Sequence variants in the 5′ flanking region of the leptin gene are associated with obesity in women

Abstract

Few mutations have been found in the human leptin gene and the relationship between leptin gene sequence variation and human overweight is uncertain. To determine whether sequence variation within the leptin gene and its regulatory elements contribute to extreme obesity, we screened " 3 kb of the 5h flanking region and the three exons in 125 unrelated extremely obese (BMI 40 kg\m#) and 86 average weight women (BMI 27 kg\m#). Within the protein coding regions only one heterozygous silent mutation was found (codon 102 ; AAC\AAT). Within the 5h flanking region, six frequent sequence variants were detected (q 0.10), and the allele frequencies of three of these variants differed between obese and average weight Caucasian women (j19, χ# l 4.46, p l 0.035 ; k1823, χ# l 4.36, p l 0.037 ; k2548, χ# l 5.73, p l 0.017). Nine infrequent sequence variants were detected (q 0.05) but they did not occur more often among obese women compared with those of average-weight. For extremely obese women, three polymorphisms (j19, k188, and k633) predicted the degree of obesity. Allelic variants may influence the regulation of the leptin gene and thereby influence body weight, particularly among extremely obese women. However, given the low variability in coding regions and the high variability in the 5h flanking region, discerning the functional significance of each variant is likely to be difficult. I Two families have been described with mutations in the protein coding regions of the leptin gene, and family members with these mutations recapitulate the phenotype of obese Lep ob mice (Montague et al. 1997 ; Strobel et al. 1998). Most obese subjects have no missense or nonsense mutations within the leptin gene (Considine et al.

Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins

“…[17][18][19][20][21][22] Because some studies used either small and/or selected samples and the criteria utilized to classify cases and controls differed largely, the relation between this SNP and type 2 diabetes Common SNPs in LEP and LEPR NY Souren et al and/or obesity is still unclear. Our data suggest that the LEP 19G4A SNP may be protective against cardiovascular disease, as G allele carriers have significantly higher HDL cholesterol levels.…”

“…In this study we therefore examined the effect of common SNPs in LEP and LEPR on birth weight and adult metabolic risk factors for type 2 diabetes measured in young twins recruited from the East Flanders Prospective Twin Survey (EFPTS). The SNPs studied have previously been associated with type 2 diabetesrelated traits in other populations, [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] and are either nonsynonymous or located in a region that might be of importance in the regulation of gene expression.…”

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

“…In the absence of measured plasma levels before the diagnosis of NHL, long-term variation in production of these adiponectins may be indicated by the polymorphisms investigated here, since the LEP 19G, LEP À2548A and LEPR 223R alleles have been associated with elevated leptin levels, and the APM1 276T allele with lower adiponectin levels (Hoffstedt et al, 2002;van Rossum et al, 2003;Filippi et al, 2004). Further, these polymorphisms have been linked with an obese phenotype in some Caucasian populations (Li et al, 1999;Mammes et al, 2000;Quinton et al, 2001;Yiannakouris et al, 2001;Nieters et al, 2002;Filippi et al, 2004;Jiang et al, 2004). Previously, Skibola et al (2004) reported that, relative to the LEP 19AA genotype, carriers of the LEP 19G allele were at increased risk of NHL, particularly FL (OR ¼ 1.9, 95% CI 1.0 -3.6).…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…150 A common A4G 5 0 UTR variant in the leptin gene has been associated with leptin levels and obesity. 152,153 In the 5 0 region, GÀ2548A has been associated with response to low calorie diet, obesity and leptin levels. [153][154][155][156][157] Furthermore, a leptin gene 3 0 -tetranucleotide repeat is associated with BMI.…”

“…152,153 In the 5 0 region, GÀ2548A has been associated with response to low calorie diet, obesity and leptin levels. [153][154][155][156][157] Furthermore, a leptin gene 3 0 -tetranucleotide repeat is associated with BMI. 158 Finally, in the most extensive study of leptin gene polymorphisms in common obesity, common variants further upstream in the 5 0 region have displayed association with BMI.…”