Genome‐wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans

Abstract

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P = 1.43 × 10 ; P = 4.70 × 10 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.

TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

“…Although genome-wide study is a powerful approach to identify the risk factors of type 2 diabetes and has revealed more than 70 SNPs associated with type 2 diabetes globally, irrespective of ethnic background [ 25 , 26 ], the biological significance of those SNPs has not yet been clarified and the collective contribution of those SNPs has yet to be reported [ 27 ]. SNPs related to the ability to secrete insulin have also been investigated in type 2 diabetes; however, the effects of the variants were shown to be modest [ 28 , 29 ]. In contrast, as shown by our previous study and the current work, TYK2PV demonstrated a consistent effect: increasing the risk of type 2 diabetes by 2.1-fold [ 14 ] and the risk of impaired insulin secretion ability by 3.2–3.5-fold.…”

The Enigmatic Emerging Role of the C-Maf Inducing Protein in Cancer

“…Finally, a potential function of CMIP in other organs and tissues can be inferred by the association of genetic variants with a number of pathologies. Accordingly, polymorphisms in CMIP sequence have been linked to the susceptibility to developing type 2 diabetes [ 22 , 23 , 24 , 25 ], to a decreased homeostasis model assessment of β-cell function and increased fasting plasma glucose [ 26 , 27 ], to adiponectin levels [ 28 , 29 ], to language impairment and autism [ 30 , 31 , 32 , 33 ], to adenylate cyclase 3 deficiency in the olfactory epithelium [ 34 ], to dyslipidemia associated with IgA nephropathy [ 35 , 36 ], to blood lipoprotein content [ 37 ], and adipocyte lipolysis [ 38 ]. Moreover, partial deletions have been described in some patients suffering from autism and gastro-intestinal disorders [ 39 ].…”

Whole-genome Resequencing Provides Insights into the Population Structure and Domestication Signatures of Ducks in Eastern China

“…4, Fupplementary table S7). In addition, ten candidate genes (Cmip, Tmem132b, Mphosph6, Smg7, Lyst, Zbtb37, Serpinc1, Npl, Tmem132c and Plcg2 ) ranking within the top 10 F ST values with log 2 (θ π ratio (θ π, wild duck /θ π, domestic duck ) ≥0.84 were functionally involved in cellular adhesion function, type 2 diabetes, lipid metabolism, cell cycle, liver cell proliferation and muscle functioning [13][14][15][16][17][18] (Table 1). [62][63] To identify the active pathways in the domestication of ducks, the positively selected genes in domestic ducks were mapped to the canonical reference pathways in the KEGG database.…”