Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These variants have, in different ethnic groups, been linked to estimates of insulin resistance and obesity. The objective of the present study was to investigate whether these genetic variants of TNF-alpha were associated with features of the insulin resistance syndrome or alterations in birth weight in two Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. All study participants underwent an iv glucose tolerance test with the addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the polymorphisms by applying PCR restriction fragment length polymorphism. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome (body mass index, waist to hip ratio, fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth weight and the ponderal index were also not associated with the polymorphisms. In conclusion, although the study was carried out on sufficiently large study samples, the study does not support a major role of the -308 or -238 substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.
Despite adiponectin's presumed role in fatty acid oxidation and energy homeostasis, little is known about the effect of gene variants on substrate oxidation, energy expenditure, and adiposity-related phenotypes.
We examined the effects of genetic variation in adiponectin (ADIPOQ) and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) on resting metabolic rate, respiratory quotient (RQ), and adiposity-related phenotypes.
We studied the associations of ADIPOQ, ADIPOR1, and ADIPOR2 polymorphisms with resting metabolic rate, RQ, and body mass index, percentage body fat, sum of 6 skinfold thicknesses, waist circumference, and total, subcutaneous, and visceral fat in 759 participants in the Québec Family Study.
The ADIPOQ 45T-->G single-nucleotide polymorphism (SNP) was significantly (P = 0.0002 to 0.04) associated with overall adiposity and abdominal adiposity; the rare homozygotes (G/G) had a leaner phenotype than did the carriers of the common allele. One SNP each in the putative promoter of ADIPOR1 (ie, -3882T-->C) and ADIPOR2 (ie, IVS1 -1352G-->A) was associated with RQ (P = 0.03 and 0.04, respectively), and the association was even stronger in nonobese persons (P = 0.02 and 0.003). Carriers of the common alleles (ADIPOR1 T and ADIPOR2 G alleles) had a lower RQ than did the rare homozygotes. A significant genotype-by-genotype interaction (P = 0.0002 to 0.02) was found between SNPs in the promoters of ADIPOQ (-3971A-->G) and ADIPOR1 (-3882T-->C). Subjects carrying the minor ADIPOQ allele (G allele) who were rare homozygotes (C/C) for the ADIPOR1 SNP had a higher RQ (P = 0.003) and greater overall (P G variant contributes to overall fatness and abdominal obesity are confirmed. Moreover, variants in the promoter region of both ADIPOR genes contribute to substrate oxidation.
Comment In: Am J Clin Nutr. 2007 Jan;85(1):1-217209169
Alpha(2) Heremans-Schmid glycoprotein (AHSG) is a plasma protein inhibiting the activity of the insulin receptor tyrosine kinase. Ahsg knock-out mice have increased insulin sensitivity and are resistant to diet-induced obesity. We hypothesized that functional variants of the AHSG gene segregating in the human population would reflect variation in body mass index (BMI). We genotyped 356 overweight or obese (BMI: 37.2 [25.0-66.5] kg/m(2)) and 148 lean (BMI: 23.7 [23.4-24.9] kg/m(2)) otherwise healthy Swedish men for three non-synonymous single-nucleotide polymorphisms (SNPs) within exon 6 (rs4917) and exon 7 (rs4918 and Arg299Cys) and one SNP in intron 1 (rs2593813) of the AHSG gene. The G/G genotype for rs2593813 was more common among lean than among obese and overweight individuals (odds ratio = 2.01, P = 0.009), whereas rs2593813 was in strong linkage disequilibrium (
> or = 0.97) with rs4917 and rs4918. Homozygosity for the rs2593813:G-rs4917:Met-rs4918:Ser haplotype conferred an increased risk for leanness (odds ratio=1.90, P = 0.027). rs4917:Met and rs4918:Ser have previously been associated with lower AHSG protein level. A common variant of AHSG, previously associated with a lower AHSG protein level, is thus more common among lean than obese and overweight men, supporting the results from Ahsg knock-out mice, namely, that AHSG modulates body mass.
OBJECTIVE: The gene encoding the alpha2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia. RESEARCH DESIGN AND METHODS: The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of >99% to replicate previous findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and beta-2-adrenergic receptor polymorphisms were investigated. RESULTS: The -469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes (P = 0.007 and P = 0.006, respectively, or P(corr) = 0.04 and P(corr) = 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study -469T>G remained significant (odds ratio 0.90 [95% CI 0.84-0.97]; P = 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia (P = 0.003 and P(corr) = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post-oral glucose tolerance test serum insulin release (P = 0.02, P(corr) = 0.1 for fasting and P = 0.04, P(corr) = 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of insulin resistance (9.0 vs. 8.6 mmol x l(-1) x pmol(-1) x l(-1); P = 0.01, P(corr) = 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations. CONCLUSIONS: Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.
We examined the contributions of genetic factors and the family environment to human fatness in a sample of 540 adult Danish adoptees who were selected from a population of 3580 and divided into four weight classes: thin, median weight, overweight, and obese. There was a strong relation between the weight class of the adoptees and the body-mass index of their biologic parents - for the mothers, P less than 0.0001; for the fathers, P less than 0.02. There was no relation between the weight class of the adoptees and the body-mass index of their adoptive parents. Cumulative distributions of the body-mass index of parents showed similar results; there was a strong relation between the body-mass index of biologic parents and adoptee weight class and no relation between the index of adoptive parents and adoptee weight class. Furthermore, the relation between biologic parents and adoptees was not confined to the obesity weight class, but was present across the whole range of body fatness - from very thin to very fat. We conclude that genetic influences have an important role in determining human fatness in adults, whereas the family environment alone has no apparent effect.
A genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS53) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS53 might already associate with insulin resistance during childhood, and we therefore aimed to investigate this in populations of Danish children and adolescents. Furthermore, we aimed to address whether the GRS associates with components of the metabolic syndrome and altered body composition in children and adolescents.
We examined a total of 689 children and adolescents who were overweight or obese and 675 children and adolescents from a population-based study. Anthropometric data, dual-energy x-ray absorptiometry scans, BP, fasting plasma glucose, fasting serum insulin and fasting plasma lipid measurements were obtained, and HOMA-IR was calculated. The GRS53 was examined for association with metabolic traits in children by linear regressions using an additive genetic model.
In overweight/obese children and adolescents, the GRS53 associated with higher HOMA-IR (ß?=?0.109?±?0.050 (SE); p?=?2.73?×?10-2), fasting plasma glucose (ß?=?0.010?±?0.005 mmol/l; p?=?2.51?×?10-2) and systolic BP SD score (ß?=?0.026?±?0.012; p?=?3.32?×?10-2) as well as lower HDL-cholesterol (ß?=?-0.008?±?0.003 mmol/l; p?=?1.23?×?10-3), total fat-mass percentage (ß?=?-0.143?±?0.054%; p?=?9.15?×?10-3) and fat-mass percentage in the legs (ß?=?-0.197?±?0.055%; p?=?4.09?×?10-4). In the population-based sample of children, the GRS53 only associated with lower HDL-cholesterol concentrations (ß?=?-0.007?±?0.003 mmol/l; p?=?1.79?×?10-2).
An adult-based GRS comprising 53 insulin resistance susceptibility SNPs associates with insulin resistance, markers of the metabolic syndrome and altered fat distribution in a sample of Danish children and adolescents who were overweight or obese.
Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86-2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.
Lamin A/C (LMNA) is located within a region on chromosome 1q that has been linked with Type II (non-insulin-dependent) diabetes mellitus in Pima Indians. Rare mutations in exon 8 of LMNA underlie Dunnigan-Type familial partial lipodystrophy, a disease characterized by regional adipocyte degeneration and frequently accompanied by insulin resistance, glucose intolerance, and diabetes. A more common variant in exon 10 (3408C/T) has recently been associated with obesity in non-diabetic aboriginal Canadian subjects. Because obesity is a strongly predisposing factor for Type II diabetes, we hypothesized that the LMNA 3408C/T variant could be associated with diabetes and body mass index in Pima Indians.
To determine whether the LMNA 3408C/T variant contributes to Type II diabetes susceptibility, we genotyped the polymorphism in 1,338 Pimas using allelic discrimination technology. The locus was screened for additional variants in 20 diabetic Pima Indians and non-diabetic Pima Indians using denaturing high performance liquid chromatography and dideoxy sequencing.
We found no evidence for association of 3408C/T with diabetes, body mass index, total cholesterol, HDL cholesterol, triglycerides, leptin concentrations, or indices of insulin sensitivity and secretion. Subsequent screening of the remaining LMNA exons and flanking sequences revealed only rare variants in intron 4 and the 3'UTR, showing no frequency differences between diabetic and non-diabetic Pima Indians. We reassessed the linkage with diabetes following adjustment for the LMNA 3408C/T variant; adjustment for the effects of LMNA did not substantially modify the evidence for linkage.
We conclude that the LMNA 3408C/T variant probably does not play a role in susceptibility to diabetes or obesity in Pima Indians.
Associations between a 45 bp 3'untranslated insertion polymorphism in the uncoupling protein 2 (UCP2) gene and both body mass index (BMI) and sleeping metabolic rate have previously been reported. We investigated the impact of this polymorphism on BMI and long-term body weight changes.
The allelic frequency of the UCP2 insertion variant was determined in a cohort of 744 obese Danish Caucasian men who had a BMI of at least 31 kg/m2 at the draft-board examinations and a randomly selected control cohort consisting of 872 draftees. Follow-up measurements of BMI were done on average 26 years after the draft-board examinations.
The prevalence of the insertion allele was 30.4% (95% confidence interval: 28.0-32.8%) among the obese and 29.6% (27.4-31.8%) in the control group (p = 0.6). In a lean group selected as the 354 subjects with a BMI less than 25 kg/m2 at 46 years of age from the control group, the frequency of insertion allele was 29.0% (27.2-30.8%) (p = 0.5 compared with the obese cohort). The BMI at the ages of 20 and 46 years did not differ between genotypes either in the obese or the control group. Similarly, the changes in BMI/year between examinations at 20 and 46 years of age did not differ between genotypes in either group.
In a large group of Danish Caucasian men we found no association between a 3'untranslated insertion polymorphism in the UCP2 gene and obesity. Neither did we identify a relation between this variant and BMI changes during adult age.
Several groups have completed autosomal genome scans for human obesity, but only two have examined the X chromosome. A French group reported linkage of BMI to Xp and Xq markers, and a Finnish group reported linkage of BMI to Xq. We scanned the X chromosome in two cohorts, 190 European-American families (940 members) and 43 African-American families (208 members). We examined five correlated obesity phenotypes, BMI, body fat percentage, hip and waist circumferences, and plasma leptin concentration. We also examined leptin resistance (leptin/BMI) and fat patterning (waist-to-hip ratio [WHR]). Variables were adjusted for age within generation, race, and sex. We genotyped 20 markers with average spacing of 10 cM and no interval >22 cM and conducted nonparametric analyses. Suggestive linkage was found for WHR only. Linkage was supported in both family sets, and support was especially strong for females. Z scores for analyses of female phenotypes were 2.69, 1.73, and 2.37 (P = 0.0036, 0.0418, and 0.0089) for African-Americans, European-Americans, and the combined sample, respectively. The peaks were 51-73 cM from the p terminus, 14-34 cM distal of the French report in Xp22. Our results suggest that a quantitative trait locus influencing fat distribution in women may lie in chromosome region Xp21-22; however, the linked interval is large and differs substantially from that of the French and Finnish groups. Given the positive but divergent results, it would be worthwhile for others to examine the X chromosome.