The role of LEP and LEPR variation in obesity and hypertension

Project title
Exploring the role of genetic variation at the leptin and leptin receptor genes (LEP and LEPR) in obesity and hypertension in a black South African cohort

Research question
The aims of this study were to determine the heritability estimates of anthropometric and blood pressure (BP) measures and leptin levels; to identify additional informative SNPs in and around the LEP and LEPR genes; and to examine the potential relationships between these SNPs and measures of obesity, hypertension and leptin levels in a black South African cohort.

Rationale
Obesity and hypertension are common, preventable disorders that are associated with increased morbidity and mortality worldwide. They have already reached epidemic levels in many industrialised countries and are fast becoming a major problem in the developing world. A large number of South African individuals are affected by obesity and hypertension, predisposing them to other non-communicable disorders like diabetes and stroke. The number of affected individuals is rapidly increasing due to lifestyle changes, but contributing factors that lead to obesity and hypertension, particularly the role of genetics in disease development and progression are not well understood. This study aimed to build on current knowledge of the genetic predisposition to obesity and hypertension, particularly in individuals of African descent. Single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes have been shown to be associated with obesity and hypertension, but have not been well explored in African populations

Participants from the African Programme on Genes in Hypertension (APOGH) with various anthropometric and BP measurements were genotyped for LEP and LEPR SNPs using the BeadXpress platform. Heritability estimates were determined using Statistical Analysis for Genetic Epidemiology (S.A.G.E.) software and relationships between LEP or LEPR SNPs and obesity, leptin levels and hypertension were assessed using SAS 9.3 and gPLINK vs2.050, taking into account family relationships, various confounders and correcting for multiple testing.  The Bonferroni method was used to correct for multiple testing and P≤0.00076 was considered as statistically significant for SNP association tests.

Seven-hundred-and-thirteen individuals were successfully genotyped and there were more women (66%) than men. The prevalence of obesity (42%) and hypertension (46%) were high in the sample. Significant heritability (h2 %, P<0.05) was noted for body weight (38%), body mass index (26%), waist (35%) and hip circumference (42%), waist-to-hip ratio (46%), skinfold thickness (44%), systolic (34%), diastolic (27%) and central systolic (33%) BP; but leptin levels were not significantly heritable (h2 %=15%, P=0.228). LEP rs17151914 (P=0.0002) and LEPR rs6690661 (P=0.0007) were significantly associated with leptin levels and diastolic BP, respectively, in women. LEP gene variants were significantly correlated with effects on leptin levels in women and the LEPR gene variants were significantly correlated with effects on diastolic BP also in women. These results indicate that further exploration of the role of genetic variation in the LEP and LEPR genes in obesity and hypertension in individuals of African ancestry is warranted.

Supervisors
Prof. Michele Ramsay; Prof. Angela Woodiwiss