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Role of lipids in development of noninsulin-dependent diabetes mellitus: lessons learned from Pima Indians
No full textThe effect of differing patterns of childhood body mass index gain on adult physiology in American Indians
No full textOBJECTIVE:
Identifying groups of individuals with similar patterns of body mass index (BMI) change during childhood may increase understanding of the relationship between childhood BMI and adult health.
METHODS:
Discrete classes of BMI z-score change were determined in 1,920 American Indian children with at least four non diabetic health examinations between the ages of 2 and 18 years using latent class trajectory analysis. In subsets of subjects, data were available for melanocortin-4 receptor (MC4R) sequencing; in utero exposure to type 2 diabetes (T2D); or, as adults, oral glucose tolerance tests, onset of T2D, or body composition.
RESULTS:
Six separate groups were identified. Individuals with a more modern birth year, an MC4R mutation, or in utero exposure to T2D were clustered in the two groups with high increasing and chronic overweight z-scores (P < 0.0001). The z-score classes predicted adult percent fat (P < 0.0001, partial r(2) = 0.18 adjusted for covariates). There was a greater risk for T2D, independent from adult BMI, in three classes (lean increasing to overweight, high increasing, and chronic overweight z-scores) compared to the two leanest groups (respectively: HRR= 3.2, P = 0.01; 6.0, P = 0.0003; 11.6, P < 0.0001).
CONCLUSIONS:
Distinct patterns of childhood BMI z-score change associate with adult adiposity and may impact risk of T2D
Differential methylation of genes in individuals exposed to maternal diabetes in utero
No full textAims/hypothesis
Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND).
Methods
DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed.
Results
Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ≤0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p ≤ 1.1 × 10−5). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p = 5.6 × 10−7), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p = 9.7 × 10−5). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p = 7.8 × 10−6; PCDHGA4: 2.8% lower, p = 3.0 × 10−5; STC1: 2.9% lower, p = 1.6 × 10−5) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p = 0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p = 0.03; STC1: 0.072 SD lower per SD of methylation decrease, p = 0.05). Seventeen CpG sites were also associated with BMI (p ≤ 0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p < 0.005) showed enrichment for three relevant biological pathways.
Conclusions/interpretation
Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes
The impact of genetic variants on BMI increase during childhood versus adulthood
No full textBACKGROUND: Genetic variants that predispose individuals to obesity may have differing influences during childhood versus adulthood, and additive effects of such variants are likely to occur. Our ongoing studies to identify genetic determinants of obesity in American Indians have identified 67 single-nucleotide polymorphisms (SNPs) that reproducibly associate with maximum lifetime non-diabetic body mass index (BMI). This study aimed to identify when, during the lifetime, these variants have their greatest impact on BMI increase. SUBJECTS/METHODS: A total of 5906 Native Americans of predominantly Pima Indian heritage with repeated measures of BMI between the ages of 5 and 45 years were included in this study. The association between each SNP with the rates of BMI increase during childhood (5-19 years) and adulthood (20-45 years) were assessed separately. The significant SNPs were used to calculate a cumulative allelic risk score (ARS) for childhood and adulthood, respectively, to assess the additive effect of these variants within each period of life. RESULTS: The majority of these SNPs (36 of 67) were associated with rate of BMI increase during childhood (P-value range: 0.00004-0.05), whereas only nine SNPs were associated with rate of BMI change during adulthood (P-value range: 0.002-0.02). These 36 SNPs associated with childhood BMI gain likely had a cumulative effect as a higher childhood-ARS associated with rate of BMI change (beta=0.032 kg m(-2) per year per risk allele, 95% confidence interval: 0.027-0.036, P<0.0001), such that at age 19 years, individuals with the highest number of risk alleles had a BMI of 10.2 kg m(-2) greater than subjects with the lowest number of risk alleles. CONCLUSIONS: Overall, our data indicates that genetic polymorphisms associated with lifetime BMI may influence the rate of BMI increase during different periods in the life course. The majority of these polymorphisms have a larger impact on BMI during childhood, providing further evidence that prevention of obesity will need to begin early in life
An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance
No full textAssessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians
No full textAIMS/HYPOTHESIS: Epidemiological studies in Pima Indians identified elevated levels of HDL-cholesterol (HDL-C) as a protective factor against type 2 diabetes risk in women. We assessed whether HDL-C-associated single-nucleotide polymorphisms (SNPs) also associate with type 2 diabetes in female Pima Indians. METHODS: Twenty-one SNPs in established HDL-C loci were initially analysed in 2,675 full-heritage Pima Indians. SNPs shown to associate with HDL-C (12 SNPs) were assessed for association with type 2 diabetes in 7,710 Pima Indians (55.6% female sex). The CETP locus provided the strongest evidence for association with HDL-C and was further interrogated by analysing tag SNPs. RESULTS: Twelve of the 21 SNPs analysed had a significant association with HDL-C in Pima Indians; five SNPs representing four loci (CETP, DOCK6, PPP1R3B and ABCA1) reached genome-wide significance. Three SNPs, at CETP, KLF14 and HNF4A, associated with type 2 diabetes only in female participants with the HDL-C-lowering allele increasing diabetes risk (p values: 3.2 x 10(-4) to 7.7 x 10(-5)); the association remained significant even after adjustment for HDL-C. Additional analysis across CETP identified rs6499863 as having the strongest association with type 2 diabetes in female participants (p = 5.0 x 10(-6)) and this association remained independent of the HDL-C association. CONCLUSIONS/INTERPRETATION: SNPs at the CETP, HNF4A and KLF14 locus are associated with HDL-C levels and type 2 diabetes (in female participants). However, since HNF4A and KLF14 are established loci for type 2 diabetes, it is unlikely that HDL-C solely mediates these associations
Functional and association analysis of an Amerindian-derived population-specific p.(Thr280Met) variant in RBPJL, a component of the PTF1 complex
No full textPTF1 complex is critical for pancreatic development and maintenance of adult exocrine pancreas. As a part of our ongoing studies to identify genetic variation that contributes to type 2 diabetes (T2D) in American Indians, we analyzed variation in genes that form this complex, namely PTF1A, RBPJ, and its paralogue RBPJL. A c.839C>T (p.(Thr280Met)) variant (rs200998587:C>T, risk allele frequency = 0.03) in RBPJL, identified only in Amerindian-derived populations, associated with T2D (OR = 1.60[1.21-2.13] per Met allele, P = 0.001) and age of diabetes onset (HR = 1.40[1.14-1.72], P = 0.001). Knockdown of Rbpjl in mouse pancreatic acinar cells resulted in a significant decrease in the mRNA expression of genes encoding exocrine enzymes including Ctrb. CTRB1/2 is an established T2D locus where the protective allele associates with increased GLP-1-stimulated insulin secretion and higher expression of CTRB1/2. In vitro studies show that cells expressing the Met280 allele had lower RBPJL protein levels than cells expressing the Thr280 allele, despite having comparable levels of RNA, suggesting that the Met280 RBPJL is less stable. Additionally, luciferase assays in HEK293 cells which examined two different RBPJL responsive promoters, including the promoter for CTRB1, also identified reduced transactivation by the Met280 RBPJL. Similarly, overexpression of both Met280 and Thr280 RBPJL in mouse pancreatic acinar cells identified a significant impairment in the expression of Cel when transactivated by the Met280 RBPJL. In summary, we identified a functional, Amerindian-derived population-specific c.839C>T (p.(Thr280Met)) variant in the pancreas specific RBPJL that may modify T2D risk by regulating exocrine enzyme expression
Assessing Variation across Eight Established East Asian Loci for Type 2 Diabetes in American Indians: Suggestive Evidence for New Sex-specific Diabetes Signals in GLIS3 and ZFAND3
No full textBACKGROUND:
Eight new loci for type 2 diabetes mellitus (T2DM) were identified in an East Asian genome-wide association study meta-analysis. We assess tag SNPs across these loci for associations with T2DM in American Indians.
METHODS:
A total of 435 SNPs that tag (R2 ≥ .85) common variation across the 8 loci were analyzed for association with T2DM (n = 7710), early onset T2DM (n = 1060), body mass index (n = 6839), insulin sensitivity (n = 555), and insulin secretion (n = 298).
RESULTS:
Tag SNPs within FITM2-R3HDML-HNF4A, GLIS3, KCNK16, and ZFAND3 associated with T2DM after accounting for locus-wide multiple testing. The T2DM association in FITM2-R3HDML-HNF4A (rs3212183; P = .0002; OR = 1.19 [1.09-1.30]) was independent from the East Asian lead SNP (rs6017317), which did not associate with T2DM in American Indians. The top signals in GLIS3 (rs7875253; P = .0004; OR = 1.23 [1.10-1.38]) and KCNK16 (rs1544050; P = .002; OR = 1.16 [1.06-1.27]) were attenuated after adjustment for the East Asian lead SNPs (rs7041847 in GLIS3; rs1535500 in KCNK16), both of which also associated with T2DM in American Indians (P = .02; OR = 1.11 [1.01-1.21]; P = .007; OR = 1.19 [1.05-1.36] respectively). The top SNP in ZFAND3 (rs9470794; P = .002; OR = 1.43 [1.14-1.80]) was the identical East Asian lead SNP. Additional SNPs in GLIS3 (rs180867004) and ZFAND3 (rs4714120 and rs9470701) had significant genotype × sex interactions (P ≤ .008). The GLIS3 SNP (rs180867004) associated with T2DM only in men (P = .00006, OR = 1.94 [1.40-2.68]). The ZFAND3 SNPs (rs4714120 and rs9470701) associated with T2DM only in women (P = .0002, OR = 1.35 [1.16-1.59]; P = .0003, OR = 1.37 [1.16-1.63] respectively).
CONCLUSIONS:
Replication of lead T2DM SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sex-specific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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