GDF15 linked to maternal risk of nausea and vomiting during pregnancy

被引：75

作者：

Fejzo, M. ^{[1
]}

Rocha, N. ^{[2
]}

Cimino, I. ^{[2
]}

Lockhart, S. M. ^{[2
]}

Petry, C. J. ^{[2
]}

Kay, R. G. ^{[2
,3
]}

Burling, K. ^{[2
,4
]}

Barker, P. ^{[2
,4
]}

George, A. L. ^{[3
]}

Yasara, N. ^{[5
]}

Premawardhena, A. ^{[6
,7
]}

Gong, S. ^{[8
,9
]}

Cook, E. ^{[8
]}

Rimmington, D. ^{[2
]}

Rainbow, K. ^{[2
]}

Withers, D. J. ^{[2
]}

Cortessis, V. ^{[10
]}

Mullin, P. M. ^{[11
]}

MacGibbon, K. W. ^{[12
]}

Jin, E. ^{[10
]}

Kam, A. ^{[11
]}

Campbell, A. ^{[13
]}

Polasek, O. ^{[14
]}

Tzoneva, G. ^{[15
]}

Gribble, F. M. ^{[2
]}

Yeo, G. S. H. ^{[2
]}

Lam, B. Y. H. ^{[2
]}

Saudek, V. ^{[2
]}

Hughes, I. A. ^{[16
]}

Ong, K. K. ^{[16
,17
]}

Perry, J. R. B. ^{[2
,17
]}

Cole, A. Sutton ^{[18
]}

Baumgarten, M. ^{[18
]}

Welsh, P. ^{[19
]}

Sattar, N. ^{[19
]}

Smith, G. C. S. ^{[8
,9
]}

Charnock-Jones, D. S. ^{[8
,9
]}

Coll, A. P. ^{[2
]}

Meek, C. L. ^{[2
]}

Mettananda, S. ^{[5
,20
]}

Hayward, C. ^{[13
,21
]}

Mancuso, N. ^{[1
,22
,23
]}

O'Rahilly, S. ^{[2
,24
]}

机构：

[1] Univ Southern Calif, Ctr Genet Epidemiol, Keck Sch Med, Dept Populat & Publ Hlth Sci, Los Angeles, CA USA

[2] Univ Cambridge, Med Res Council, Inst Metab Sci, Metab Dis Unit, Cambridge, England

[3] Univ Cambridge, Inst Metab Sci, Peptid & Prote Core Facility, Cambridge, England

[4] Cambridge Univ Hosp NHS Fdn Trust, Core Biochem Assay Lab, Cambridge, England

[5] Univ Kelaniya, Fac Med, Dept Paediat, Thalagolla Rd, Ragama, Sri Lanka

[6] North Colombo Teaching Hosp, Univ Med Unit, Adolescent & Adult Thalassaemia Care Ctr, Kadawatha, Sri Lanka

[7] Univ Kelaniya, Fac Med, Dept Med, Ragama, Sri Lanka

[8] Univ Cambridge, NIHR Cambridge Biomed Res Ctr, Dept Obstet & Gynaecol, Cambridge, England

[9] Univ Cambridge, CTR, Dept Physiol Dev & Neurosci, Cambridge, England

[10] Univ Southern Calif, Keck Sch Med, Dept Populat & Publ Hlth Sci, Los Angeles, CA USA

[11] Univ Southern Calif, Keck Sch Med, Dept Obstet & Gynaecol, Los Angeles, CA USA

[12] Hyperemesis Educ & Res Fdn, Clackamas, OR USA

[13] Univ Edinburgh, Inst Genet & Canc, Ctr Genom & Expt Med, Edinburgh, Scotland

[14] Univ Split, Fac Med, Split 21000, Croatia

[15] Regeneron Genet Ctr, Tarrytown, NY USA

[16] Univ Cambridge, Dept Paediat, Cambridge, England

[17] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[18] Cambridge Univ Hosp NHS Fdn Trust, Dept Obstet & Gynaecol, Cambridge, England

[19] Univ Glasgow, Sch Cardiovasc & Metab Hlth, Glasgow City, Scotland

[20] Colombo North Teaching Hosp, Univ Paediat Unit, Ragama, Sri Lanka

[21] Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Scotland

[22] Univ Southern Calif, Dept Quantitat & Computat Biol, Los Angeles, CA USA

[23] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA USA

[24] NIHR Cambridge Biomed Res Ctr, Cambridge, England

来源：

NATURE | 2024年 / 625卷 / 7996期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

HYPEREMESIS GRAVIDARUM; ASSOCIATION;

D O I：

10.1038/s41586-023-06921-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with beta-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG. Elevated circulating levels of GDF15 in pregnant women are associated with severe nausea and vomiting, and sensitivity to such symptoms during pregnancy is partly determined by prepregnancy levels of this hormone.

引用

页码：760 / 767

页数：23

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