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FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 3; FGQTL3

FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 3; FGQTL3

Cytogenetic location: 11q21-q22 Genomic coordinates (GRCh38): 11:93,000,000-110,600,000▼ MappingProkopenko et al. (2009) examined the leading association sig...

Cytogenetic location: 11q21-q22 Genomic coordinates (GRCh38): 11:93,000,000-110,600,000

▼ Mapping
Prokopenko et al. (2009) examined the leading association signals in 10 genomewide association studies (GWAS) involving a total of 36,610 individuals of European descent. Variants in the MTNR1B gene (600804) were consistently associated with fasting glucose across all 10 studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% confidence interval 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09; confidence interval 1.05-1.12, per G allele P = 3.3 x 10(-7)) in a metaanalysis of 13 case-control studies totaling 18,236 cases and 64,453 controls.

Lyssenko et al. (2009) found that the common variant rs10830963 in the MTNR1B gene, or at least 1 variant in linkage disequilibrium with it, increased risk of future type 2 diabetes by causing impaired early insulin secretion and was associated with high fasting glucose levels. They performed their analysis in 2 large prospective studies. The risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. Lyssenko et al. (2009) also showed that MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with type 2 diabetes showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. Lyssenko et al. (2009) concluded that their data suggested that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of type 2 diabetes. Given the increased expression of MTNR1B in individuals at risk of type 2 diabetes, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells.

In a GWAS of 2,151 nondiabetic French subjects, Bouatia-Naji et al. (2009) identified rs1387153, near the MTNR1B gene, as a modulator of fasting plasma glucose (P = 1.3 x 10(-7)). In European populations, the rs1387153 T allele was associated with increased fasting plasma glucose (beta = 0.06 mmol/l, P = 7.6 x 10(-29), 16,094 individuals), type 2 diabetes risk (odds ratio = 1.15, 95% confidence interval = 1.08-1.22, P = 6.3 x 10(-5), 6,332 cases), and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio = 1.20, 95% confidence interval = 1.06-1.36, P = 0.005, 515 incident cases). RT-PCR analyses confirmed the presence of MTNR1B transcripts in neural tissues and showed MTNR1B expression in human pancreatic islets and beta cells. Bouatia-Naji et al. (2009) concluded that their data suggested a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.

To identify new loci influencing glycemic traits, Dupuis et al. (2010) performed metaanalyses of 21 genomewide association studies informative for fasting glucose, fasting insulin, and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and 2 loci associated with fasting insulin and HOMA-IR. Dupuis et al. (2010) identified association of the G allele of rs10830963 with elevation of fasting blood glucose (global p = 5.8 x 10(-175)). This SNP was also associated with decreased HOMA-B values (p = 2.7 x 10(-43)) and increased risk of type 2 diabetes (relative risk 1.09, 95% CI 1.06-1.12, p = 8.0 x 10(-13)).

Bonnefond et al. (2012) identified rare nonfunctional variants in the MTNR1B gene (A42P, 600804.0001; L60R, 600804.0002; P95L, 600804.0003; and Y308S, 600804.0004) that were significantly associated with type 2 diabetes (125853).

Tags: 11q22, 11q21

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