholesterol), T2DM markers (fasting glucose, free insulin, and HOMA-IR), and hormones (FSH, LH, testosterone, and progesterone)&mdash;exhibited statistically significant changes in PCOS patients. The distributions of TNF-&alpha; (rs1800629), CCR5-delta32, and CXCR2 (rs2230054) genotypes analyzed within PCOS patients and healthy controls in the considered population were significant (p &lt; 0.05). The heterozygosity of CXCR2-CA, TNF-&alpha; GA, and CCR5(WT+&Delta;32*) genotypes was significantly associated with PCOS susceptibility, with high OR and p &lt; 0.05 in the codominant model. Similarly, the A allele of the TNF-&alpha; and CXCR2 genes, along with the CCR5&Delta;32*(mutant) allele, was significantly associated with PCOS susceptibility, with high OR and p &lt; 0.05. Likewise, the CXCR2 (CA+AA) vs CC genotype was associated with increased susceptibility to PCOS, with OR 2.25, p &lt; 0.032. Conclusions: Our study concludes that TNF-&alpha; rs1800629G&gt;A, CXCR2-rs2230054C&gt;T, and CCR5-Delta32 rs333 are potential loci for developing PCOS in the Tabuk population. These findings might eventually be useful in identifying and classifying those who are at risk for PCOS. To validate these results, it is advised that further longitudinal studies be conducted in diverse ethnic populations and with larger sample sizes

Adiponectin (<i>ADIPOQ</i>) gene variants and haplotypes in Saudi Arabian women with polycystic ovary syndrome (PCOS): a case–control study

The aim of this study is to assess the association of nine SNPs on ADIPOQ on the PCOS risk among Saudi Arabian Women. A case–control study, including 162 cases and 162 controls in Saudi Arabia, was enrolled. Genotyping was carried out by the allelic discrimination method. Estimated haplotype frequencies were assessed using the maximum likelihood method. Results showed that ADIPOQ SNPs were not associated with PCOS for allelic and genotypic frequencies (p > .05). In haplotype estimation analysis, a significant positive association was detected between 21211 haplotype (rs2241766/rs1501299/rs2241767/rs3774261/rs17366743) in additive model with increased risk of PCOS (p = .009, OR = 2.16 [1.22–3.82] CI 95%). None of the nine SNPs illustrated significant association with the quantitative traits after multiple test corrections. These results support a significant association of 21211 haplotype (rs2241766/rs1501299/rs2241767/rs3774261/rs17366743) of ADIPOQ gene in Saudi women with polycystic ovary syndrome.</p

Common polymorphisms of calpain-10 and the risk of Type 2 Diabetes in a Tunisian Arab population: a case-control study

Abstract Background Genetic variations in the calpain-10 gene (CAPN10), in particular the at-risk diplotype (112/121), were previously implicated with increased risk of type 2 diabetes (T2D). Methods We examined the association of CAPN10 UCSNP-43 (rs3792267), UCSNP-19 (rs3842570), and UCSNP-63 (rs5030952) SNPs with T2D in 917 Tunisian T2D patients and 748 non-diabetic controls. CAPN10 genotyping was done by PCR-RFLP. Results Enrichment of UCSNP-19 2R (minor) allele and 2R/2R genotype was found in T2D patients; the allele and genotype distribution of UCSNP-43 and UCSNP-63 alleles and genotypes were not significantly different between patient groups and non-diabetic control subjects. Regression analysis demonstrated progressive increases in T2D risk in 3R/2R [OR (95% CI) = 1.35 (1.08 - 1.68)] and 2R/2R [OR (95% CI) = 1.61 (1.20 - 2.18)] genotypes. Of the six haplotypes detected, enrichment of haplotype 111 (UCSNP-43/UCSNP-19/UCSNP-63) was seen in patients (Pc = 0.034); the distribution of the other haplotypes was comparable between patients and control subjects; neither haplotype 211 nor haplotype 212 was observed. Furthermore, the frequency of all CAPN10 diplotypes identified, including the "high-risk diplotype (112/121) reported for Mexican-Americans and Northern Europeans, were comparable between patients and controls. Conclusions CAPN10 UCSNP-19 variant, and the 111 haplotype contribute to the risk of T2D in Tunisian subjects; no significant associations between CAPN10 diplotypes and T2D were demonstrated for Tunisians.</p