The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications

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obesity 141 endocrinologydiseases
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cortisol 16240 levels in Swedish [[70]] and Danish [[71]] men. However, this INDEL was not associated with salivary cortisol [[72]], obesity, and related traits [[63], [71]].Melanocortin 4 receptor gene (MC4R)Like FTO, MC4R has
Select Disease Character Offset Disease Term Instance
childhood obesity 37618 family-based design in more than 1000 French or German Caucasian families, this VNTR was not associated with childhood obesity and variance of insulin resistance, insulin secretion, and birth weight [[191]].VNTRs in inflammatory
hyperinsulinemia 34716 signaling, which will lead to insulin resistance [[165]]. As a consequence, increased insulin production ( hyperinsulinemia ) in the pancreas is needed to maintain normal values of glycemia, which, in turn, converts the liver
hypertriglyceridemia 1021 measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia , hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome). Hence, this
hypertriglyceridemia 7909 measurements, biochemical variables, and eating behavior) and its related complications (like hypertension, hypertriglyceridemia , hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome), INDELs and
hypertriglyceridemia 43408 [[231]] and insulin resistance [[232]–[234]]. eNOS SNPs also appear to increase susceptibility for hypertriglyceridemia and low HDL [[235]] and worsen endothelial function in individuals prone to T2D [[236]]. However, neither
hypertriglyceridemia 45827 magnitude of the association between childhood gain in upper body adiposity, insulin resistance, and hypertriglyceridemia [[254]] and by increasing carbohydrate intake in morbidly obese Czech population [[255]]. In contrast,
metabolic syndrome 1112 hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome ). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with
metabolic syndrome 8000 hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome ), INDELs and VNTRs have received far less coverage and attention. In fact, INDELs and VNTRs could have
metabolic syndrome 34965 with all of its negative downstream effects [[165]].A gene that may be involved in the development of metabolic syndrome is the gene codifying for insulin itself (INS). INS is located between TH and the insulin-like growth
metabolic syndrome 44736 infarction [[244]], and hypertrophic cardiomyopathy [[245]] to obesity-related complications such as metabolic syndrome [[246]], T2D [[247]], and reduced HDL-C levels [[248]].Research on the association of this INDEL with
obesity 141 AnthropologyThe association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complicationsYee-How SayPublication date (epub): 6/2017Publication date (pmc-release):
obesity 766 variations (CNVs), especially in genome-wide association studies (GWAS) of complex diseases like polygenic obesity . This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its
obesity 863 polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity , its related traits (like anthropometric measurements, biochemical variables, and eating behavior),
obesity 1233 Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications.Main body of the abstractThese INDELs and VNTRs could be found
obesity 1352 related traits and complications.Main body of the abstractThese INDELs and VNTRs could be found in the obesity loci or genes from the earliest GWAS and candidate gene association studies, like FTO, genes in the
obesity 1595 pathway, and UCP2/3. Given the important role of the brain serotonergic and dopaminergic reward system in obesity susceptibility, the association of INDELs and VNTRs in these neurotransmitters’ metabolism and transport
obesity 1721 the association of INDELs and VNTRs in these neurotransmitters’ metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since
obesity 1777 neurotransmitters’ metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since recent large-scale studies failed to replicate the earlier
obesity 1916 questionable, since recent large-scale studies failed to replicate the earlier positive associations. As obesity results in chronic low-grade inflammation of the adipose tissue, the proinflammatory cytokine gene IL1RA
obesity 2103 proinflammatory cytokine gene IL1RA and anti-inflammatory cytokine gene IL4 have VNTRs that are implicated in obesity . A systemic proinflammatory state in combination with activation of the renin–angiotensin system and
obesity 2265 activation of the renin–angiotensin system and decreased nitric oxide bioavailability as found in obesity leads to endothelial dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could
obesity 2404 dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could be predisposing factors of obesity . Finally, two novel genes, DOCK5 and PER3, which are involved in the regulation of the Akt/MAPK pathway
obesity 2603 Akt/MAPK pathway and circadian rhythm, respectively, have VNTRs and INDEL that might be associated with obesity .Short conclusionIn conclusion, INDELs and VNTRs could have important functional consequences in the
obesity 2730 conclusion, INDELs and VNTRs could have important functional consequences in the pathophysiology of obesity , and research on them should be continued to facilitate obesity prediction, prevention, and treatment.BackgroundObesity
obesity 2794 consequences in the pathophysiology of obesity, and research on them should be continued to facilitate obesity prediction, prevention, and treatment.BackgroundObesity and its genetic factorsThe worldwide prevalence
obesity 2924 prevention, and treatment.BackgroundObesity and its genetic factorsThe worldwide prevalence of overweight and obesity , which rose by 27.5% in adults and 47.1% in children between 1980 and 2013 [[1]], has been described
obesity 3299 related to several conditions such as type 2 diabetes (T2D) and cardiovascular disease [[2]]. While obesity is mainly caused by environmental factors such as dietary habits and physical activity, it still has
obesity 4049 involved in body weight regulation in humans heavily extrapolated from studies on rodent monogenic obesity models in the 1990s. Monogenic obesity is a rare form of severe obesity that results from gene mutations
obesity 4088 humans heavily extrapolated from studies on rodent monogenic obesity models in the 1990s. Monogenic obesity is a rare form of severe obesity that results from gene mutations that have large effect sizes. By screening
obesity 4121 studies on rodent monogenic obesity models in the 1990s. Monogenic obesity is a rare form of severe obesity that results from gene mutations that have large effect sizes. By screening children with severe, young-onset
obesity 4239 results from gene mutations that have large effect sizes. By screening children with severe, young-onset obesity for the genetic defects identified in mice, loss-of-function (LOF) mutations causing deficiencies are
obesity 4609 [[8]], and melanocortin 4 receptor (MC4R) [[9]]. As these LOF variants are only found in monogenic obesity , they are uncommon in the general population. Therefore, various genetic approaches like candidate gene
obesity 4854 genome-wide linkage studies have been performed to identify susceptibility genetic loci for common polygenic obesity instead in the early 2000s. However, these approaches have been met with little success as the genes
obesity 4999 these approaches have been met with little success as the genes or loci found to be associated with obesity vary heavily across ethnic populations and are therefore difficult to replicate due to several reasons
obesity 5407 of high-throughput genotyping techniques as well as bioinformatics and statistical methods, various obesity genome-wide association studies (GWAS) were conducted from 2006 [[13]]. In GWAS, thousands of genetic
obesity 5595 thousands of genetic variants are genotyped on a single microarray technology for association with obesity and its related traits and complications [[14]]. In the recent decade, numerous GWAS among Caucasians
obesity 5890 East Asians, and Africans, each analyzing >50,000 individual subjects, have identified >90 loci for obesity (reviewed in [[16]]).The potential of INDELs and VNTRs in obesityGenetic variations in the human genome
obesity 5956 subjects, have identified >90 loci for obesity (reviewed in [[16]]).The potential of INDELs and VNTRs in obesity Genetic variations in the human genome present as (i) single nucleotide polymorphisms (SNPs), (ii) insertions/deletions
obesity 7749 association of SNPs and larger forms of structural variation like copy number variations (CNVs) with obesity and its related traits (like anthropometric measurements, biochemical variables, and eating behavior)
obesity 8630 highlights the functional consequences of INDELs and VNTRs in the human genome and their association with obesity and related traits. With the advent of faster and cheaper next-generation genome and exome sequencing,
obesity 8980 [[29]]), it is hoped that association and functional characterization studies between INDELs/VNTRs and obesity should be continued and not neglected.Main textINDELs and VNTRs in obesity genes from the earliest GWAS
obesity 9055 between INDELs/VNTRs and obesity should be continued and not neglected.Main textINDELs and VNTRs in obesity genes from the earliest GWAS and candidate gene studiesNumerous INDELs and VNTRs are located around
obesity 9163 genes from the earliest GWAS and candidate gene studiesNumerous INDELs and VNTRs are located around obesity -susceptible genes or loci identified by the earliest GWAS and candidate gene studies. These mainly include
obesity 9379 genes that are involved in energy balance, appetite regulation, and adipogenesis, i.e., fat mass and obesity -associated protein gene (FTO), and genes in the leptin–proopiomelanocortin pathway and uncoupling
obesity 9566 pathway and uncoupling protein families. It is possible that the association between INDELs/VNTRs and obesity is affected by the obesity-related SNPs because of strong linkage disequilibrium, and the risk or protective
obesity 9593 protein families. It is possible that the association between INDELs/VNTRs and obesity is affected by the obesity -related SNPs because of strong linkage disequilibrium, and the risk or protective variants of INDELs/VNTRs
obesity 9770 or protective variants of INDELs/VNTRs are linked to the counterparts of the focal SNPs.Fat mass and obesity -associated protein gene (FTO)Genetic variants of FTO were the first common genetic variants to be associated
obesity 9902 (FTO)Genetic variants of FTO were the first common genetic variants to be associated with increased obesity and BMI [[30]], with 89 genetic variants in introns 1 and 2 that have the strongest genome-wide association
obesity 10235 distinct ethnic populations (reviewed in [[33]]), making FTO the single strongest genetic factor of obesity . Most studies have focused on variants of a 42-kb haplotype block around the lead SNP rs9939609 in the
obesity 10449 first intron, and recently, a causal variant rs142108 resulting in cellular phenotypes consistent with obesity , like increased triglyceride accumulation and decreased mitochondrial energy generation, has been identified
obesity 10684 very large gene containing nine exons, spanning 412 kb. However, only a few studies have identified obesity -associated SNPs in other regions of the gene, in introns 2, 3 [[35]], and 8 [[36]]. By using massive
obesity 11101 potential novel INDELs [[37]]. Three insertions (minor allele frequency < 5%) reside within the obesity -associated haplotype of intron 1. However, none of these INDELs contributed to obesity association [[37]].Leptin
obesity 11188 reside within the obesity-associated haplotype of intron 1. However, none of these INDELs contributed to obesity association [[37]].Leptin gene (LEP)The discovery that the mouse obesity phenotype ob has been attributed
obesity 11261 these INDELs contributed to obesity association [[37]].Leptin gene (LEP)The discovery that the mouse obesity phenotype ob has been attributed to mutations in the mouse leptin gene [[38]], and that mutations in
obesity 11422 mouse leptin gene [[38]], and that mutations in the human homolog (LEP) cause early-onset monogenic obesity in humans [[6], [39]], has led to significant progress in understanding the etiology of obesity. Analysis
obesity 11518 monogenic obesity in humans [[6], [39]], has led to significant progress in understanding the etiology of obesity . Analysis of the leptin–proopiomelanocortin (LEP–POMC) pathway has revealed the role of the pathway
obesity 11740 hypothalamic control of feeding behavior and energy balance [[40], [41]]. A GWAS which identified 14 known obesity susceptibility variants and 18 new loci that were associated with BMI found that some of these loci
obesity 11979 pathway, i.e., LEP and its receptor LEPR, POMC and MC4R [[42]].While mutations in LEP cause monogenic obesity , there have been numerous research in determining whether genetic variations in or near LEP influences
obesity 12118 research in determining whether genetic variations in or near LEP influences susceptibility to polygenic obesity . Using STR markers flanking the LEP locus at human chromosome 7q31.3-32.1, several groups reported evidence
obesity 12287 7q31.3-32.1, several groups reported evidence of linkage and/or association between these STRs and obesity -related traits, albeit with inconsistencies [[43]–[47]]. A meta-analysis of the linkage data concluded
obesity 12440 [[43]–[47]]. A meta-analysis of the linkage data concluded that the evidence of a gene influencing obesity in the region of the LEP locus was extremely strong [[48]]. A tetranucleotide VNTR, (CTTT)n, was first
obesity 12843 (121–145 bp) and longer class II alleles (197–225 bp); however, they were not significantly associated with obesity and T2D [[49]]. Nevertheless, the same group subsequently found a significant association between class
obesity 13007 subsequently found a significant association between class I/class I genotype and hypertension, independent of obesity [[50]]. In another study among populations worldwide, Moffett et al. grouped this VNTR into three general
obesity 13281 (165–193 bp), and type 3 alleles (210–254 bp), but they did not investigate the association with obesity or related traits [[51]]. In the Brazilian population, this VNTR was significantly associated with obesity-related
obesity 13388 or related traits [[51]]. In the Brazilian population, this VNTR was significantly associated with obesity -related traits and leptinemia, where the frequency of class I alleles was significantly higher in obese
obesity 13544 frequency of class I alleles was significantly higher in obese than in nonobese [[52], [53]]. The risk for obesity was two times higher in class I allele carriers; class I allele was associated with increased BMI and
obesity 13834 VNTR/SNP class I/G combined genotypes (I/IGG, I/IGA, and I/IIGG) were significantly associated with obesity and increased BMI, WC, leptin, and triglycerides in women [[53]]. However, Nauruan (Pacific Islander)
obesity 14414 BMI and fat mass [[56]]. The LEPR D1S200 17 allele was associated with increased susceptibility to obesity and increased BMI, WC, and WHR in Brazilian individuals [[57]]. Other STRs flanking LEPR by approximately
obesity 15173 variant in the 1078Y codon of LEPR (containing a putative phosphorylation site) was not associated with obesity in Dutch Caucasians [[61]].Proopiomelanocortin gene (POMC)A genome-wide scan found that D2S1788 GATA-tetranucleotide
obesity 15782 together with four others near POMC—D2S2170, D2S144, D2S1268, and D2S1348—showed no association with obesity in Samoans [[55]]. Out of three VNTRs (D2S2221, D2S171, D2S2337) screened for association with obesity
obesity 15885 obesity in Samoans [[55]]. Out of three VNTRs (D2S2221, D2S171, D2S2337) screened for association with obesity and related traits in French Caucasian families, only D2S2337 had linkage with serum leptin levels [[68]].
obesity 16257 [[70]] and Danish [[71]] men. However, this INDEL was not associated with salivary cortisol [[72]], obesity , and related traits [[63], [71]].Melanocortin 4 receptor gene (MC4R)Like FTO, MC4R has been extensively
obesity 16380 traits [[63], [71]].Melanocortin 4 receptor gene (MC4R)Like FTO, MC4R has been extensively studied in obesity research. To date, more than 160 mutations in MC4R, mostly heterozygous (codominant inheritance), were
obesity 16673 deletion, and frameshift mutations. Therefore, MC4R is the most commonly known monogenic cause of human obesity (reviewed in [[73], [74]]). In 1998, two groups reported the first functionally relevant MC4R mutations
obesity 16789 (reviewed in [[73], [74]]). In 1998, two groups reported the first functionally relevant MC4R mutations for obesity [[75], [76]]. Yeo et al. identified a hyperphagic individual who was heterozygous for a deletion of
obesity 17100 Another frameshift mutation (4-bp insertion after codon 244) was detected in a woman with early-onset obesity , whose family members who carried the same mutation were obese whereas the noncarriers were not obese
obesity 17309 [[76]]. The first mutation analysis in 306 obese individuals further confirmed the role of MC4R in obesity [[77]]. As the focus of this review is on common polygenic obesity, the examples of INDELs in MC4R which
obesity 17376 further confirmed the role of MC4R in obesity [[77]]. As the focus of this review is on common polygenic obesity , the examples of INDELs in MC4R which lead to rare monogenic obesity will not be further discussed here.
obesity 17445 review is on common polygenic obesity, the examples of INDELs in MC4R which lead to rare monogenic obesity will not be further discussed here. The association of MC4R SNPs with polygenic obesity will also not
obesity 17533 rare monogenic obesity will not be further discussed here. The association of MC4R SNPs with polygenic obesity will also not be further discussed here. Nevertheless, recent GWAS have identified SNPs in the MC4R
obesity 17691 Nevertheless, recent GWAS have identified SNPs in the MC4R 3′ UTR region to have a strong association with obesity , with rs17782313 showing the second strongest association signal after FTO [[78]] and rs129070134 showing
obesity 18032 gene—D18S851, D18S487, D18S69, D18S858, D18S849, D18S1155, D18S64, D18S38—have demonstrated linkage with obesity in Finnish sib pairs, with D18S849 showing the strongest linkage [[81]]. The D18S858 11/12 allele was
obesity 18263 increased BMI and WC in Brazilian subjects [[57]]. This locus was also found to be related to other obesity -related complications, like systolic BP (SBP) [[82]] and cancer [[83]].Uncoupling protein 2 and 3 genes
obesity 18584 thermogenesis. Genetic variants in the UCP2/UCP3 cluster have been considered candidate markers for obesity , diabetes, and fat metabolism in humans [[84]]. D11S912 and other STRs flanking UCP2 and UCP3 showed
obesity 18723 in humans [[84]]. D11S912 and other STRs flanking UCP2 and UCP3 showed some evidence of linkage with obesity and BMI [[4], [81]]. The 43 allele of D11S912 STR was associated with increased risk for obesity in
obesity 18820 with obesity and BMI [[4], [81]]. The 43 allele of D11S912 STR was associated with increased risk for obesity in Brazilians [[57]], consistent with a genome-wide linkage scan study in the Framingham Heart Study
obesity 19276 that other STRs flanking UCP2–UCP3 are unlikely to have a substantial effect on the expression of obesity -related phenotypes in Mexican American [[86]] and Caucasian [[87]] populations.A 45-bp INDEL variant
obesity 19688 studies showed that carriers of the I (insertion) allele had significantly higher risk of developing obesity and BMI compared to the D (deletion) allele [[88], [91]–[94]]. In our study, we found that this INDEL
obesity 19820 D (deletion) allele [[88], [91]–[94]]. In our study, we found that this INDEL was associated with obesity and overall adiposity among females [[95]]. However, when adjusted for age and ethnicity, this association
obesity 19953 among females [[95]]. However, when adjusted for age and ethnicity, this association was abolished for obesity but remained significant for overall adiposity; those carrying the ID genotype or I allele had almost
obesity 20681 genesGiven the important role of the brain serotonergic and dopaminergic reward system in weight gain and obesity susceptibility, investigation of the candidate genes of these neurotransmitters’ metabolism and transport
obesity 22475 [[105]]. Another study with young American adults obtained similar results, whereby the prevalence of obesity combined with overweight was significantly lower among L allele carriers compared with individuals homozygous
obesity 23221 [[107]]. Furthermore, Lan et al. described an age-dependent modification of 5-HTTLPR association with obesity development; they demonstrated that the SS genotype was associated with BMI and obesity in nonelderly
obesity 23309 association with obesity development; they demonstrated that the SS genotype was associated with BMI and obesity in nonelderly patients with stroke but not in elderly patients [[108]]. Recently, it was found that
obesity 23720 [[109]]. The S allele was also strongly associated with the presence of T2D in Greeks independent of obesity status [[110]], but no association with T2D and obesity was found in the Pakistani population [[111]].On
obesity 23776 the presence of T2D in Greeks independent of obesity status [[110]], but no association with T2D and obesity was found in the Pakistani population [[111]].On the other hand, Bah et al. showed different results
obesity 24248 S allele with development of depressive temperament while the L allele was associated with greater obesity and prevalence of depression in Polish adults [[113]]. There was no significant association observed
obesity 24497 Turkish studies [[114], [115]].The first study which investigated the association between STin2 VNTR and obesity found no significant effect on obesity in Turkish adults [[115]]. However, when combined with 5-HTTLPR,
obesity 24536 study which investigated the association between STin2 VNTR and obesity found no significant effect on obesity in Turkish adults [[115]]. However, when combined with 5-HTTLPR, the L/10 allele haplotype showed a
obesity 24684 combined with 5-HTTLPR, the L/10 allele haplotype showed a significant association with overweight/ obesity in Portuguese adults [[116]]. Moreover, in inactive individuals, overweight/obesity was found nominally
obesity 24768 with overweight/obesity in Portuguese adults [[116]]. Moreover, in inactive individuals, overweight/ obesity was found nominally associated with the STin2 10 allele but significantly associated with the 5-HTTLPR
obesity 25611 also has greater DA signaling in the reward circuitry than the L allele [[119]]. The likelihood of obesity in African-American smokers with the LL genotype was 5.16 times compared with the SS or SL genotypes
obesity 25921 increases in BMI than L allele carriers [[121]]. However, in a Turkish study, no effect of this VNTR on obesity was observed [[115]].More literature reported on the association between this VNTR and eating behavior.
obesity 27807 association of another genetic variant that modulates the density of DRD2—DRD2/ANKK1-TaqIA SNP—with both obesity [[126]] and addictive disorders [[128], [129]] instead, which is out of the scope of this review.Dopamine
obesity 29288 other environmental factors. For example, 7R allele/season-of-birth interactions increase the risk for obesity in women with either seasonal affective disorder [[139]] or bulimia nervosa [[140]]. A study of Kenyan
obesity 29755 influenced by maternal sensitivity (response to a child’s emotional signals) as it relates to overweight/ obesity risk [[142]]. However, there was no association between this VNTR alleles with AN, underweight, or extreme
obesity 29882 However, there was no association between this VNTR alleles with AN, underweight, or extreme early-onset obesity [[143]]. Similarly, no association was detected between alleles/genotypes and BMI, BMI-SDS, or skinfold
obesity 30141 loss intervention in obese German children [[144]]. Similarly, there was no association found with obesity in Turkish adults [[115]]. There was also no association found between level of physical activity and
obesity 31492 plausible candidate for affecting individual differences in physiological and psychological traits, such as obesity , personality traits, and alcoholism risk [[150]]. A previous study showed a significant association
obesity 32021 higher activity 4R allele. Meanwhile, another study showed a significant association of this VNTR with obesity in a mixed-ethnic American population [[154]], while Dias et al. [[116]] and our unpublished studies
obesity 33731 dependence [[161]], and personality traits [[162]]. However, the association of this polymorphism with obesity is still elusive as there is scarce data on it. TH mRNA expression was significantly decreased in the
obesity 34036 high-fat-diet-induced obese and obese-resistant mice compared to controls [[163]]. Individuals with central obesity had lower TH expression in their peripheral blood mononuclear cells (PBMCs) compared with controls,
obesity 34320 [[164]]. In our unpublished study, we found that Malaysian subjects with TH VNTR was not associated with obesity , but nevertheless, subjects with the T9 allele had significantly highest SBP and visceral fat level
obesity 36677 reported in a family-based study [[182]].The putative contribution of the INS VNTR in the genetic risk for obesity was first investigated in children. Strong evidence for a family-based association with 1.8-fold increased
obesity 36812 children. Strong evidence for a family-based association with 1.8-fold increased risk of early-onset obesity for class I allele was found, when this allele is paternally inherited [[183]]. An earlier study by
obesity 37628 in more than 1000 French or German Caucasian families, this VNTR was not associated with childhood obesity and variance of insulin resistance, insulin secretion, and birth weight [[191]].VNTRs in inflammatory
obesity 38710 particularly homozygosity for allele II, has been variably associated with various conditions such as obesity , inflammatory bowel disease, and coronary artery disease (reviewed in [[198]]). IL1RA allele II has
obesity 38983 human subjects, its carrier had higher levels than the noncarrier individuals [[199]]. With regard to obesity , two previous Asian studies with relatively small sample sizes found no significant association between
obesity 39228 [[200]] and North Indians [[201]]. Similarly, our study found no association with BMI value or overall obesity status, but IL1RA II allele VNTR was associated with higher TBF value and higher risk for overall adiposity
obesity 40579 sclerosis [[212]], rheumatoid arthritis [[213]], and systemic lupus erythematosus [[214]]. With regard to obesity , there are limited studies on this VNTR, where two studies showed no association [[215], [216]]. Our
obesity 42885 progression of increase in body fat [[229]].A pioneer study investigating the effect of this VNTR on obesity in a sample of the Tunisian population found that carriers of the (b) allele presented 1.7 times higher
obesity 43005 of the Tunisian population found that carriers of the (b) allele presented 1.7 times higher risk of obesity [[230]]. Correlations with anthropometric parameters also revealed that carriers of the bb genotype
obesity 44187 stimulating and inhibiting the production of Ang II [[239]], suggesting a possible link between ACE and obesity (reviewed in [[240]]). In 1990, Rigat et al. first described an INDEL in ACE, defined as either the
obesity 44698 essential hypertension [[243]], myocardial infarction [[244]], and hypertrophic cardiomyopathy [[245]] to obesity -related complications such as metabolic syndrome [[246]], T2D [[247]], and reduced HDL-C levels [[248]].Research
obesity 44857 [[246]], T2D [[247]], and reduced HDL-C levels [[248]].Research on the association of this INDEL with obesity specifically has been growing in the past two decades, mainly showing the role of the D allele or DD
obesity 45008 two decades, mainly showing the role of the D allele or DD genotype in increased risk for overweight/ obesity . The DD genotype was associated with larger increases in body weight and BP in older Italian men, as
obesity 45280 subjects with coronary heart disease (CHD) and DD/ID genotypes had significantly higher prevalence of obesity and abdominal fat deposit and higher values of weight and WC [[250]]. The DD genotype and D allele occurred
obesity 45687 association with BP [[253]]. The DD genotype also heightened the effects of traditional risk factors for obesity , for example by increasing the magnitude of the association between childhood gain in upper body adiposity,
obesity 46253 association was abolished [[256]]. However, other studies reported that this INDEL was not associated with obesity -related traits in overweight sedentary American women [[257]], Korean women [[258], [259]], and a large
obesity 46786 of DOCK5) found a significant association of these VNTRs and INDEL with childhood and adult severe obesity [[261]]. Support for a functional effect of the DOCK5 VNTRs and deletion was also evidenced by the association
obesity 47053 adipose tissue from a Swedish family sample [[261]]. The mechanism of how DOCK5 could contribute to obesity is currently unknown, but it has been postulated that DOCK5, a member of the DOCK family of guanine
obesity 47833 daytime sleepiness [[264]]. In a single study, this VNTR has been investigated for association with obesity -related anthropometric traits, sleep, and nutritional behavior [[265]]. No association with obesity
obesity 47933 obesity-related anthropometric traits, sleep, and nutritional behavior [[265]]. No association with obesity was found. Nevertheless, individuals with the 55 genotype had a higher percentage of daily energy derived
obesity 48270 increase in cholesterol intake [[265]].Points of concernA review paper on the role of INDELs and VNTRs in obesity is virtually nonexistent. Hence, this paper reviews the types of INDELs and VNTRs that have been studied
obesity 48404 Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications, as summarized in Table 1. Some studies showed significant
obesity 48551 complications, as summarized in Table 1. Some studies showed significant associations between INDELs/VNTRs and obesity -related traits whereas other studies were not the case.Table 1Summary of INDELs and VNTRs that have
obesity 48710 case.Table 1Summary of INDELs and VNTRs that have been studied for association with common polygenic obesity and its related traits and complicationsGene/nearest geneINDEL/VNTRType(s) [pivotal reference]Location
obesity 52393 as a genetic maker for linkage and candidate gene association analyses of polygenic traits including obesity , as evidenced by the numerous obesity sequence tagged sites (STSs) as stated in the earlier part of
obesity 52431 candidate gene association analyses of polygenic traits including obesity, as evidenced by the numerous obesity sequence tagged sites (STSs) as stated in the earlier part of the review. This is because genotyping
obesity 52628 genotyping of INDELs and VNTRs is easy with low-resolution gel electrophoresis methods. Virtually, obesity loci identified in the past studies using INDELs or VNTRs were not replicated in the SNP-based GWAS
obesity 52805 replicated in the SNP-based GWAS with enough sample sizes. It suggests that the many of old-fashioned obesity loci were unfortunately false positive. Besides insufficient sample size, these false positive loci
obesity 53702 ethnicity), phenotypic heterogeneity (different definitions, measurements, and categorizations for obesity ), and subjective interpretation of data.Some of these pitfalls in obesity loci discovery and replication
obesity 53776 measurements, and categorizations for obesity), and subjective interpretation of data.Some of these pitfalls in obesity loci discovery and replication genetic association studies could be overcome by following the recommendations
obesity 54702 candidate gene association studies could be highly prioritized in the candidate gene approach in finding obesity loci. INDELs and VNTRs would greatly expand the number of high-scoring variants besides SNPs that are
obesity 54826 VNTRs would greatly expand the number of high-scoring variants besides SNPs that are identified in obesity candidate gene studies and GWAS. As an association does not always imply causality, biological insights
obesity 55277 elucidate the mechanistic effects of the risk alleles in plausible biological pathways involved in obesity . This could be followed by comprehensive in vivo animal studies to ultimately identify the risk allele
obesity 55412 comprehensive in vivo animal studies to ultimately identify the risk allele as a causal variant for obesity and/or its related traits and complications. Inclusion of INDELs and VNTRs in genetic association studies
obesity 55610 association studies would help in defining the genetic architecture of complex traits and diseases like obesity and also to provide new insights into its normal physiology and disease pathophysiology. Identification
obesity 55779 and disease pathophysiology. Identification of the causal relationships between INDELs and VNTRs and obesity risk would facilitate the prediction of obesity onset, early diagnosis of obesity, and the development
obesity 55827 the causal relationships between INDELs and VNTRs and obesity risk would facilitate the prediction of obesity onset, early diagnosis of obesity, and the development of novel and potentially patient-specific therapeutic
obesity 55861 INDELs and VNTRs and obesity risk would facilitate the prediction of obesity onset, early diagnosis of obesity , and the development of novel and potentially patient-specific therapeutic targets

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