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Endocrine Care: Yao-Zhong Liu, Yan-Fang Guo, Peng Xiao, Dong-Hai Xiong, Lan-Juan Zhao, Hui Shen, Yong-Jun Liu, Volodymyr Dvornyk, Ji-Rong Long, Hong-Yi Deng, Jin-Long Li, and Hong-Wen Deng Epistasis between Loci on Chromosomes 2 and 6 Influences Human Height J Clin Endocrinol Metab 2006; 91: 3821-3825 [Abstract] [Full text] [PDF]

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Genetic epistasis in congenital adrenal hyperplasia: a hypothesis yet to be validated

Hong-Wen Deng, Yao-Zhong Liu   (13 February 2007)

Final height in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: is it all hormonal?

Ron S Newfield, Saroj Nimkarn, and Maria I. New (Mount Sinai School of Medicine)   (19 December 2006)

Genetic epistasis in congenital adrenal hyperplasia: a hypothesis yet to be validated 13 February 2007
Hong-Wen Deng, Professor, Franklin D. Dickson/Missouri Endowed Chair, Director of Orthopedic Research Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri – Kansas City, Yao-Zhong Liu Send letter to journal: Re: Genetic epistasis in congenital adrenal hyperplasia: a hypothesis yet to be validated dengh{at}umkc.edu Hong-Wen Deng, et al.	We thank Newfield et al. for suggesting an interesting scenario that might be supported by our recent findings regarding epistasis between 6p21 and 2q21 influencing human height (1). This deserves further focused analyses. They speculate that short stature caused by mutations of the CYP21A2 gene in congenital adrenal hyperplasia (21-OHD CAH) might have other pathologic reasons beyond insufficient adrenal hormones as the patients usually have a stature lower than the predicted target height even under good hormonal treatment (2). Given the genomic location of the CYP21A2 gene at 6p21 and our recent evidence of the region’s epistasis with 2q21, an interesting hypothesis to explain the ineffectiveness of hormone treatment in 21-OHD CAH patients is that interaction between the CYP21A2 gene and other loci, possibly on 2q21, may exert significant effects on height development in those patients. The mechanism for such interaction may be at a level different from, and possibly more crucial and immediate to the growth plate development than, the actions of glucocorticoids. Such a hypothesis is underpinned by the fact that the growth plate is an organ with a convergence of many interactive factors and pathways, both local and systemic (3). However, this hypothesis needs further validation, as 1) there is no well-known candidate gene involving in height development at the 2q21 region; 2) the two epistatic regions 6p21 and 2q21 identified by linkage analyses are too wide and hence the signals of epistasis detected cannot be decisively attributed to a certain gene without further fine-mapping studies; and 3) the epistasis between 6p21 and 2q21 for height was detected in a normal healthy population and the relevance of such finding to a patient group with severe endocrinological disturbances needs further investigation. Nevertheless, the case of 21-OHD CAH is an interesting example supporting our findings of epistasis and provides for substantiation a novel candidate gene, CYP21A2 that may influence height through a unique mechanism of interaction with other genes. Reference 1. Liu YZ, Guo YF, Xiao P, Xiong D-H, Zhao L-J, Shen H, Liu Y-J, Dvornyk V, Long J-R, Deng H-Y, Li J-L, Deng H-W. Epistasis between Loci on Chromosomes 2 and 6 Influences Human Height. J Clin Endocrinol Metab 91:3821-3825 2. Eugster EA, DiMeglio LA, Wright JC, Freidenberg GR, Seshadri R, Pescovitz OH. 2001. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: A meta-analysis. J Ped 138:26-32 3. van der Eerden BCJ, Karperien M, Wit JM. 2003. Systemic and Local Regulation of the Growth Plate. Endocr Rev 24:782-801
Final height in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: is it all hormonal? 19 December 2006
Ron S Newfield, MD University of California San Diego, Saroj Nimkarn, and Maria I. New (Mount Sinai School of Medicine) Send letter to journal: Re: Final height in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: is it all hormonal? rnewfield{at}ucsd.edu Ron S Newfield, et al.	We were intrigued by the recent article by Yao-Zhong Liu et al (1), who used a two-locus epistatic model in a large Caucasian population to show that significant genetic interaction between 6p21 and 2q21 loci affects adult stature. The 6p21 locus also includes CYP21A2, the gene for a key enzyme (P450c21) in the steroidogenesis pathway. Therefore, CYP21A2 at 6p21.3 may be another candidate gene in 6p21 or in linkage disequilibrium with other candidate genes such as COL11A2 or RXRB. Point mutations, complex gene rearrangements and deletions of both alleles of CYP21A2 result in congenital adrenal hyperplasia (CAH) due to 21- hydroxyase deficiency (21-OHD). Hormonally and clinically defined forms of 21-OHD CAH are associated with distinct genotypes. Final height in simple virilizing and salt-wasting patients is usually shorter than the predicted target height, even when there is good compliance and hormonal control. In a meta-analysis (2), the difference between final and target height for 204 subjects was –1.21 SD; in a smaller cohort of 65 subjects from a single center the difference for all subjects was –1.03, and for those with good compliance was only –0.72 SD. Similar results were recently presented in an abstract, showing the poorest outcomes for salt-wasters and males (3). It has always been argued that compromised final height in well controlled CAH is due to the higher than physiological treatment doses of glucocorticoids required in order to suppress the elevated androgen levels inherent to 21-OHD CAH. However, this report may suggest there is also a genetic component to final height in 21-OHD CAH. The notion of hormonal influence on final height in CAH is supported by the short final heights in patients with 11ß hydroxylase deficiency (11 ß OHD). Of note, the CYP11B1 gene which encodes the 11 ß hydroxylase enzyme, is located on 8q21, not on chromosome 2 or 6. Since the authors estimate that approximately 20% of variation in height may be due to an interaction between 2q21 and 6p21, it is not surprising that obligate heterozygote parents of children with 21-OHD CAH have average target heights (2, 3). Would the authors care to speculate whether the epistasis noted between 2q21 and 6p21 may affect final height in CAH due to 21-hydroxylase deficiency? Could the authors narrow down which markers on 6p21 enhance the LOD score and interaction with 2q21? References 1. Liu YZ, Guo YF, Xiao P, Xiong D-H, Zhao L-J, Shen H, Liu Y-J, Dvornyk V, Long J-R, Deng H-Y, Li J-L, Deng H-W. 2006. Epistasis between loci on chromosomes 2 and 6 influences human height. J Clin Endocrinol Metab 91:3821-3825 2. Eugster EA, Dimeglio LA, Wright JC, Freidenberg GR, Seshadri R, Pescovitz OH. 2001. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 138:26-32 3. Trinh L, Nimkarn S, Obeid J, New M, Su K. 2006. Growth and Pubertal Characteristics in Patients with Congenital Adrenal Hyperplasia Due to 21- Hydroxylase Deficiency. ENDO 2006 The Endocrine Society's 88th Annual Meeting, Boston, MA, p 368