Genetic Variation in Candidate Genes Like the HMGA2 Gene in the Extremely Tall

Abstract

Background/Aims: Genetic variation in several candidate genes has been associated with short stature. Recently, a high-mobility group A2 (HMGA2) gene SNP has been robustly associated with height in the general population. Only few have attempted to study these genes in extremely tall stature. We therefore studied common genetic variation in candidate genes for height in extremely tall Dutch. Methods: We included 116 constitutionally tall cases with height >2 SD and 103 controls with normally distributed height <2 SD. We genotyped 10 common polymorphisms previously associated with height variation. Results: The HMGA2 gene SNP was significantly associated with tall stature. Using a logistic regression model, we calculated that carrying the HMGA2 (rs1042725) C allele significantly increased the odds of being tall (OR = 1.53, 95% CI 1.02–2.28; p = 0.03). In addition, controls with one or two copies of the C allele were significantly taller than controls carrying the TT genotype [TC: mean (SD) +0.61 (0.21) SDS; p = 0.004, and CC: +0.77 (0.25) SDS; p = 0.003]. Conclusion: Our study shows that a common polymorphism in the HMGA2 gene is not only associated with height variation in the general population but also plays an important role in one of the extremes of the height distribution.

Hmga1/Hmga2 double knock-out mice display a “superpygmy” phenotype

“…Indeed, mice overexpressing Hmga2 showed a giant phenotype that was a mirror image of the pygmy phenotype (Battista et al, 1998; Battista et al, 1999; Baldassarre et al, 2001). Moreover, HMGA2 is an important genetic determinant for human adult height (Weedon et al, 2008; Buysse et al, 2009; Hodge et al, 2009; Yang et al, 2010; Hendriks et al, 2011; Carty et al, 2012; Makvandi-Nejad et al, 2012). Consistently, an 8-year-old boy carrying a truncated HMGA2 gene displayed extreme somatic overgrowth with features strikingly similar to those observed in the Hmga2 transgenic mice (Ligon et al, 2005).…”

12q14 microdeletion associated with HMGA2 gene disruption and growth restriction

“…Haploinsufficiency for HMGA2 has been proposed to cause growth restriction, and an intragenic HMGA2 deletion has been reported with isolated short stature in a single pedigree [Menten et al, 2007; Buysse et al, 2009]. Conversely, in 116 Dutch individuals with height greater than 2 standard deviations, Hendriks et al [2011] demonstrated a significant association between the C allele at coding SNP rs1042725 in the HMGA2 gene with tall stature. Overexpression of HMGA2 has been noted in many tumor types including breast and lung with elevated expression a poor prognostic factor [Rogalla et al, 1997; Meyer et al, 2007].…”

<p><em>HMGA2</em> Gene rs8756 A>C Polymorphism Reduces Neuroblastoma Risk in Chinese Children: A Four-Center Case-Control Study</p>

“…40 Further study by Hendriks et al indicated that rs1042725 is not only associated with height variation in the general population but also plays an important role in one of the extremes of the height distribution. 55 Alkayyali et al found HMGA2 rs1531343 polymorphism was associated with increased risk of developing nephropathy in patients with type 2 diabetes. 41 Moreover, another 3ʹ UTR polymorphism in HMGA2, rs8756 was shown to be associated with human stature in an Icelandic population.…”