Research ArticleGENETICS

The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

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Science Advances  16 Jun 2017:
Vol. 3, no. 6, e1602025
DOI: 10.1126/sciadv.1602025
  • Fig. 1 Percentage of d3-GHR homozygosity among female (black) (F) and male (gray) (M) Ashkenazi centenarians (95F and 102M), offspring (113F and 110M), and controls (53F and 94M).
  • Fig. 2 d3-GHR age prevalence within and between cohorts.

    Prevalence of d3-GHR homozygotes in relation to age groups in: (A) Ashkenazi Jew (AJ) (female and male of control and centenarian, n = 344) combined and (A1) split by gender (196 males and 148 females), (B) OOA 152 males, (C) 61 white males of the CHS, and (D) 61 French white males and (E) mega analysis of the four cohorts (470 males). In each of the cohorts, there is increased prevalence of the homozygote d3-GHR (*P < 0.05 for the trend).

  • Fig. 3 Distribution of GHBP (in pM) among the centenarians (95F and 102M), their offspring (113F and 110M), and controls (53F and 94M), all of whom are of Ashkenazi (AJ) descent, in recessive model [homozygous GHR deletion of exon 3 (d3-GHR) versus heterozygote (Het) and WT combined], adjusted for gender and age (*P < 0.05).
  • Fig. 4 Kaplan-Maier survival curves of 196 male AJ centenarians (n = 102) and control (n = 94) of d3-GHR in recessive model [homozygous GHR deletion of exon 3 (d3-GHR) versus heterozygote (Het) and WT combined].
  • Fig. 5 Functional effect of d3-GHR carriers.

    (A) In vitro effect of GH stimulation (100 ng/ml) on proliferation of transformed lymphocytes from male AJ centenarians. In the basal state [serum-free (SF)], lymphocytes from d3-GHR homozygous subjects have reduced proliferation rates; however, in the presence of GH, there is enhanced responsiveness and overall higher growth rates. This is compatible with reports in humans showing an increased responsiveness to GH only in studies that use high doses of GH. AU, arbitrary units. (B) Phosphorylation of ERK in homozygous WT and d3-GHR transformed lymphocytes from male AJ centenarians. Lymphocytes from d3-GHR homozygotes displayed significantly lower pERK levels under serum-free conditions but higher activation of ERK in response to GH treatment (100 ng/ml), compared to WT (fl/fl) carriers (**P < 0.01).

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/6/e1602025/DC1

    fig. S1. Phosphorylation of STAT5 and AKT in homozygous WT and d3-GHR transformed lymphocytes from male AJ centenarians.

    table S1. Analysis (allelic, dominant, additive, and recessive models) of various variables (means ± SE), includes all AJs groups (n = 567) and adjusted for gender, age, and group.

    table S2. Analysis (allelic, dominant, additive, and recessive) of various variables (means ± SE), includes AJ centenarian (C) and control (C) groups (n = 344) and adjusted for gender, age, and group.

    table S3. Groups analysis of various variables (means ± SE) adjusted for gender and age within AJs.

    table S4. Analysis (allelic, dominant, additive, and recessive models) of various variables (means ± SE), includes AJ offspring (O) and control (C) (n = 370) and adjusted for gender, age, and group.

    table S5A. Genotyping efforts among the four cohorts (n = 841): AJ (n = 567, 56% female), OOA 152 males, CHS 61 males, and FLLS 61 males.

    table S5B. Crude measurements of various variables (means ± SE) in the three AJs (n = 567) study groups.

    table S6. PCR procedure using primers.

  • Supplementary Materials

    This PDF file includes:

    • fig. S1. Phosphorylation of STAT5 and AKT in homozygous WT and d3-GHR transformed lymphocytes from male AJ centenarians.
    • table S1. Analysis (allelic, dominant, additive, and recessive models) of various variables (means ± SE), includes all AJs groups (n = 567) and adjusted for gender, age, and group.
    • table S2. Analysis (allelic, dominant, additive, and recessive) of various variables (means ± SE), includes AJ centenarian (C) and control (C) groups (n = 344) and adjusted for gender, age, and group.
    • table S3. Groups analysis of various variables (means ± SE) adjusted for gender and age within AJs.
    • table S4. Analysis (allelic, dominant, additive, and recessive models) of various variables (means ± SE), includes AJ offspring (O) and control (C) (n = 370) and adjusted for gender, age, and group.
    • table S5A. Genotyping efforts among the four cohorts (n = 841): AJ (n = 567, 56% female), OOA 152 males, CHS 61 males, and FLLS 61 males.
    • table S5B. Crude measurements of various variables (means ± SE) in the three AJs (n = 567) study groups.
    • table S6. PCR procedure using primers.

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