A single nucleotide polymorphism on Exon-4 of the gene encoding PPAR delta is associated with reduced height inadults and children

Context: Peroxisome proliferator-activated receptor (PPAR)-delta is a nuclear transcription factor that plays a key role in many metabolic processes, including energy metabolism, and lipid and glucose metabolism. Candidate gene studies have identified a putative functional variant, rs2016520, in the gene encoding PPAR delta ( PPARD), which is associated in some studies with metabolic traits. In addition, this single-nucleotide polymorphism was associated with adult height in several whole-genome scans, but this association did not achieve whole genome significance.

Objective: This study sought to determine whether PPARD variation influenced height.

Design: Haplotype tagging analysis across PPARD was performed in about 11,000 individuals from the Wellcome Trust U. K. Type 2 Diabetes Case Control Collection (Go-DARTS2).

Results: There was an association between rs2016520 and height in both patients with type 2 diabetes and controls without diabetes (combined P = 5 X 10(-5)). In a metaanalysis using published data from Caucasian cohorts totaling more than 38,000 participants, compelling evidence was found for this locus and its association with height (P = 10(-8)) with an overall effect size of about 0.5 cm per allele. A similar analysis in a group of 2700 prepubescent children also displayed a similar effect size to that seen in the adults.

Conclusion: PPARD variation is clearly associated with a phenotype of reduced stature in both adults and children. Because height is an important indicator of metabolic and nutritional status, this provides additional support for a key role for PPAR delta in critical metabolic functions. PPAR delta may affect height through a variety of mechanisms including altered metabolic efficiency or effects on osteoclast function. (J Clin Endocrinol Metab 94: 2587-2593, 2009)