Whole-Exome Sequencing Analyses Support a Role of Vitamin D Metabolism in Ischemic Stroke.

BACKGROUND: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. METHODS: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE-a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data. RESULTS: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels (P<5×10-8). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk (P=2.6×10-6), exceeding the Bonferroni-corrected threshold for 16 074 tests (P<3.1×10-6). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P=0.003), with IS recurrence in the VISP trial (gene-based test, P=0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P<0.05). CONCLUSIONS: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Polygenic Susceptibility to Hypertension and Blood Pressure Control in Stroke Survivors.

BACKGROUND AND OBJECTIVES: Blood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors. METHODS: We conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke. To model the PSH, we created polygenic risk scores (PRSs) for systolic and diastolic BP using 732 genetic variants. We divided the PRSs into quintiles and used linear/logistic regression to test whether higher PSH led to higher observed BP, uncontrolled BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg), and resistant BP (uncontrolled BP despite being on ≥3 antihypertensive drugs). We conducted an independent replication using data from the Vitamin Intervention for Stroke Prevention (VISP) trial. RESULTS: We analyzed 5,940 stroke survivors. When comparing stroke survivors with very low vs very high PSH, the mean systolic BP was 137 (SD 18) vs 143 (SD 20, p < 0.001), the mean diastolic BP was 81 (SD 10) vs 84 (SD 11, p < 0.001), the prevalence of uncontrolled BP was 42.8% vs 57.2% (p < 0.001), and the prevalence of resistant hypertension was 3.9% vs 11% (p < 0.001). Results remained significant using multivariable models (p < 0.001) and were replicated in the VISP study (all tests with p < 0.05). DISCUSSION: A higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population.

Sex difference in initial thermoregulatory response to dehydrated exercise in the heat.

Although it is well established that dehydration has a negative impact on thermoregulation during exercise in the heat, it is unclear whether this effect of dehydration is different between men and women, or across the phases of the menstrual cycle (MC). Twelve men and seven women (men: 20 ± 2 years, 70.13 ± 10.5 kg, 173.4 ± 6.0 cm, 54.2 ± 8.6 ml kg-1  min-1 ; women: 20 ± 2 years, 57.21 ± 7.58 kg, 161 ± 5 cm, 40.39 ± 3.26 ml kg-1  min-1 ) completed trials either euhydrated (urine specific gravity, USG ≤ 1.020, Euhy) or dehydrated (USG > 1.020, Dehy). Trial order was randomized and counterbalanced; men completed two trials (MEuhy and MDehy) and women completed four over two MC phases (late follicular: days 10-13, FDehy, FEuhy; midluteal: days 18-22, LDehy, LEuhy). Each trial consisted of 1.5 h, split into two 30 min blocks of exercise (B1 and B2, 15 min at 11 W/kg & 15 min at 7 W/kg) separated by 15 min rest in between and after. Rectal temperature (Tre ) was measured continuously and estimated sweat loss was calculated from the body mass measured before and after each block of exercise. When dehydrated, the rate of rise in Tre was greater in women in the first block of exercise compared to men, independently of the MC phase (MDehy: 0.03 ± 0.03°C/min, FDehy: 0.06 ± 0.02, LDehy: 0.06 ± 0.02, p = 0.03). Estimated sweat loss was lower in all groups in B1 compared to B2 when dehydrated (p < 0.05), with no difference between sexes for either hydration condition. These data suggest that women may be more sensitive to the negative thermoregulatory effects of dehydration during the early stages of exercise in the heat.