Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele

Abstract

Uterine leiomyomata (UL) are the most common female pelvic tumors and the primary indication for hysterectomy in the United States. We assessed genetic liability for UL by a known embryonic proliferation modulator, HMGA2, in 248 families ascertained through medical record-confirmed affected sister-pairs. Using a (TC)( n ) repeat in the 5' UTR and 17 SNPs spanning HMGA2, permutation-based association tests identified a significant increase in transmission of a single TC repeat allele (TC227) with UL (allele-specific P = 0.00005, multiple testing corrected min-P = 0.0049). The hypothesis that TC227 is a pathogenic variant is supported by a trend towards higher HMGA2 expression in TC227 allele-positive compared with non-TC227 UL tissue as well as by absence of culpable exonic sequence variants. HMGA2 has also been suggested recently by three genome-wide SNP studies to influence human height variation, and our examination of the affected sister-pair families revealed a significant association of TC227 with decreased height (allele-specific P = 0.00033, multiple testing corrected min-P = 0.016). Diminished stature and elevated risk of UL development have both been correlated with an earlier age of menarche, which may be the biological mechanism for TC227 effects as a tendency of women with TC227 to have an earlier onset of menarche was identified in our study population. These results indicate HMGA2 has a role in two growth-related phenotypes, UL predisposition and height, of which the former may affect future medical management decisions for many women.

Fig 1

TC repeat allele frequency assessment. A comparison in White women between the affected sister-pair population (ASF) and a previously published U.S. sample (Ishwad et al. 1997) demonstrated a similar allele frequency distribution between the two studies.

Fig 2

Global association tests for the TC repeat and 17 SNPs located throughout HMGA2 with UL or height as the outcome in the ASF population. Bolded global p-values indicate those markers that met screening criteria (global p-value ≤ 0.10) for use in subsequent allele-specific analyses. The +/− signs indicate direction of association based on large sample Z statistics (exluding the highly polymorphic TC repeat), with those associations labeled NC for not calculable resulting from too few informative families or a nearly monomorphic SNP. Markers, represented by orange rectangles in the order presented in the embedded table, are aligned to a schematic of HMGA2 and to a schematic of a linkage disequilibrium map (increasing LD as measured by D’ is denoted by progression towards red). The middle of each column defines marker position in the LD map.

Fig 3

Real-time PCR expression analysis of HMGA2. In White women, the median and interquartile range for TC227 negative UL tissue (227-) are 2.15 [0.08, 5.03] (n = 47) compared to TC227 positive UL tissue (227+) which are 5.39 [1.57, 8.58] (n = 11) (one sided p-value = 0.16). The trend indicates the presence of the TC227 allele is associated with increased expression of HMGA2 in UL.