Analysis of genetic selection at insulin receptor substrate-2 gene loci.

PURPOSE: Type 2 diabetes mellitus (T2DM) is highly heritable and exhibits significant variability in prevalence between different populations. Prevalence of T2DM is higher in Asian and African relative to European populations. During evolution, traditional feast-famine cycles likely led to significant natural selection impacting metabolic genes. Human adaptation to environmental changes (food supply, lifestyle, climate, and geography) likely influenced differential selection of T2DM-associated genes. Together, insulin receptor substrate-1 and -2 (IRS1 and IRS2) genes encode the major ligands of insulin and IGF1 receptors. Irs2-deficient mice exhibit a T2DM phenotype with severe insulin resistance, and a common IRS2 polymorphism is associated with T2DM. Therefore, the present study sought evidence of natural selection at IRS2 loci. METHODS: Data were sourced from the HapMap and 1000 Genomes projects, comprising four different populations with distinct ancestries: European, Yoruba, Han Chinese, and Japanese. A three-step method was applied to detect IRS2 locus selection. The long-range haplotype (LRH) test detected unusual extended haplotypes, the integrated haplotype score (iHS) detected selection, and Wright's F-statistics (particularly Wright's fixation index: FST) were calculated as a measure of population differentiation. RESULTS: The African population exhibited highly significant LRH findings (percentile >99.9, p = 0.005-0.0009), while both the European and African populations exhibited extreme positive iHS test scores ([iHS] >2.5). CONCLUSION: These findings indicate that genetic selection has occurred at the IRS2 locus, warranting further research into the adaptive evolution of metabolic disorder-associated genes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00745-y.

Analysis of Evolution and Ethnic Diversity at Glucose-Associated SNPs of Circadian Clock-Related Loci with Cryptochrome 1, Cryptochrome 2, and Melatonin receptor 1B.

Diabetes shows high heritability and, worldwide, causes significant health problems including cardiovascular disease and stroke. There is significant variation in the frequency of diabetes between different populations. Both Cryptochromes and Melatonin have a major role to regulate the circadian clock. Circadian clock failure causes metabolic dysfunctions including diabetes and obesity. Variations in the Cryptochrome 1, the Cryptochrome 2, and the Melatonin receptor 1B (MTNR1B) genes show associations with fasting glucose, and are also related to circadian clock. Here, we analyzed evidence for genetic selection and ethnic diversity at circadian clock- and glucose-related gene loci associated with Cryptochrome 1, Cryptochrome 2, and MTNR1B. We carried out a 3-step genetic method to investigate genetic selection at the Cryptochrome 1, Cryptochrome 2, and MTNR1B on four populations from the 1000 Genomes Project and HapMap. First we used F-statistics to quantify genetic population differences and find ethnic diversity. Then we applied a long-range haplotype test to detect significant extreme long haplotypes, and then the integrated haplotype score (iHS) to find genetic selection at Cryptochrome 1, Cryptochrome 2, and MTNR1B. We observed genetic population differences and ethnic diversity at one glucose-associated Cryptochrome 1 single-nucleotide polymorphism (SNP) (rs8192440), one glucose-associated Cryptochrome 2 SNP (rs11605924), and one glucose-associated MTNR1B SNP (rs10830963) by F-statistics. Both Cryptochrome 1 and MTNR1B also showed selection by the iHS. These observations show new evidence for evolution at Cryptochrome 1, Cryptochrome 2 and MTNR1B. Further investigation should continue to examine the evolution of circadian clock- and glucose-related genes.

Evidence for natural selection at the melanocortin-3 receptor gene in European and African populations.

AIMS: Obesity is increasing steadily in worldwide prevalence and is known to cause serious health problems in association with type 2 diabetes mellitus (T2DM), including hypertension, stroke, and cardiovascular diseases. According to the thrifty gene hypothesis, the natural selection of obesity-related genes is important during feast and famine because they control body weight and fat levels. Past human adaptations to environmental changes in food supply, lifestyle, and geography may have influenced the selection of genes associated with the metabolism of glucose, lipids, and energy. The melanocortin-3 receptor gene (MC3R) is associated with obesity, with MC3R-deficient mice showing increased fat mass. MC3R variations are also linked with childhood obesity and insulin resistance. Here, we aimed to uncover evidence of selection at MC3R. METHODS: We performed a three-step method to detect selection at MC3R using HapMap population data. We used Wright's F statistics as a measure of population differentiation, the long-range haplotype test to identify extended haplotypes, and the integrated haplotype score (iHS) to detect selection at MC3R. RESULTS: We observed high population differentiation between European and African populations at two MC3R childhood obesity- and insulin resistance-associated single-nucleotide polymorphisms (rs3746619 and rs3827103) using Wright's F statistics. The iHS revealed evidence of natural selection at MC3R. CONCLUSIONS: These findings provide evidence for natural selection at MC3R. Further investigation is warranted into adaptive evolution at T2DM- and obesity-associated genes.

Evidence of selection at insulin receptor substrate-1 gene loci.

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by insulin resistance and defect of insulin secretion. The worldwide prevalence of T2DM is steadily increasing. T2DM is also significantly associated with obesity, coronary artery disease (CAD), and metabolic syndrome. There is a clear difference in the prevalence of T2DM among populations, and T2DM is highly heritable. Human adaptations to environmental changes in food supply, lifestyle, and geography may have pressured the selection of genes associated with the metabolism of glucose, lipids, carbohydrates, and energy. The insulin receptor substrate-1 (IRS1) gene is considered a major T2DM gene, and common genetic variations near the IRS1 gene were found to be associated with T2DM, insulin resistance, adiposity, and CAD. Here, we aimed to find evidence of selection at the IRS1 gene loci using the HapMap population data. We investigated a 3-step test procedure-Wright's F statistics (Fst), the long-range haplotype (LRH) test, and the integrated haplotype score (iHS) test-to detect selection at the IRS1 gene loci using the HapMap population data. We observed that 1 CAD-associated SNP (rs2943634) and 1 adiposity- and insulin resistance-associated SNP (rs2943650) exhibited high Fst values. We also found selection at the IRS1 gene loci by the LRH test and the iHS test. These findings suggest evidence of selection at the IRS1 gene loci and that further studies should examine the adaptive evolution of T2DM genes.

Variation in the perilipin gene (PLIN) affects glucose and lipid metabolism in non-Hispanic white women with and without polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. It is characterized by chronic anovulation, hyperandrogenism, obesity and a predisposition to type 2 diabetes mellitus (T2DM). Since obesity plays an important role in the etiology of PCOS, we sought to determine if variants in the perilipin gene (PLIN), a gene previously implicated in the development of obesity, were also associated with PCOS. We typed six single nucleotide polymorphisms (haplotype tagging and/or previously associated with obesity or related metabolic traits) in PLIN in 305 unrelated non-Hispanic white women (185 with PCOS and 120 without PCOS). None of the variants was associated with PCOS (P<0.05). However, the variant rs1052700*A was associated with increased risk for glucose intolerance (impaired glucose tolerance or T2DM) in both non-PCOS (OR=1.75 [1.02-3.01], P=0.044) and PCOS subjects (OR=1.67 [1.08-2.59], P=0.022). It was also associated with increased LDL (P=0.007) and total cholesterol levels (P=0.042). These results suggest that genetic variation in PLIN may affect glucose and lipid metabolism in women both with and without PCOS.

Association of the calpain-10 gene with type 2 diabetes mellitus in a Mexican population.

Variation in the calpain-10 gene (CAPN10) has been associated with risk of type 2 diabetes in the Mexican American population of Starr County, Texas. We typed five polymorphisms in the calpain-10 gene (SNP-43, -43, -63, and -110 and Indel-19) to test for association with type 2 diabetes in 248 individuals representative of the mestizo population of Mexico City and Orizaba, Mexico including 134 patients with type 2 diabetes and 114 subjects with normal fasting blood glucose levels. We found a significant difference in SNP-44 allele and genotype frequencies between type 2 diabetic and non-diabetic subjects. The rare allele at SNP-44 was associated with increased risk of type 2 diabetes (odds ratio (OR)=2.72, 95% confidence interval (CI)=1.16-6.35, P=0.017). SNP-110, which is in perfect linkage disequilibrium with SNP-44, was also associated with type 2 diabetes. The SNP-43, Indel-19, and SNP-63 haplogenotype 112/121 associated with significantly increased risk (OR=2.16, 95% CI=1.31-3.57) of type 2 diabetes in Mexican Americans was not associated with significantly increased in risk in Mexicans (OR=1.15, 95% CI=0.57-2.34). The results suggest that variation in CAPN10 affects risk of type 2 diabetes in the mestizo population of central Mexico (Mexico City and Orizaba) and in Mexican Americans (Starr County, Texas).

Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome.

Insulin resistance is a key component in the pathogenesis of polycystic ovary syndrome (PCOS) and type 2 diabetes. Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp), influence susceptibility to type 2 diabetes. This study was undertaken to assess the influence of these polymorphisms on insulin resistance, glucose tolerance, and androgen levels in nondiabetic PCOS women. We studied 227 PCOS subjects including 126 and 48 nondiabetic white and African-American subjects, respectively. The IRS-1 Gly(972)Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. The IRS-2 Gly(1057)Asp allele frequencies were 0.85 (Gly) and 0.15 (Asp) in African-Americans and 0.59 (Gly) and 0.41 (Asp) in whites. There was no association of IRS-1 genotype with any clinical or hormonal measure in nondiabetic white or African-American PCOS subjects. However, nondiabetic subjects with the IRS-2 Gly/Gly genotype had significantly higher 2-h oral glucose tolerance test glucose levels compared with those with Gly/Asp and Asp/Asp genotypes in whites or Gly/Asp genotype in African-Americans (there were no Asp/Asp subjects in our modest size African-American sample). These results suggest that the IRS-2 Gly(1057)Asp polymorphism influences blood glucose levels in nondiabetic white and African-American women with PCOS. Thus, individuals with the common IRS-2 Gly/Gly genotype may be at increased risk of developing type 2 diabetes.

Thyroid hormone receptor interacting protein 3 (trip3) is a novel coactivator of hepatocyte nuclear factor-4alpha.

Mutations of the hepatocyte nuclear factor-4alpha (HNF-4alpha) gene are associated with a subtype of maturity-onset diabetes of the young (MODY1) that is characterized by impaired insulin secretion in response to a glucose load. HNF-4alpha, which is a transcription factor expressed in pancreatic beta-cells, plays an important role in regulating the expression of genes involved in glucose metabolism. Thus, cofactors that interact with HNF-4alpha and modify its transcriptional activity might also play an important role in regulating the metabolic pathways in pancreatic beta-cells, and the genes of such cofactors are plausible candidate genes for MODY. In the present study, we showed, using a yeast two-hybrid screening assay, that thyroid hormone receptor interacting protein 3 (Trip3) interacted with HNF-4alpha, and their interaction was confirmed by the glutathione S-transferase pull-down assay. Human Trip3 cDNA contained an open reading frame for a protein of 155 amino acids, and the gene was expressed in both pancreatic islets and MIN6 cells. Cotransfection experiments indicated that Trip3 could enhance (two- to threefold) the transcription activity of HNF-4alpha in COS-7 cells and MIN6 cells. These results suggest that Trip3 is a coactivator of HNF-4alpha. Mutation screening revealed that variation of the Trip3 gene is not a common cause of MODY/early-onset type 2 diabetes in Japanese individuals. Trip3 may play an important role in glucose metabolism by regulating the transcription activity of HNF-4alpha.