A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance

Abstract

Objective: Previous studies suggested that polymorphisms in the coding region of the preproghrelin were involved in the etiology of obesity and might modulate glucose-induced insulin secretion. We evaluated the association of a new variation, À604C4T, in the promoter region of the ghrelin gene, of Leu72Met (247C4A) and of Gln90Leu (265A4T), all haplotypetagging single nucleotide polymorphisms (SNPs), with measures of insulin sensitivity in 1420 adult individuals. Research methods: The three SNPs were genotyped using ABI PRISM 7900 HT Sequence Detection System. We used multiple linear regression analysis for quantitative traits and THESIAS software for haplotype analysis. Results: We observed a protective effect exerted by Met72 variant of Leu72Met SNP on insulin resistance parameters; a significant decreasing trend from Leu/Leu to Leu/Met and to Met/Met homozygous subjects in triglycerides, fasting insulin levels and HOMA-IR index (P ¼ 0.02, 0.01 and 0.003, respectively), and, consistently, an increase in ghrelin levels (P ¼ 0.003) was found. A significant decrease from CC to TC and to TT genotypes in insulin levels and HOMA-IR index was also detected (P ¼ 0.00l for both), but only in subjects homozygous for Leu72, where the protective effect of Met72 was not present. The haplotype analysis results supported the data obtained by the evaluation of each single SNP, showing the highest value of insulin levels and HOMA-IR index in the À604 T 247 C and lowest value in À604 C 247 A . Conclusion: Our observations suggest a protective role of the Met72 variant and of À604 T allele in modulating insulin resistance. These SNPs or an unknown functional variant in linkage disequilibrium could increase ghrelin levels and probably insulin sensitivity.

Association Studies on Ghrelin and Ghrelin Receptor Gene Polymorphisms With Obesity

“…This finding is concordant with the association between ghrelin promoter polymorphism rs26311 and homeostasis model assessment‐insulin resistance that was reported in a Korean cohort (68). Another group also suggested that ghrelin rs27647 and rs696217 variants can modulate insulin sensitivity (69). We could further speculate that ghrelin and GHSR genes may modulate the programming of glucose‐insulin metabolism and of growth hormone/insulin‐like growth factor 1/insulin axis, the latter regulating the former together with the nutritional environment (70,71).…”

The association between rs4684677 T/A polymorphism in preproghrelin gene and predisposition to autoimmune thyroid diseases in children

“…Zavarella et al evaluated the association of a new variation, À604C4T, in the promoter region of the ghrelin gene, of Leu72Met (247C4A) and of Gln90Leu (265A4T), all haplotype-tagging SNPs, with measures of insulin sensitivity in 1420 adult individuals. They suggested a protective role of the Met72 variant and of À604 T allele in modulating insulin resistance [4]. Kim et al observed that the preproghrelin Leu72Met polymorphisms is not associated with DM type 2.…”

“…We wanted to assess the role of these two polymorphisms in AITDs, as in the current literature they were more frequently responsible for endocrinopathies, such as type 2 diabetes, obesity, insulin resistance, metabolic syndrome, anorexia nervosa. The other polymorphism, such as rs34911341 C4T, is rare [4][5][6][7][8].…”

Genetic Variability in Energy Balance and Pancreatic Cancer Risk in a Population-Based Case-Control Study in Minnesota

“…The single nucleotide polymorphisms (SNPs) considered in this study were leptin ( LEP ) (rs7799039), leptin receptor ( LEPR ) (rs1137101), ghrelin/obestatin prepropeptide ( GHRL ) (rs696217), neuropeptide Y ( NPY ) (rs16139), adrenoceptor beta 2, surface ( ADRB2 ) (rs1042713), adrenoceptor beta-3 ( ADRB3 ) (rs4994), and uncoupling protein 3 (mitochondrial, proton carrier) ( UCP3 ) (rs1800849). These SNPs were selected because 1) their genes regulate energy intake ( LEP, LEPR, GHRL, and NPY) or energy expenditure ( ADRB2, ADRB3, and UCP3) , 14,15,22 2) they have established or potential functional impact; 14,23–30 the five of the seven selected SNPs are missense mutations (rs7799039 and rs1800849 are not missense), and 3) they are common (minor allele frequency >5%) among European Americans (the NCBI SNP database: http://www.ncbi.nlm.nih.gov). SNP genotyping was conducted with TaqMan SNP Genotyping Assays (Life Technology, Grand Island, NY) in a laboratory (Fred Kadlubar, PhD) of the Division of Medical Genetics, University of Arkansas for Medical Sciences.…”