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Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis.

ABSTRACT: Genome-wide association studies have identified many obesity/body mass index (BMI)-associated loci in Europeans and East Asians. Since then, a large number of studies have investigated the role of BMI-associated loci in the development of type 2 diabetes (T2D). However, the results have been inconsistent. The objective of this study was to investigate the associations of eleven obesity/BMI loci with T2D risk and explore how BMI influences this risk.We retrieved published literature from PubMed and Embase. The pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using fixed- or random-effect models.In the meta-analysis of 42 studies for 11 obesity/BMI-associated loci, we observed a statistically significant association of the FTO rs9939609 polymorphism (66 425 T2D cases/239 689 normoglycaemic subjects; P = 1·00 × 10(-41) ) and six other variants with T2D risk (17 915 T2D cases/27 531 normoglycaemic individuals: n = 40 629-130 001; all P < 0·001 for SH2B1 rs7498665, FAIM2 rs7138803, TMEM18 rs7561317, GNPDA2 rs10938397, BDNF rs925946 and NEGR1 rs2568958). After adjustment for BMI, the association remained statistically significant for four of the seven variants (all P < 0·05 for FTO rs9939609, SH2B1 rs7498665, FAIM2 rs7138803, GNPDA2 rs10938397). Subgroup analysis by ethnicity demonstrated similar results.This meta-analysis indicates that several BMI-associated variants are significantly associated with T2D risk. Some variants increase the T2D risk independent of obesity, while others mediate this risk through obesity.

SUBMITTER: Xi B

PROVIDER: S-EPMC5568704 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis.

Xi Bo B Takeuchi Fumihiko F Meirhaeghe Aline A Kato Norihiro N Chambers John C JC Morris Andrew P AP Cho Yoon Shin YS Zhang Weihua W Mohlke Karen L KL Kooner Jaspal S JS Shu Xiao Ou XO Pan Hongwei H Tai E Shyong ES Pan Haiyan H Wu Jer-Yuarn JY Zhou Donghao D Chandak Giriraj R GR

Clinical endocrinology 20140313 5

<h4>Objective</h4>Genome-wide association studies have identified many obesity/body mass index (BMI)-associated loci in Europeans and East Asians. Since then, a large number of studies have investigated the role of BMI-associated loci in the development of type 2 diabetes (T2D). However, the results have been inconsistent. The objective of this study was to investigate the associations of eleven obesity/BMI loci with T2D risk and explore how BMI influences this risk.<h4>Methods</h4>We retrieved ...[more]

PMID: 24528214

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Project description:The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ?2/?3/?4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (? = -1.29, p = 3.97 × 10-9 ; ? = -1.38, p = 2.78 × 10-10 ; and ? = 0.58, p = 3.04 × 10-2 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (? = -0.63, p = 3.99 × 10-2 and ? = -0.94, p = 2.17 × 10-3 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (? = -1.68, p = 3.00 × 10-9 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (? = -4.11, p = 2.78 × 10-3 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, ? = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 × 10-1 for 3,068 individuals aged ?30 years and ? = -4.28, CI = -5.65, -2.92, p = 7.71 × 10-10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ?4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.

Project description:ImportanceObesity is associated with a number of noncommunicable chronic diseases and is purported to cause premature death.ObjectiveTo summarize evidence on the temporality of the association between higher body mass index (BMI) and 2 potential mediators: chronic inflammation and hyperinsulinemia.Data sourcesMEDLINE (1946 to August 20, 2019) and Embase (from 1974 to August 19, 2019) were searched, although only studies published in 2018 were included because of a high volume of results. The data analysis was conducted between January 2020 and October 2020.Study selection and measuresLongitudinal studies and randomized clinical trials that measured fasting insulin level and/or an inflammation marker and BMI with at least 3 commensurate time points were selected.Data extraction and synthesisSlopes of these markers were calculated between time points and standardized. Standardized slopes were meta-regressed in later periods (period 2) with standardized slopes in earlier periods (period 1). Evidence-based items potentially indicating risk of bias were assessed.ResultsOf 1865 records, 60 eligible studies with 112 cohorts of 5603 participants were identified. Most standardized slopes were negative, meaning that participants in most studies experienced decreases in BMI, fasting insulin level, and C-reactive protein level. The association between period 1 fasting insulin level and period 2 BMI was positive and significant (β = 0.26; 95% CI, 0.13-0.38; I2 = 79%): for every unit of SD change in period 1 insulin level, there was an ensuing associated change in 0.26 units of SD in period 2 BMI. The association of period 1 fasting insulin level with period 2 BMI remained significant when period 1 C-reactive protein level was added to the model (β = 0.57; 95% CI, 0.27-0.86). In this bivariable model, period 1 C-reactive protein level was not significantly associated with period 2 BMI (β = -0.07; 95% CI, -0.42 to 0.29; I2 = 81%).Conclusions and relevanceIn this meta-analysis, the finding of temporal sequencing (in which changes in fasting insulin level precede changes in weight) is not consistent with the assertion that obesity causes noncommunicable chronic diseases and premature death by increasing levels of fasting insulin.

Project description:Background/objectiveBody mass index (BMI) is a surrogate measure of adiposity but does not distinguish fat from lean or bone mass. The genetic determinants of BMI are thought to predominantly influence adiposity but this has not been confirmed. Here we characterise the association between BMI-related genetic variants and body composition in adults.Subjects/methodsAmong 9667 adults aged 29-64 years from the Fenland study, a genetic risk score for BMI (BMI-GRS) was calculated for each individual as the weighted sum of BMI-increasing alleles across 96 reported BMI-related variants. Associations between the BMI-GRS and body composition, estimated by dual-energy X-ray absorptiometry (DXA) scans, were examined using age-adjusted linear regression models, separately by sex.ResultsThe BMI-GRS was positively associated with all fat, lean and bone variables. Across body regions, associations of the greatest magnitude were observed for adiposity variables, for example, for each s.d. increase in BMI-GRS predicted BMI, we observed a 0.90 s.d. (95% confidence interval (CI): 0.71, 1.09) increase in total fat mass for men (P=3.75 × 10-21) and a 0.96 s.d. (95% CI: 0.77, 1.16) increase for women (P=6.12 × 10-22). Associations of intermediate magnitude were observed with lean variables, for example, total lean mass: men: 0.68 s.d. (95% CI: 0.49, 0.86; P=1.91 × 10-12); women: 0.85 s.d. (95% CI: 0.65, 1.04; P=2.66 × 10-17) and of a lower magnitude with bone variables, for example, total bone mass: men: 0.39 s.d. (95% CI: 0.20, 0.58; P=5.69 × 10-5); women: 0.45 s.d. (95% CI: 0.26, 0.65; P=3.96 × 106). Nominally significant associations with BMI were observed for 28 single-nucleotide polymorphisms. All 28 were positively associated with fat mass and 13 showed adipose-specific effects.ConclusionsIn adults, genetic susceptibility to elevated BMI influences adiposity more than lean or bone mass. This mirrors the association between BMI and body composition. The BMI-GRS can be used to model the effects of measured BMI and adiposity on health and other outcomes.

Project description:ImportanceMaternal obesity, pregestational type 1 diabetes, and gestational diabetes have been reported to increase the risks for large birth weight and preterm birth in offspring. However, the associations for insulin-treated diabetes and non-insulin-treated type 2 diabetes, as well as the associations for joint diabetes disorders and maternal body mass index, with these outcomes are less well documented.ObjectiveTo examine associations of maternal diabetes disorders, separately and together with maternal underweight or obesity, with the offspring being large for gestational age and/or preterm at birth.Design, setting, and participantsThis population-based cohort study used nationwide registries to examine all live births (n = 649 043) between January 1, 2004, and December 31, 2014, in Finland. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.ExposuresMaternal prepregnancy body mass index, pregestational diabetes with insulin treatment, pregestational type 2 diabetes without insulin treatment, and gestational diabetes.Main outcomes and measuresOffspring large for gestational age (LGA) at birth and preterm delivery. Logistic regression models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status.ResultsOf the 649 043 births, 4000 (0.62%) were delivered by mothers who had insulin-treated diabetes, 3740 (0.57%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were born in Finland. Statistically significant interactions existed between maternal body mass index and diabetes on offspring LGA and prematurity (insulin-treated diabetes: LGA F = 3489.0 and prematurity F = 1316.4 [P < .001]; type 2 diabetes: LGA F = 147.3 and prematurity F = 21.9 [P < .001]; gestational diabetes: LGA F = 1374.6 and prematurity F = 434.3 [P < .001]). Maternal moderate obesity, compared with normal-weight mothers with no diabetes, was associated with a mildly increased risk of having an offspring LGA (1069 [3.5%] vs 5151 [1.5%]; adjusted odds ratio [aOR], 2.45; 95% CI, 2.29-2.62), and mothers with insulin-treated diabetes had markedly elevated risks of having an offspring LGA (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% CI, 40.88-46.93) and a preterm birth (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93). Mothers who were moderately obese with type 2 diabetes were at increased risks of LGA (132 [16.4%] vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03) and prematurity (83 [10.3%] vs 17 481 [5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). Mothers who were moderately obese with gestational diabetes had a milder risk of LGA (1195 [6.7%] vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04). Among spontaneous deliveries, the risks were strongest for moderately preterm births, but insulin-treated diabetes was associated with an increased risk also for very and extremely preterm births.Conclusions and relevanceMaternal insulin-treated diabetes appeared to be associated with markedly increased risks for LGA and preterm births, whereas obesity in mothers with type 2 diabetes had mild to moderately increased risks; these findings may have implications for counseling and managing pregnancies.

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Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis.

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Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis.

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