Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study

Abstract

OBJECTIVE: To investigate linkage and association between the leptin receptor (LEPR) gene and body composition variables in the Que  bec Family Study (QFS). DESIGN: Single-point linkage analysis using families, and covariance and chi-square analyses using normal weight and obese unrelated subjects from QFS. SUBJECTS: 169 nuclear families were used for linkage study. 308 unrelated subjects (146 males; 162 females) from these families were used for chi-square testing of genotype and allele distributions between subjects with body mass index (BMI)`27 kgam 2 (n 167) and those with BMI ! 27 kgam 2 (n 141), and for a series of covariance analyses using age, plus height for fat mass (FM) and fat free mass (FFM), as covariates. A corrected P value (P*) for multiple tests has been calculated according to P* 1-(1-P) number of phenotypes . MEASUREMENTS: Variables were BMI (in kgam 2 ), sum of six skinfolds (SF6 in mm), FM (in kg), percent body fat (%FAT) and FFM (in kg). Polymerase chain react restricted fragment length polymorphisms PCR-RFLP) was used to identi®ed a K109R substitution in exon 4, a Q223R in exon 6, a K656N in exon 14 and an automatic DNA sequencer for a CA microsatellite repeat in intron 3, and heteroduplex pattern on non-denaturing gel for a CTTT repeat in intron 16. RESULTS: Good evidence of linkage was observed for Q223R with FM (P 0.005; P* 0.02), and for the CTTT repeat with FFM (P 0.007; P* 0.03). Weaker linkages (0.02 P 0.05) were also observed between Q223R and BMI, SF6 and FFM, between the CA repeat and BMI, SF6 and FM, and between the CTTT repeat and FM. Moreover, FFM values were found to be different among genotypes for the CTTT repeat polymorphism with heavier females, carriers of the 123* allele at the CTTT repeat, showing 4 kg less of FFM (43.6 AE 1.0, n 21 vs 47.7 AE 0.8, n 30; P 0.005; P* 0.02) than non-carriers. Also, at the Q223R polymorphism, in lower BMI males, carriers of the Q223 allele were 4 kg lighter in FFM (53.4 AE 0.6, n 47 vs 56.6 AE 0.9, n 18; P 0.005; P* 0.02) than non-carriers. No signi®cant differences were observed between lower and higher BMI subjects in genotype and allele frequency distributions for any of the polymorphisms. CONCLUSIONS: These results indicate that the LEPR gene is involved in the regulation of the body composition in human particularly of FFM in the QFS.

Maternal leptin receptor gene variant Gln223Arg is not associated with variation in birth weight or maternal body mass index in UK and South Asian populations

“…14 No association was found between the Gln223Arg variant and BMI in females as reported in the Quebec Family Study. 11 In contrast, an association has previously been observed between Gln223Arg and BMI variation in Caucasian male subjects. 10 It has been documented that maternal serum leptin concentrations correlate positively with gestational age, gestational weight gain or maternal BMI, and subsequently placental leptin levels with birth weight in a study of 52 pregnant women from Egypt.…”

“…1 A common variant in exon 6 of LEPR, which causes an amino acid change, Gln223Arg (located in the extracellular domain), and has been associated with variation in BMI, fat mass and fat-free mass in middle aged Caucasian males. 10,11 We investigated the possible association of this sequence variant with foetal birth weight and maternal BMI during early pregnancy.…”

SNP analyses of postprandial responses in (an)orexigenic hormones and feelings of hunger reveal long-term physiological adaptations to facilitate homeostasis

“…The 668A4G SNP (LEPR) was hypothesized earlier to affect the functionality of the LEPR, with the variant G allele (Arg) resulting in a leptin-resistant state. 14,32 Resistance to leptin is known to increase food intake, in extreme cases resulting in early-onset morbid obesity. 33,34 However, subjects homozygous for the 223Arg-encoding allele had a higher BMI than subjects homozygous for the common 223Gln-encoding allele in some, 14,35,36 but not all studies.…”

Contribution of several candidate gene polymorphisms in the determination of adiposity changes: results from the Québec Family Study

“…Details of markers genotyping are described elsewhere. 9,[23][24][25][26][27][28] Briefly, all polymorphisms but NMB p.P73T were restriction fragment length polymorphism (see Table 1 for endonucleases used). NMB p.P73T was genotyped using a minisequencing technique.…”