Primary Hypertriglyceridemia: A Look Back on the Clinical Classification and Genetics of the Disease.

INTRODUCTION: Hypertriglyceridemia (HTG) is one of the most common metabolic disorders leading to pancreatitis and cardiovascular disease. HTG develops mostly due to impaired metabolism of triglyceride-rich lipoproteins. Although monogenic types of HTG exist, most reported cases are polygenic in nature. AIM: This review article is focused on the classification of Primary HTG and the genetic factors behind its development with the aim of providing clinicians a useful tool for early detection of the disease in order to administer proper and effective treatment. DISCUSSION: HTG is often characterized by a complex phenotype resulting from interactions between genetic and environmental factors. In many instances, the complexity, perplexing causes, and classification of HTG make it difficult for clinicians to properly diagnose and manage the disorder. Better availability of information on its pathophysiology, genetic factors involved, environmental causes, and their interactions could help in understanding such complex disorders and could support its effective diagnosis and treatment. CONCLUSION: The current review has summarized the case definition, epidemiology, pathophysiology, clinical presentation, classification, associated genetic factors, and scope of genetic screening in the diagnosis of primary HTG.

Design of Arab Diabetes Gene-Centric Array (ADGCA) in population with an epidemic of Type 2 Diabetes: A population specific SNP evaluation.

In the case of diabetes and other complex diseases, the challenge has always been to find genetic markers that explain the excess risk associated with development of the disease. In the last 12 years, advances in genotyping technology provided substantial development in the discovery of loci contributing to Type 2 diabetes (T2D) susceptibility. Therefore, the aim of this study is to custom design, for the first time in Arab world, an "Arab Diabetes Gene Centric Array" (ADGCA) that assays 643, 745 SNP markers including 50,617 diabetes associated SNPs. The array content was designed after comprehensive literature search prioritizing Diabetes associated SNPs. PCA was performed to evaluate the relationship between world populations and the Saudi population in building the backbone for the array. A genotype data matrix for PCA analysis was produced by including the genotypes of the 270 HapMap samples including JPT, CHB, YRI and CEU to genotypes of the 1457 Saudi samples. Imputation was executed using IMPUTE2 software and the 1000GP Phase III reference panel. All markers incorporated to ADGCA were validated. Quality checks and evaluation of its capacity and performance as a platform for genetic screening for T2D was performed using the latest stastical tools available. We were successful in designing ADGCA as a custom made chip array designed with a motive to capture genetic variation in loci known or reported to be associated with the development of T2D. However, implementation of ADGCA is currently being performed by our research group using 2000 DNA samples respectively from diabetic and non diabetic individuals which could further validate the use of ADGSA in genetic screening of T2D.

Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways.

BACKGROUND: Diabetes mellitus is the most common chronic endocrine disorder, affecting an estimated population of 382 million people worldwide. It is associated with microvascular and macrovascular complications, including diabetic nephropathy (DN); primary cause of end-stage renal disease. Different inflammatory and angiogenic molecules in various pathways are important modulators in the pathogenesis and progression of diabetic nephropathy. Differential disease risk in DN may be partly attributable to genetic susceptibility. In this meta-analysis, we aimed to determine which of the previously investigated genetic variants in these pathways are significantly associated with the development of DN and to examine the functional role of these genes. METHODS: A systematic search was conducted to collect and analyze all studies published till June 2013; that investigated the association between genetic variants involved in inflammatory cytokines and angiogenesis and diabetic nephropathy. Genetic variants associated with DN were selected and analyzed by using Comprehensive Meta Analysis software. Pathway analysis of the genes with variants showing significant positive association with DN was performed using Genomatix Genome Analyzer (Genomatix, Munich, Germany). RESULTS: After the inclusion and exclusion criteria for this analysis, 34 studies were included in this meta-analysis. 11 genetic variants showed significant positive association with DN in a random-effects meta-analysis. These included genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10. rs1800871 (T) genetic variant in IL-10 showed protective effect for DN. Most of these eleven genetic variants were involved in GPCR signaling and receptor binding pathways whereas four were involved in chronic kidney failure. rs833061 [OR 2.08 (95% CI 1.63-2.66)] in the VEGFA gene and rs3917887 [OR 2.04 (95% CI 1.64-2.54)] in the CCL2 gene showed the most significant association with the risk of diabetic nephropathy. CONCLUSIONS: Our results indicate that 11 genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10 showed significant positive association with diabetic nephropathy. Gene Ontology or pathway analysis showed that these genes may contribute to the pathophysiology of DN. The functional relevance of the variants and their pathways can lead to increased biological insights and development of new therapeutic targets.

ACE I/D and MTHFR C677T polymorphisms are significantly associated with type 2 diabetes in Arab ethnicity: a meta-analysis.

In this meta-analysis study, SNPs were investigated for their association with type 2 diabetes (T2D) in both Arab and Caucasian ethnicities. A total of 55 SNPs were analyzed, of which 11 fulfilled the selection criteria, and were used for analysis. It was found that TCF7L2 rs7903146 was significantly associated with a pooled OR of 1.155 (95%C.I.=1.059-1.259), p<0.0001 and I(2)=78.30% among the Arab population, whereas among Caucasians, the pooled OR was 1.45 (95%C.I.=1.386-1.516), p<0.0001 and I(2)=77.20%. KCNJ11 rs5219 was significantly associated in both the populations with a pooled OR of 1.176(1.092-1.268), p<0.0001 and I(2)=32.40% in Caucasians and a pooled OR of 1.28(1.111-1.475), p=0.001 among Arabs. The ACE I/D polymorphism was found to be significantly associated with a pooled OR of 1.992 (95%C.I.=1.774-2.236), p<0.0001 and I(2)=83.20% among the Arab population, whereas among Caucasians, the pooled OR was 1.078 (95%C.I.=0.993-1.17), p=0.073 and I(2)=0%. Similarly, MTHFR C677T polymorphism was also found to be significantly associated among Arabs with a pooled OR of 1.924 (95%C.I.=1.606-2.304), p<0.0001 and I(2)=27.20%, whereas among Caucasians, the pooled OR was 0.986 (95%C.I.=0.868-1.122), p=0.835 and I(2)=0%. Meanwhile PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, IGF2BP2 rs4402960, HHEX rs7923837, CDKAL1 rs7754840, EXT2 rs1113132 and SLC30A8 rs13266634 were found to have no significant association with T2D among Arabs. In conclusion, it seems from this study that both Arabs and Caucasians have different SNPs associated with T2D. Moreover, this study sheds light on the profound necessity for further investigations addressing the question of the genetic components of T2D in Arabs.