Common polymorphic variation in the genetically diverse African insulin gene and its association with size at birth.
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ABSTRACT:
SUBMITTER: Petry CJ
PROVIDER: S-EPMC2760954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hypertension, type 2 diabetes, and obesity are common complex disorders that contribute to cardiovascular (CV) disease. Insulin resistance increases CV risk and is present in these disorders. Adiponectin, a protein secreted by adipocytes with metabolic and vascular protective effects, is lower in obesity and insulin resistance. Several single nucleotide polymorphisms (SNP) have been identified in the adiponectin (ADIPOQ) gene. Associations of ADIPOQ polymorphisms with diabetes and obesity have been described in Caucasians and Asians. The purpose of this study was to determine if genetic variants of ADIPOQ are associated with insulin resistance and CV risk in African Americans. Metabolic traits (lipids, glucose, insulin, and insulin sensitivity) and blood pressure were measured in 273 African Americans. DNA was examined by DNA sequence analysis and SNPs of candidate genes including ADIPOQ were studied. Statistica analyses were performed by regression of the quantitative trait phenotypes on the groups defined by the SNP genotypes, adjusting for age, sex, and body mass index (BMI). SNP 712 (rs3774261) ofthe/lD/POQgene showed significant association with insulin resistance (p= 0.001). Despite the relatively small sample, our results indicate that genes that regulate adipocyte function may have a regulatory role in the expression of metabolic traits in obesity-associated chronic disease.
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Project description:The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.
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Project description:BackgroundPolygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest.MethodsTo select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas.ResultsWe confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components.ConclusionOur work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.
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Project description:The IGF2 gene (IGF2) plays a key role in growth and is a candidate for association with obesity. Previous studies have reported that polymorphisms in IGF2 are associated with body weight and body mass index (BMI), but the results have been inconsistent.The aim of this study was primarily to confirm the association with BMI and, secondarily, to study the associations with other indices of body size.In a sample of 2797 women and 2203 men aged 39-79 participating in the Norfolk arm of the European Prospective Investigation of Cancer, we genotyped three single nucleotide polymorphisms (SNPs) in the IGF2 gene that were previously associated with BMI [6815 A/T, 1156 T/C (G/A), and 820 G/A (ApaI)].No significant associations were observed between these SNPs and BMI. However, all three SNPs were significantly associated with height (P = 0.03 to 0.001). In a backward elimination regression analysis, two SNPs, 1156 T/C (G/A) and 820 G/A, remained independently associated with height (P = 0.003 and P = 0.038, respectively). Haplotype analysis of these two SNPs showed that carriers of the GA haplotype were shorter than carriers of each of the other three haplotypes (P < 0.001 for all comparisons).We did not confirm the previously reported associations between IGF2 polymorphisms and BMI. However, our results suggest that common variation in the IGF2 gene may be associated with adult height. IGF2 could be considered as a candidate gene for future research on mechanisms for the association between height and chronic diseases, such as cancer, diabetes, and coronary heart disease.
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Project description:BackgroundPreterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery.ObjectiveThe objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women.Study designThis is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks' gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks' gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term.ResultsOf the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term.ConclusionWe identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.
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