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Pathways involved in diabetes

McCarthy reported that the loci with the strongest evidence of association with type 2 diabetes impact insulin secretion. Examples include cyclin-dependent kinases CDKAL1, CDKNL2A, and CDKN2B. At these loci, risk variants predispose to reduced pancreatic beta cell mass. The diabetes risk alleles in TCF7L2, MTNR1B, and KCNJ11 predispose to beta cell dysfunction.

Risk alleles in the FTO locus (gene related to fat mass and obesity) contribute to obesity and to peripheral resistance to insulin. The PPARG and IRS1 (insulin receptor substrate 1) loci impact insulin resistance and obesity.

In the monogenic forms of diabetes and in autoimmune diabetes in adults, information about the underlying causative gene can influence therapeutic decisions, such as whether insulin is required, whether dietary management may be sufficient, or whether sulfonylureas are required. In type 1 diabetes commonly associated with HLA variants (latent autoimmune diabetes) or with defects in the insulin genes INS or PTPN22 (protein tyrosine phosphatase non receptor type 22), insulin is likely necessary. Maturity-onset diabetes of the young (MODY) due to GCK (glucokinase) deficiency may respond adequately to dietary management. MODY due to HNF1A deficiency may require treatment with sulfonylureas.

McCarthy reviewed the results of genome wide association studies designed to identify common variants associated with increased body mass index (BMI) and noted that at least 30 such loci have been associated. The strongest signal is associated with the FTO locus (gene related to fat mass obesity). He noted that signals of risk alleles were also detected in genes with neuronal function, such as BDNF (brain derived neurotrophic factor), SH2B1 (signaling protein), and NEGR1 (neuronal growth regulator). He indicated that obesity may be partly a disease of disordered hypothalamic function. In studies that involved analyzing fat mass distribution, risk alleles in 15 loci were identified. Evidence indicates that risk alleles at these loci impact adipocyte development and function.

McCarthy noted that clinical translation of these findings is impacted at least partly by the modest effect of the risk alleles. Homozygotes for the FTO risk allele are an average of 2 to 3 kilograms heavier than in individuals without the risk allele. However, he noted that identifying risk-altering genes contributes to our understanding of the biology of disease. Another important consideration is that most of the risk alleles lie outside the coding regions of genes, and it's not clear how they impact the regulation of gene expression.

McCarthy predicted that large-scale genome-wide resequencing efforts now underway would clarify relationships between sequence variants and clinical phenotypes.

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