Bardet-Biedl Syndrome Gene Variants Are Associated With Both Childhood and Adult Common Obesity in French Caucasians

Abstract

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P ‫؍‬ 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P ‫؍‬ 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P ‫؍‬ 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity.

Association between BBS6/MKKS gene polymorphisms, obesity and metabolic syndrome in the Greek population

“…This result for coding variants was replicated in another study in French Caucasians, in which no association was found for four BBS6 coding polymorphisms, including G532V. 12 Furthermore, in the French population two noncoding variants (985 þ 33C4G, À18,597A4T) were found to be significantly more prevalent in obese children compared with control individuals. Children homozygous for the rare G allele of the first variant had significantly higher postprandial glycaemia and triglycerides and decreased HDL-to-total cholesterol ratio, which are all characteristic features of atherogenic dyslipidaemia and hyperglycaemia, and are together with central obesity the component traits of the MS.…”

“…It is one of the genes causing BBS, 8,9 where obesity is the prominent clinical feature, and it has therefore been postulated that it might be involved in the pathogenesis of obesity. 11,12 We studied the BBS6 gene in a cohort of Greeks to further investigate its exact role in the development of common obesity. BBS6 gene variants have previously been analysed in two other cohorts.…”

“…BBS6 gene variants have previously been analysed in two other cohorts. 11,12 A study of BBS6 coding variants in a Danish obese population failed to identify a major role for this gene in obesity. 11 The G532V variant was identified by mutation analysis of the coding region of the gene in the Danish obese group, but due to its very low frequency it was not included in the association analysis.…”

“…They concluded that MKKS variants are unlikely to play a major role in the pathogenesis of obesity, with the exception of the Ala242Ser variant that may influence disease manifestation in rare cases. Benzinou et al, 12 however, suggested that variations in BBS genes were indeed associated with an increased risk for common obesity in a population of French Caucasians. They found an association of two single-nucleotide polymorphisms (SNPs) of BBS6 with common early-onset childhood obesity and adult severe obesity.…”

“…[14][15][16] We analysed six MKKS gene polymorphisms (I178I, G532 V, 985 þ 33C4G, 985 þ 16T4G, 986À29A4T and 1161 þ 58A4G) in the Greek population and investigated for possible association between these polymorphisms and obesity-related phenotypes or the metabolic syndrome. The first three SNPs had been studied previously in two other populations, the Danish 11 and the French Caucasians, 12 whereas the last three were selected after their detection in a Greek patient with the BBS.…”